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Berchuck, Andrew

Overview:

Dr. Andrew Berchuck is Director of the Duke Division of Gynecologic Oncology and holds the F. Bayard Carter Distinguished Professorship. He is a practicing oncologist who is actively involved in the surgical and chemotherapy management of women with ovarian, endometrial and lower genital tract cancers. This includes minimally invasive laparoscopic surgical approaches. He also has developed a research program that focuses on the molecular-genetic alterations involved in malignant transformation of the ovarian and endometrial epithelium. He has published over 300 peer-reviewed papers in these areas. The objectives of his research include 1) identification of ovarian cancer susceptibility polymorphisms through a population-based case-control molecular epidemiologic study, and 2) use of genomic approaches  to elucidate the molecular heterogenetity of ovarian cancer. Thirty fellows and residents have worked in his lab, several of whom are now funded investigators. His research efforts have been recognized nationally and he has received awards for best oral presentation at the annual meetings of both the Society of Gynecologic Oncology and the International Gynecologic Cancer Society. Dr. Berchuck was awarded the Barbara Thomason Ovarian Cancer Research Professorship by the American Cancer Society in 2006. He has served as editor of several books in the field including Principles and Practice of Gynecologic Oncology. Dr. Berchuck also has a major commitment to national activities, and was President of the Society of Gynecologic Oncology in 2008. He served as chair of the scientific advisory committee of the Ovarian Cancer Research Fund (http://www.ocrf.org/">http://www.ocrf.org) in New York City. Finally, he is also head of the steering committee of the international Ovarian Cancer Association Consortium (OCAC), a group of 50 case-control studies that are working together to identify ovarian cancer susceptibility polymorphisms (http://www.srl.cam.ac.uk/consortia/ocac/index.html">www.srl.cam.ac.uk/co...).

Positions:

James M. Ingram Professor of Gynecologic Oncology

Obstetrics and Gynecology, Gynecologic Oncology
School of Medicine

Professor of Obstetrics and Gynecology

Obstetrics and Gynecology, Gynecologic Oncology
School of Medicine

Chief of Gynecologic Oncology

Obstetrics and Gynecology, Gynecologic Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1980

M.D. — Case Western Reserve University

News:

Grants:

Mutation analysis of pap smear samples and associated tissues for ovarian cancer diagnostics

Administered By
Pathology
AwardedBy
Genendeavor LLC
Role
Collaborator
Start Date
October 12, 2017
End Date
October 11, 2022

Building Interdisciplinary Research Careers in Women's Health

Administered By
Obstetrics and Gynecology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 26, 2002
End Date
July 31, 2022

Translational Research in Surgical Oncology

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
January 01, 2002
End Date
August 31, 2021

Kastan Gray Foundation Project

Administered By
Duke Cancer Institute
AwardedBy
Gray Foundation
Role
Researcher
Start Date
October 01, 2017
End Date
September 30, 2019

Triggering human anti-tumor stringent response to target recurrent ovarian cancer

Administered By
Molecular Genetics and Microbiology
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
May 01, 2017
End Date
April 30, 2019

Discovery of Novel Rare Variants as Ovarian Cancer Susceptibility Factors

Administered By
Obstetrics and Gynecology, Gynecologic Oncology
AwardedBy
MD Anderson Cancer Center
Role
Principal Investigator
Start Date
August 01, 2016
End Date
July 31, 2017

Tissue and Data Acquisition Activity for the Study of Gynecologic Disease

Administered By
Obstetrics and Gynecology, Gynecologic Oncology
AwardedBy
Henry M. Jackson Foundation
Role
Collaborator
Start Date
August 19, 2016
End Date
May 31, 2017

Clinical Oncology Research Career Development Program

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 29, 2009
End Date
July 31, 2015

Endometrial Cancer TCGA Project

Administered By
Obstetrics and Gynecology, Gynecologic Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 20, 2010
End Date
March 31, 2015

Epidemiology of Ovarian Cancer in African-American Women

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
June 01, 2010
End Date
February 28, 2015

TGCA Purchase Order

Administered By
Obstetrics and Gynecology, Gynecologic Oncology
AwardedBy
Leidos Biomedical Research, Inc.
Role
Principal Investigator
Start Date
October 30, 2014
End Date
November 12, 2014

Gene Regulation in Recurrent Ovarian Cancers

Administered By
Obstetrics and Gynecology, Gynecologic Oncology
AwardedBy
Gynecologic Cancer Foundation
Role
Co Investigator
Start Date
December 01, 2011
End Date
June 30, 2014

The Molecular Epidemiology Of Ovarian Cancer

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1998
End Date
June 30, 2012

Tissue and Data Acquisition Activity for the Study of Gynecologic Disease

Administered By
Obstetrics and Gynecology, Gynecologic Oncology
AwardedBy
United States Army Medical Research and Materiel Command
Role
Co Investigator
Start Date
November 01, 2010
End Date
May 31, 2011

Society of Gynecologic Investigation Annual Meeting

Administered By
Obstetrics and Gynecology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 24, 2004
End Date
March 23, 2009

Genomics Tests for Ovarian Cancer Detection and Management

Administered By
Institutes and Centers
AwardedBy
Agency for Healthcare Research and Quality
Role
Investigator
Start Date
September 30, 2005
End Date
November 30, 2006

(CGN Supplement): CGN Ovarian Cancer Screening in High Risk Women Pilot 2

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
August 01, 2001
End Date
July 31, 2003

Spore In Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1995
End Date
August 31, 1998

Spore In Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1995
End Date
August 31, 1998

Spore In Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1995
End Date
August 31, 1998

Molecular Epidemiolgy Of Epithelial Ovarian Cancer

Administered By
Community and Family Medicine
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
June 17, 1994
End Date
May 31, 1997

Growth Regulation & Transformation Of Ovarian Cancer Epith

Administered By
Obstetrics and Gynecology, Gynecologic Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 01, 1994
End Date
January 31, 1997

Growth Regulation And Transformation Of Ovarian Epithelium

Administered By
Obstetrics and Gynecology, Gynecologic Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 01, 1992
End Date
January 31, 1997

Molecular Epidemiology Of Epithelial Ovarian Cancer

Administered By
Community and Family Medicine
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
June 17, 1994
End Date
May 31, 1996

Hyperthermia And Perfusion Effects In Cancer Therapy

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
June 01, 1993
End Date
May 31, 1995
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Publications:

Race-specific molecular alterations correlate with differential outcomes for black and white endometrioid endometrial cancer patients.

The objective of this study was to identify molecular alterations associated with disease outcomes for white and black patients with endometrioid endometrial cancer (EEC).EEC samples from black (n = 17) and white patients (n = 13) were analyzed by proteomics (liquid chromatography-tandem mass spectrometry) and transcriptomics (RNA-seq). Coordinate alterations were validated with RNA-seq data from black (n = 49) and white patients (n = 216). Concordantly altered candidates were further tested for associations with race-specific progression-free survival (PFS) in black (n = 64) or white patients (n = 267) via univariate and multivariate Cox regression modeling and log-rank testing.Discovery analyses revealed significantly altered candidate proteins and transcripts between black and white patients, suggesting modulation of tumor cell viability in black patients and cell death signaling in black and white patients. Eighty-nine candidates were validated as altered between these patient cohorts, and a subset significantly correlated with differential PFS. White-specific PFS candidates included serpin family A member 4 (SERPINA4; hazard ratio [HR], 0.89; Wald P value = .02), integrin subunit α3 (ITGA3; HR, 0.76; P = .03), and Bet1 Golgi vesicular membrane trafficking protein like (BET1L; HR, 0.48; P = .04). Black-specific PFS candidates included family with sequence similarity 228 member B (FAM228B; HR, 0.13; P = .001) and HEAT repeat containing 6 (HEATR6; HR, 4.94; P = .047). Several candidates were also associated with overall survival (SERPINA4 and ITGA3) as well as PFS independent of disease stage, grade and myometrial invasion (SERPINA4, BET1L and FAM228B).This study has identified and validated molecular alterations in tumors from black and white EEC patients, including candidates significantly associated with altered disease outcomes within these patient cohorts. Cancer 2017;123:4004-12. © 2017 American Cancer Society.

Authors
Bateman, NW; Dubil, EA; Wang, G; Hood, BL; Oliver, JM; Litzi, TA; Gist, GD; Mitchell, DA; Blanton, B; Phippen, NT; Tian, C; Zahn, CM; Cohn, DE; Havrilesky, LJ; Berchuck, A; Shriver, CD; Darcy, KM; Hamilton, CA; Conrads, TP; Maxwell, GL
MLA Citation
Bateman, NW, Dubil, EA, Wang, G, Hood, BL, Oliver, JM, Litzi, TA, Gist, GD, Mitchell, DA, Blanton, B, Phippen, NT, Tian, C, Zahn, CM, Cohn, DE, Havrilesky, LJ, Berchuck, A, Shriver, CD, Darcy, KM, Hamilton, CA, Conrads, TP, and Maxwell, GL. "Race-specific molecular alterations correlate with differential outcomes for black and white endometrioid endometrial cancer patients." Cancer 123.20 (October 2017): 4004-4012.
PMID
28654152
Source
epmc
Published In
Cancer
Volume
123
Issue
20
Publish Date
2017
Start Page
4004
End Page
4012
DOI
10.1002/cncr.30813

Genome-wide association study evaluating single-nucleotide polymorphisms and outcomes in patients with advanced stage serous ovarian or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study.

This study evaluated single nucleotide polymorphisms (SNPs) associated with progression free (PFS) and overall survival (OS) in patients with advanced stage serous EOC.Patients enrolled in GOG-172 and 182 who provided specimens for translational research and consent were included. Germline DNA was evaluated with the Illumina's HumanOMNI1-Quad beadchips and scanned using Illumina's iScan optical imaging system. SNPs with allele frequency>0.05 and genotyping rate>0.98 were included. Analysis of SNPs for PFS and OS was done using Cox regression. Statistical significance was determined using Bonferroni corrected p-values with genomic control adjustment.The initial GWAS analysis included 1,124,677 markers in 396 patients. To obtain the final data set, quality control checks were performed and limited to serous tumors and self-identified Caucasian race. In total 636,555 SNPs and 289 patients passed all the filters. The pre-specified statistical level of significance was 7.855e(-08). No SNPs met this criteria for PFS or OS, however, two SNPs were close to significance (rs10899426 p-2.144e(-)(08)) (rs6256 p-9.774e(-07)) for PFS and 2 different SNPs were identified (rs295315 p-7.536e(-)(07); rs17693104 p-7.734e(-)(07)) which were close to significance for OS.Using the pre-specified level of significance of 1×10(-08), we did not identify any SNPs of statistical significance for OS or PFS, however several were close. The SNP's identified in this GWAS study will require validation and these preliminary findings may lead to identification of novel pathways and biomarkers.

Authors
Moore, KN; Tritchler, D; Kaufman, KM; Lankes, H; Quinn, MCJ; Ovarian Cancer Association Consortium, ; Van Le, L; Berchuck, A; Backes, FJ; Tewari, KS; Lee, RB; Kesterson, JP; Wenham, RM; Armstrong, DK; Krivak, TC; Bookman, MA; Birrer, MJ
MLA Citation
Moore, KN, Tritchler, D, Kaufman, KM, Lankes, H, Quinn, MCJ, Ovarian Cancer Association Consortium, , Van Le, L, Berchuck, A, Backes, FJ, Tewari, KS, Lee, RB, Kesterson, JP, Wenham, RM, Armstrong, DK, Krivak, TC, Bookman, MA, and Birrer, MJ. "Genome-wide association study evaluating single-nucleotide polymorphisms and outcomes in patients with advanced stage serous ovarian or primary peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study." Gynecologic oncology (September 18, 2017).
PMID
28935272
Source
epmc
Published In
Gynecologic Oncology
Publish Date
2017
DOI
10.1016/j.ygyno.2017.08.024

Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors.

It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer-specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition. These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations.

Authors
Janouskova, H; El Tekle, G; Bellini, E; Udeshi, ND; Rinaldi, A; Ulbricht, A; Bernasocchi, T; Civenni, G; Losa, M; Svinkina, T; Bielski, CM; Kryukov, GV; Cascione, L; Napoli, S; Enchev, RI; Mutch, DG; Carney, ME; Berchuck, A; Winterhoff, BJN; Broaddus, RR; Schraml, P; Moch, H; Bertoni, F; Catapano, CV; Peter, M; Carr, SA; Garraway, LA; Wild, PJ; Theurillat, J-PP
MLA Citation
Janouskova, H, El Tekle, G, Bellini, E, Udeshi, ND, Rinaldi, A, Ulbricht, A, Bernasocchi, T, Civenni, G, Losa, M, Svinkina, T, Bielski, CM, Kryukov, GV, Cascione, L, Napoli, S, Enchev, RI, Mutch, DG, Carney, ME, Berchuck, A, Winterhoff, BJN, Broaddus, RR, Schraml, P, Moch, H, Bertoni, F, Catapano, CV, Peter, M, Carr, SA, Garraway, LA, Wild, PJ, and Theurillat, J-PP. "Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors." Nature medicine 23.9 (September 2017): 1046-1054.
PMID
28805821
Source
epmc
Published In
Nature Medicine
Volume
23
Issue
9
Publish Date
2017
Start Page
1046
End Page
1054
DOI
10.1038/nm.4372

Menstrual pain and risk of epithelial ovarian cancer: Results from the Ovarian Cancer Association Consortium.

Menstrual pain, a common gynecological condition, has been associated with increased risk of ovarian cancer in some, but not all studies. Furthermore, potential variations in the association between menstrual pain and ovarian cancer by histologic subtype have not been adequately evaluated due to lack of power. We assessed menstrual pain using either direct questions about having experienced menstrual pain, or indirect questions about menstrual pain as indication for use of hormones or medications. We used multivariate logistic regression to calculate the odds ratio (OR) for the association between severe menstrual pain and ovarian cancer, adjusting for potential confounders and multinomial logistic regression to calculate ORs for specific histologic subtypes. We observed no association between ovarian cancer and menstrual pain assessed by indirect questions. Among studies using direct question, severe pain was associated with a small but significant increase in overall risk of ovarian cancer (OR = 1.07, 95% CI: 1.01-1.13), after adjusting for endometriosis and other potential confounders. The association appeared to be more relevant for clear cell (OR = 1.48, 95% CI: 1.10-1.99) and serous borderline (OR = 1.31, 95% CI: 1.05-1.63) subtypes. In this large international pooled analysis of case-control studies, we observed a small increase in risk of ovarian cancer for women reporting severe menstrual pain. While we observed an increased ovarian cancer risk with severe menstrual pain, the possibility of recall bias and undiagnosed endometriosis cannot be excluded. Future validation in prospective studies with detailed information on endometriosis is needed.

Authors
Babic, A; Harris, HR; Vitonis, AF; Titus, LJ; Jordan, SJ; Webb, PM; Australian Ovarian Cancer Study Group, ; Risch, HA; Rossing, MA; Doherty, JA; Wicklund, K; Goodman, MT; Modugno, F; Moysich, KB; Ness, RB; Kjaer, SK; Schildkraut, J; Berchuck, A; Pearce, CL; Wu, AH; Cramer, DW; Terry, KL
MLA Citation
Babic, A, Harris, HR, Vitonis, AF, Titus, LJ, Jordan, SJ, Webb, PM, Australian Ovarian Cancer Study Group, , Risch, HA, Rossing, MA, Doherty, JA, Wicklund, K, Goodman, MT, Modugno, F, Moysich, KB, Ness, RB, Kjaer, SK, Schildkraut, J, Berchuck, A, Pearce, CL, Wu, AH, Cramer, DW, and Terry, KL. "Menstrual pain and risk of epithelial ovarian cancer: Results from the Ovarian Cancer Association Consortium." International journal of cancer (August 22, 2017).
PMID
28833087
Source
epmc
Published In
International Journal of Cancer
Publish Date
2017
DOI
10.1002/ijc.31010

Prospective Evaluation of Lymph Node Processing at Staging Surgery for High-grade Endometrial Cancer.

To determine whether the processing of additional adipose tissue collected during lymph node (LN) dissection results in the identification of additional LNs during endometrial cancer (EC) staging and to determine if the division of LNs into nodal basin-specific specimens has an effect on the number of LNs identified during EC staging. A prospective randomized controlled trial was performed on women with high-grade EC undergoing surgical staging. Subjects were randomized to collection of LNs into nodal basin-specific containers on the randomized side versus simple labeling on the nonrandomized side. The total number of LNs and total number of LNs with metastases on the randomized versus the nonrandomized side were compared. The remaining adipose tissue from each LN specimen was submitted for histologic examination. We analyzed the number of LNs with and without metastases identified from additional adipose tissue. Of 120 consented subjects, 56 had sufficient data for analysis. The additional adipose tissue contained 7.5 additional LNs per patient on average (range: 0-26). In 2/54 total cases (3.7%) and 2/5 cases with nodal metastases (40%), the additional adipose contained LNs with metastases. In both cases, metastases were also detected in grossly identified LN candidates. The mean number of LNs identified was not significantly different based on method of collection (P=0.22). The mean number of LNs containing metastases per side was not significantly different (P=0.58). Processing of adipose tissue does increase the total number of LNs identified, however, it does not influence EC stage. No difference in LN counts was noted with basin-specific collection.

Authors
Davidson, BA; Ehrisman, J; Abbott, S; Harmon, Z; Secord, AA; Berchuck, A; Lee, PS; Valea, FA; Li, X; Havrilesky, LJ; Hall, AHS
MLA Citation
Davidson, BA, Ehrisman, J, Abbott, S, Harmon, Z, Secord, AA, Berchuck, A, Lee, PS, Valea, FA, Li, X, Havrilesky, LJ, and Hall, AHS. "Prospective Evaluation of Lymph Node Processing at Staging Surgery for High-grade Endometrial Cancer." July 11, 2017.
PMID
28700428
Source
epmc
Published In
International Journal of Gynecological Pathology
Publish Date
2017
DOI
10.1097/pgp.0000000000000418

The hereditary nature of small cell carcinoma of the ovary, hypercalcemic type: two new familial cases.

Small cell carcinoma of the ovary, hypercalcemic type, (SCCOHT) is the most common undifferentiated ovarian cancer in women aged under 40 years. SCCOHT is a monogenic disease, characterized by germline and somatic SMARCA4 mutations. Recent studies have stressed its morphological and clinical similarity to malignant rhabdoid tumours, which are usually caused by mutations in the related gene, SMARCB1. While familial tumours are rare, the incidence of germline mutations is relatively high, with up to 43% of SCCOHTs and 35% of rhabdoid tumours caused by germline mutations in SMARCA4 and SMARCB1, respectively. We report two new familial cases of SCCOHT. Affected members in both families and the associated tumours were found to carry SMARCA4 germline and somatic mutations, respectively, leading to loss of SMARCA4 protein expression in the tumours. Despite the rarity of familial SCCOHT, the high incidence of germline mutations is important to note, as without a family history of the disease, the hereditary nature of SCCOHT may be missed, especially if the mutation was inherited from the father or acquired de novo. The similarity between SCCOHT and rhabdoid tumours should be recognized, as infant carriers of SMARCA4 mutations may be at risk for these tumours in addition to SCCOHT.

Authors
Witkowski, L; Donini, N; Byler-Dann, R; Knost, JA; Albrecht, S; Berchuck, A; McCluggage, WG; Hasselblatt, M; Foulkes, WD
MLA Citation
Witkowski, L, Donini, N, Byler-Dann, R, Knost, JA, Albrecht, S, Berchuck, A, McCluggage, WG, Hasselblatt, M, and Foulkes, WD. "The hereditary nature of small cell carcinoma of the ovary, hypercalcemic type: two new familial cases." Familial cancer 16.3 (July 2017): 395-399.
PMID
27866340
Source
epmc
Published In
Familial Cancer
Volume
16
Issue
3
Publish Date
2017
Start Page
395
End Page
399
DOI
10.1007/s10689-016-9957-6

Early Detection of Ovarian Cancer using the Risk of Ovarian Cancer Algorithm with Frequent CA125 Testing in Women at Increased Familial Risk - Combined Results from Two Screening Trials.

Purpose: Women at familial/genetic ovarian cancer risk often undergo screening despite unproven efficacy. Research suggests each woman has her own CA125 baseline; significant increases above this level may identify cancers earlier than standard 6- to 12-monthly CA125 > 35 U/mL.Experimental Design: Data from prospective Cancer Genetics Network and Gynecologic Oncology Group trials, which screened 3,692 women (13,080 woman-screening years) with a strong breast/ovarian cancer family history or BRCA1/2 mutations, were combined to assess a novel screening strategy. Specifically, serum CA125 q3 months, evaluated using a risk of ovarian cancer algorithm (ROCA), detected significant increases above each subject's baseline, which triggered transvaginal ultrasound. Specificity and positive predictive value (PPV) were compared with levels derived from general population screening (specificity 90%, PPV 10%), and stage-at-detection was compared with historical high-risk controls.Results: Specificity for ultrasound referral was 92% versus 90% (P = 0.0001), and PPV was 4.6% versus 10% (P > 0.10). Eighteen of 19 malignant ovarian neoplasms [prevalent = 4, incident = 6, risk-reducing salpingo-oophorectomy (RRSO) = 9] were detected via screening or RRSO. Among incident cases (which best reflect long-term screening performance), three of six invasive cancers were early-stage (I/II; 50% vs. 10% historical BRCA1 controls; P = 0.016). Six of nine RRSO-related cases were stage I. ROCA flagged three of six (50%) incident cases before CA125 exceeded 35 U/mL. Eight of nine patients with stages 0/I/II ovarian cancer were alive at last follow-up (median 6 years).Conclusions: For screened women at familial/genetic ovarian cancer risk, ROCA q3 months had better early-stage sensitivity at high specificity, and low yet possibly acceptable PPV compared with CA125 > 35 U/mL q6/q12 months, warranting further larger cohort evaluation. Clin Cancer Res; 23(14); 3628-37. ©2017 AACR.

Authors
Skates, SJ; Greene, MH; Buys, SS; Mai, PL; Brown, P; Piedmonte, M; Rodriguez, G; Schorge, JO; Sherman, M; Daly, MB; Rutherford, T; Brewster, WR; O'Malley, DM; Partridge, E; Boggess, J; Drescher, CW; Isaacs, C; Berchuck, A; Domchek, S; Davidson, SA; Edwards, R; Elg, SA; Wakeley, K; Phillips, K-A; Armstrong, D; Horowitz, I; Fabian, CJ; Walker, J; Sluss, PM; Welch, W; Minasian, L; Horick, NK; Kasten, CH; Nayfield, S; Alberts, D; Finkelstein, DM; Lu, KH
MLA Citation
Skates, SJ, Greene, MH, Buys, SS, Mai, PL, Brown, P, Piedmonte, M, Rodriguez, G, Schorge, JO, Sherman, M, Daly, MB, Rutherford, T, Brewster, WR, O'Malley, DM, Partridge, E, Boggess, J, Drescher, CW, Isaacs, C, Berchuck, A, Domchek, S, Davidson, SA, Edwards, R, Elg, SA, Wakeley, K, Phillips, K-A, Armstrong, D, Horowitz, I, Fabian, CJ, Walker, J, Sluss, PM, Welch, W, Minasian, L, Horick, NK, Kasten, CH, Nayfield, S, Alberts, D, Finkelstein, DM, and Lu, KH. "Early Detection of Ovarian Cancer using the Risk of Ovarian Cancer Algorithm with Frequent CA125 Testing in Women at Increased Familial Risk - Combined Results from Two Screening Trials." Clinical cancer research : an official journal of the American Association for Cancer Research 23.14 (July 2017): 3628-3637.
PMID
28143870
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
23
Issue
14
Publish Date
2017
Start Page
3628
End Page
3637
DOI
10.1158/1078-0432.ccr-15-2750

Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci.

We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p<1×10-5). Larger patient numbers will be needed to convincingly identify any true associations at these loci.

Authors
Glubb, DM; Johnatty, SE; Quinn, MCJ; O'Mara, TA; Tyrer, JP; Gao, B; Fasching, PA; Beckmann, MW; Lambrechts, D; Vergote, I; Velez Edwards, DR; Beeghly-Fadiel, A; Benitez, J; Garcia, MJ; Goodman, MT; Thompson, PJ; Dörk, T; Dürst, M; Modungo, F; Moysich, K; Heitz, F; du Bois, A; Pfisterer, J; Hillemanns, P; Karlan, BY; Lester, J; Goode, EL; Cunningham, JM; Winham, SJ; Larson, MC; McCauley, BM; Kjær, SK; Jensen, A; Schildkraut, JM; Berchuck, A; Cramer, DW; Terry, KL; Salvesen, HB; Bjorge, L et al.
MLA Citation
Glubb, DM, Johnatty, SE, Quinn, MCJ, O'Mara, TA, Tyrer, JP, Gao, B, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Velez Edwards, DR, Beeghly-Fadiel, A, Benitez, J, Garcia, MJ, Goodman, MT, Thompson, PJ, Dörk, T, Dürst, M, Modungo, F, Moysich, K, Heitz, F, du Bois, A, Pfisterer, J, Hillemanns, P, Karlan, BY, Lester, J, Goode, EL, Cunningham, JM, Winham, SJ, Larson, MC, McCauley, BM, Kjær, SK, Jensen, A, Schildkraut, JM, Berchuck, A, Cramer, DW, Terry, KL, Salvesen, HB, and Bjorge, L et al. "Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci." Oncotarget (June 15, 2017).
PMID
28644137
Source
epmc
Published In
Oncotarget
Publish Date
2017
DOI
10.18632/oncotarget.18501

Cigarette smoking is associated with adverse survival among women with ovarian cancer: Results from a pooled analysis of 19 studies.

Cigarette smoking is associated with an increased risk of developing mucinous ovarian tumors but whether it is associated with ovarian cancer survival overall or for the different histotypes is unestablished. Furthermore, it is unknown whether the association between cigarette smoking and survival differs according to strata of ovarian cancer stage at diagnosis. In a large pooled analysis, we evaluated the association between various measures of cigarette smoking and survival among women with epithelial ovarian cancer. We obtained data from 19 case-control studies in the Ovarian Cancer Association Consortium (OCAC), including 9,114 women diagnosed with ovarian cancer. Cox regression models were used to estimate adjusted study-specific hazard ratios (HRs), which were combined into pooled hazard ratios (pHR) with corresponding 95% confidence intervals (CIs) under random effects models. Overall, 5,149 (57%) women died during a median follow-up period of 7.0 years. Among women diagnosed with ovarian cancer, both current (pHR = 1.17, 95% CI: 1.08-1.28) and former smokers (pHR = 1.10, 95% CI: 1.02-1.18) had worse survival compared with never smoking women. In histotype-stratified analyses, associations were observed for mucinous (current smoking: pHR = 1.91, 95% CI: 1.01-3.65) and serous histotypes (current smoking: pHR = 1.11, 95% CI: 1.00-1.23; former smoking: pHR = 1.12, 95% CI: 1.04-1.20). Further, our results suggested that current smoking has a greater impact on survival among women with localized than disseminated disease. The identification of cigarette smoking as a modifiable factor associated with survival has potential clinical importance as a focus area to improve ovarian cancer prognosis.

Authors
Praestegaard, C; Jensen, A; Jensen, SM; Nielsen, TSS; Webb, PM; Nagle, CM; DeFazio, A; Australian Ovarian Cancer Study Group, ; Høgdall, E; Rossing, MA; Doherty, JA; Wicklund, KG; Goodman, MT; Modugno, F; Moysich, K; Ness, RB; Edwards, R; Matsuo, K; Hosono, S; Goode, EL; Winham, SJ; Fridley, BL; Cramer, DW; Terry, KL; Schildkraut, JM; Berchuck, A; Bandera, EV; Paddock, LE; Massuger, LF; Wentzensen, N; Pharoah, P; Song, H; Whittemore, A; McGuire, V; Sieh, W; Rothstein, J; Anton-Culver, H et al.
MLA Citation
Praestegaard, C, Jensen, A, Jensen, SM, Nielsen, TSS, Webb, PM, Nagle, CM, DeFazio, A, Australian Ovarian Cancer Study Group, , Høgdall, E, Rossing, MA, Doherty, JA, Wicklund, KG, Goodman, MT, Modugno, F, Moysich, K, Ness, RB, Edwards, R, Matsuo, K, Hosono, S, Goode, EL, Winham, SJ, Fridley, BL, Cramer, DW, Terry, KL, Schildkraut, JM, Berchuck, A, Bandera, EV, Paddock, LE, Massuger, LF, Wentzensen, N, Pharoah, P, Song, H, Whittemore, A, McGuire, V, Sieh, W, Rothstein, J, and Anton-Culver, H et al. "Cigarette smoking is associated with adverse survival among women with ovarian cancer: Results from a pooled analysis of 19 studies." International journal of cancer 140.11 (June 2017): 2422-2435.
PMID
28063166
Source
epmc
Published In
International Journal of Cancer
Volume
140
Issue
11
Publish Date
2017
Start Page
2422
End Page
2435
DOI
10.1002/ijc.30600

History of hypertension, heart disease, and diabetes and ovarian cancer patient survival: evidence from the ovarian cancer association consortium.

Survival following ovarian cancer diagnosis is generally low; understanding factors related to prognosis could be important to optimize treatment. The role of previously diagnosed comorbidities and use of medications for those conditions in relation to prognosis for ovarian cancer patients has not been studied extensively, particularly according to histological subtype.Using pooled data from fifteen studies participating in the Ovarian Cancer Association Consortium, we examined the associations between history of hypertension, heart disease, diabetes, and medications taken for these conditions and overall survival (OS) and progression-free survival (PFS) among patients diagnosed with invasive epithelial ovarian carcinoma. We used Cox proportional hazards regression models adjusted for age and stage to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and within strata of histological subtypes.History of diabetes was associated with increased risk of mortality (n = 7,674; HR = 1.12; 95% CI = 1.01-1.25). No significant mortality associations were observed for hypertension (n = 6,482; HR = 0.95; 95% CI = 0.88-1.02) or heart disease (n = 4,252; HR = 1.05; 95% CI = 0.87-1.27). No association of these comorbidities was found with PFS in the overall study population. However, among patients with endometrioid tumors, hypertension was associated with lower risk of progression (n = 339, HR = 0.54; 95% CI = 0.35-0.84). Comorbidity was not associated with OS or PFS for any of the other histological subtypes. Ever use of beta blockers, oral antidiabetic medications, and insulin was associated with increased mortality, HR = 1.20; 95% CI = 1.03-1.40, HR = 1.28; 95% CI = 1.05-1.55, and HR = 1.63; 95% CI = 1.20-2.20, respectively. Ever use of diuretics was inversely associated with mortality, HR = 0.71; 95% CI = 0.53-0.94.Histories of hypertension, diabetes, and use of diuretics, beta blockers, insulin, and oral antidiabetic medications may influence the survival of ovarian cancer patients. Understanding mechanisms for these observations could provide insight regarding treatment.

Authors
Minlikeeva, AN; Freudenheim, JL; Cannioto, RA; Szender, JB; Eng, KH; Modugno, F; Ness, RB; LaMonte, MJ; Friel, G; Segal, BH; Odunsi, K; Mayor, P; Zsiros, E; Schmalfeldt, B; Klapdor, R; Dӧrk, T; Hillemanns, P; Kelemen, LE; Kӧbel, M; Steed, H; de Fazio, A; Australian Ovarian Cancer Study Group, ; Jordan, SJ; Nagle, CM; Risch, HA; Rossing, MA; Doherty, JA; Goodman, MT; Edwards, R; Matsuo, K; Mizuno, M; Karlan, BY; Kjær, SK; Høgdall, E; Jensen, A; Schildkraut, JM; Terry, KL; Cramer, DW; Bandera, EV et al.
MLA Citation
Minlikeeva, AN, Freudenheim, JL, Cannioto, RA, Szender, JB, Eng, KH, Modugno, F, Ness, RB, LaMonte, MJ, Friel, G, Segal, BH, Odunsi, K, Mayor, P, Zsiros, E, Schmalfeldt, B, Klapdor, R, Dӧrk, T, Hillemanns, P, Kelemen, LE, Kӧbel, M, Steed, H, de Fazio, A, Australian Ovarian Cancer Study Group, , Jordan, SJ, Nagle, CM, Risch, HA, Rossing, MA, Doherty, JA, Goodman, MT, Edwards, R, Matsuo, K, Mizuno, M, Karlan, BY, Kjær, SK, Høgdall, E, Jensen, A, Schildkraut, JM, Terry, KL, Cramer, DW, and Bandera, EV et al. "History of hypertension, heart disease, and diabetes and ovarian cancer patient survival: evidence from the ovarian cancer association consortium." Cancer causes & control : CCC 28.5 (May 2017): 469-486.
PMID
28293802
Source
epmc
Published In
Cancer Causes & Control
Volume
28
Issue
5
Publish Date
2017
Start Page
469
End Page
486
DOI
10.1007/s10552-017-0867-1

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

Authors
Phelan, CM; Kuchenbaecker, KB; Tyrer, JP; Kar, SP; Lawrenson, K; Winham, SJ; Dennis, J; Pirie, A; Riggan, MJ; Chornokur, G; Earp, MA; Lyra, PC; Lee, JM; Coetzee, S; Beesley, J; McGuffog, L; Soucy, P; Dicks, E; Lee, A; Barrowdale, D; Lecarpentier, J; Leslie, G; Aalfs, CM; Aben, KKH; Adams, M; Adlard, J; Andrulis, IL; Anton-Culver, H; Antonenkova, N; AOCS study group, ; Aravantinos, G; Arnold, N; Arun, BK; Arver, B; Azzollini, J; Balmaña, J; Banerjee, SN; Barjhoux, L; Barkardottir, RB; Bean, Y et al.
MLA Citation
Phelan, CM, Kuchenbaecker, KB, Tyrer, JP, Kar, SP, Lawrenson, K, Winham, SJ, Dennis, J, Pirie, A, Riggan, MJ, Chornokur, G, Earp, MA, Lyra, PC, Lee, JM, Coetzee, S, Beesley, J, McGuffog, L, Soucy, P, Dicks, E, Lee, A, Barrowdale, D, Lecarpentier, J, Leslie, G, Aalfs, CM, Aben, KKH, Adams, M, Adlard, J, Andrulis, IL, Anton-Culver, H, Antonenkova, N, AOCS study group, , Aravantinos, G, Arnold, N, Arun, BK, Arver, B, Azzollini, J, Balmaña, J, Banerjee, SN, Barjhoux, L, Barkardottir, RB, and Bean, Y et al. "Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer." Nature genetics 49.5 (May 2017): 680-691.
PMID
28346442
Source
epmc
Published In
Nature Genetics
Volume
49
Issue
5
Publish Date
2017
Start Page
680
End Page
691
DOI
10.1038/ng.3826

Is There a Role for Ovarian Cancer Screening in High-Risk Women?

Authors
Berchuck, A; Havrilesky, LJ; Kauff, ND
MLA Citation
Berchuck, A, Havrilesky, LJ, and Kauff, ND. "Is There a Role for Ovarian Cancer Screening in High-Risk Women?." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 35.13 (May 2017): 1384-1386.
PMID
28447911
Source
epmc
Published In
Journal of Clinical Oncology
Volume
35
Issue
13
Publish Date
2017
Start Page
1384
End Page
1386
DOI
10.1200/jco.2016.72.0045

Use of common analgesic medications and ovarian cancer survival: results from a pooled analysis in the Ovarian Cancer Association Consortium.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with improved survival in some cancers, but evidence for ovarian cancer is limited.Pooling individual-level data from 12 Ovarian Cancer Association Consortium studies, we evaluated the association between self-reported, pre-diagnosis use of common analgesics and overall/progression-free/disease-specific survival among 7694 women with invasive epithelial ovarian cancer (4273 deaths).Regular analgesic use (at least once per week) was not associated with overall survival (pooled hazard ratios, pHRs (95% confidence intervals): aspirin 0.96 (0.88-1.04); non-aspirin NSAIDs 0.97 (0.89-1.05); acetaminophen 1.01 (0.93-1.10)), nor with progression-free/disease-specific survival. There was however a survival advantage for users of any NSAIDs in studies clearly defining non-use as less than once per week (pHR=0.89 (0.82-0.98)).Although this study did not show a clear association between analgesic use and ovarian cancer survival, further investigation with clearer definitions of use and information about post-diagnosis use is warranted.

Authors
Dixon, SC; Nagle, CM; Wentzensen, N; Trabert, B; Beeghly-Fadiel, A; Schildkraut, JM; Moysich, KB; deFazio, A; Australian Ovarian Cancer Study Group, ; Risch, HA; Rossing, MA; Doherty, JA; Wicklund, KG; Goodman, MT; Modugno, F; Ness, RB; Edwards, RP; Jensen, A; Kjær, SK; Høgdall, E; Berchuck, A; Cramer, DW; Terry, KL; Poole, EM; Bandera, EV; Paddock, LE; Anton-Culver, H; Ziogas, A; Menon, U; Gayther, SA; Ramus, SJ; Gentry-Maharaj, A; Pearce, CL; Wu, AH; Pike, MC; Webb, PM
MLA Citation
Dixon, SC, Nagle, CM, Wentzensen, N, Trabert, B, Beeghly-Fadiel, A, Schildkraut, JM, Moysich, KB, deFazio, A, Australian Ovarian Cancer Study Group, , Risch, HA, Rossing, MA, Doherty, JA, Wicklund, KG, Goodman, MT, Modugno, F, Ness, RB, Edwards, RP, Jensen, A, Kjær, SK, Høgdall, E, Berchuck, A, Cramer, DW, Terry, KL, Poole, EM, Bandera, EV, Paddock, LE, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Pearce, CL, Wu, AH, Pike, MC, and Webb, PM. "Use of common analgesic medications and ovarian cancer survival: results from a pooled analysis in the Ovarian Cancer Association Consortium." British Journal of Cancer 116.9 (April 2017): 1223-1228.
PMID
28350790
Source
epmc
Published In
British Journal of Cancer
Volume
116
Issue
9
Publish Date
2017
Start Page
1223
End Page
1228
DOI
10.1038/bjc.2017.68

Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer.

Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs.Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia.This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation.

Authors
Zuber, V; Bettella, F; Witoelar, A; PRACTICAL Consortium, ; CRUK GWAS, ; BCAC Consortium, ; TRICL Consortium, ; Andreassen, OA; Mills, IG; Urbanucci, A
MLA Citation
Zuber, V, Bettella, F, Witoelar, A, PRACTICAL Consortium, , CRUK GWAS, , BCAC Consortium, , TRICL Consortium, , Andreassen, OA, Mills, IG, and Urbanucci, A. "Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer." BMC genomics 18.1 (March 31, 2017): 270-.
PMID
28359301
Source
epmc
Published In
BMC Genomics
Volume
18
Issue
1
Publish Date
2017
Start Page
270
DOI
10.1186/s12864-017-3620-y

No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival.

Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses.Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival.Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P < 3.5 × 10-5), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival.Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes.Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420-4. ©2016 AACR.

Authors
Sucheston-Campbell, LE; Cannioto, R; Clay, AI; Etter, JL; Eng, KH; Liu, S; Battaglia, S; Hu, Q; Szender, JB; Minlikeeva, A; Joseph, JM; Mayor, P; Abrams, SI; Segal, BH; Wallace, PK; Soh, KT; Zsiros, E; Anton-Culver, H; Bandera, EV; Beckmann, MW; Berchuck, A; Bjorge, L; Bruegl, A; Campbell, IG; Campbell, SP; Chenevix-Trench, G; Cramer, DW; Dansonka-Mieszkowska, A; Dao, F; Diergaarde, B; Doerk, T; Doherty, JA; du Bois, A; Eccles, D; Engelholm, SA; Fasching, PA; Gayther, SA; Gentry-Maharaj, A et al.
MLA Citation
Sucheston-Campbell, LE, Cannioto, R, Clay, AI, Etter, JL, Eng, KH, Liu, S, Battaglia, S, Hu, Q, Szender, JB, Minlikeeva, A, Joseph, JM, Mayor, P, Abrams, SI, Segal, BH, Wallace, PK, Soh, KT, Zsiros, E, Anton-Culver, H, Bandera, EV, Beckmann, MW, Berchuck, A, Bjorge, L, Bruegl, A, Campbell, IG, Campbell, SP, Chenevix-Trench, G, Cramer, DW, Dansonka-Mieszkowska, A, Dao, F, Diergaarde, B, Doerk, T, Doherty, JA, du Bois, A, Eccles, D, Engelholm, SA, Fasching, PA, Gayther, SA, and Gentry-Maharaj, A et al. "No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 26.3 (March 2017): 420-424.
PMID
27677730
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
26
Issue
3
Publish Date
2017
Start Page
420
End Page
424
DOI
10.1158/1055-9965.epi-16-0631

Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci.

Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis.All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals).The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10-5 (including six with P<5 × 10-8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation.Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.

Authors
Kar, SP; Adler, E; Tyrer, J; Hazelett, D; Anton-Culver, H; Bandera, EV; Beckmann, MW; Berchuck, A; Bogdanova, N; Brinton, L; Butzow, R; Campbell, I; Carty, K; Chang-Claude, J; Cook, LS; Cramer, DW; Cunningham, JM; Dansonka-Mieszkowska, A; Doherty, JA; Dörk, T; Dürst, M; Eccles, D; Fasching, PA; Flanagan, J; Gentry-Maharaj, A; Glasspool, R; Goode, EL; Goodman, MT; Gronwald, J; Heitz, F; Hildebrandt, MAT; Høgdall, E; Høgdall, CK; Huntsman, DG; Jensen, A; Karlan, BY; Kelemen, LE; Kiemeney, LA et al.
MLA Citation
Kar, SP, Adler, E, Tyrer, J, Hazelett, D, Anton-Culver, H, Bandera, EV, Beckmann, MW, Berchuck, A, Bogdanova, N, Brinton, L, Butzow, R, Campbell, I, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Dansonka-Mieszkowska, A, Doherty, JA, Dörk, T, Dürst, M, Eccles, D, Fasching, PA, Flanagan, J, Gentry-Maharaj, A, Glasspool, R, Goode, EL, Goodman, MT, Gronwald, J, Heitz, F, Hildebrandt, MAT, Høgdall, E, Høgdall, CK, Huntsman, DG, Jensen, A, Karlan, BY, Kelemen, LE, and Kiemeney, LA et al. "Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci." British journal of cancer 116.4 (February 2017): 524-535.
PMID
28103614
Source
epmc
Published In
British Journal of Cancer
Volume
116
Issue
4
Publish Date
2017
Start Page
524
End Page
535
DOI
10.1038/bjc.2016.426

The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers.

Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits.The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers, and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background.The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis.Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures.Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. Cancer Epidemiol Biomarkers Prev; 26(1); 126-35. ©2016 AACR.

Authors
Amos, CI; Dennis, J; Wang, Z; Byun, J; Schumacher, FR; Gayther, SA; Casey, G; Hunter, DJ; Sellers, TA; Gruber, SB; Dunning, AM; Michailidou, K; Fachal, L; Doheny, K; Spurdle, AB; Li, Y; Xiao, X; Romm, J; Pugh, E; Coetzee, GA; Hazelett, DJ; Bojesen, SE; Caga-Anan, C; Haiman, CA; Kamal, A; Luccarini, C; Tessier, D; Vincent, D; Bacot, F; Van Den Berg, DJ; Nelson, S; Demetriades, S; Goldgar, DE; Couch, FJ; Forman, JL; Giles, GG; Conti, DV; Bickeböller, H; Risch, A; Waldenberger, M et al.
MLA Citation
Amos, CI, Dennis, J, Wang, Z, Byun, J, Schumacher, FR, Gayther, SA, Casey, G, Hunter, DJ, Sellers, TA, Gruber, SB, Dunning, AM, Michailidou, K, Fachal, L, Doheny, K, Spurdle, AB, Li, Y, Xiao, X, Romm, J, Pugh, E, Coetzee, GA, Hazelett, DJ, Bojesen, SE, Caga-Anan, C, Haiman, CA, Kamal, A, Luccarini, C, Tessier, D, Vincent, D, Bacot, F, Van Den Berg, DJ, Nelson, S, Demetriades, S, Goldgar, DE, Couch, FJ, Forman, JL, Giles, GG, Conti, DV, Bickeböller, H, Risch, A, and Waldenberger, M et al. "The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 26.1 (January 2017): 126-135.
PMID
27697780
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
26
Issue
1
Publish Date
2017
Start Page
126
End Page
135
DOI
10.1158/1055-9965.epi-16-0106

Pelvic Inflammatory Disease and the Risk of Ovarian Cancer and Borderline Ovarian Tumors: A Pooled Analysis of 13 Case-Control Studies.

Inflammation has been implicated in ovarian carcinogenesis. However, studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent. We investigated the association between PID and the risk of epithelial ovarian cancer according to tumor behavior and histotype. We pooled data from 13 case-control studies, conducted between 1989 and 2009, from the Ovarian Cancer Association Consortium (OCAC), including 9,162 women with ovarian cancers, 2,354 women with borderline tumors, and 14,736 control participants. Study-specific odds ratios were estimated and subsequently combined into a pooled odds ratio using a random-effects model. A history of PID was associated with an increased risk of borderline tumors (pooled odds ratio (pOR) = 1.32, 95% confidence interval (CI): 1.10, 1.58). Women with at least 2 episodes of PID had a 2-fold increased risk of borderline tumors (pOR = 2.14, 95% CI: 1.08, 4.24). No association was observed between PID and ovarian cancer risk overall (pOR = 0.99, 95% CI: 0.83, 1.19); however, a statistically nonsignificantly increased risk of low-grade serous tumors (pOR = 1.48, 95% CI: 0.92, 2.38) was noted. In conclusion, PID was associated with an increased risk of borderline ovarian tumors, particularly among women who had had multiple episodes of PID. Although our results indicated a histotype-specific association with PID, the association of PID with ovarian cancer risk is still somewhat uncertain and requires further investigation.

Authors
Rasmussen, CB; Kjaer, SK; Albieri, V; Bandera, EV; Doherty, JA; Høgdall, E; Webb, PM; Jordan, SJ; Rossing, MA; Wicklund, KG; Goodman, MT; Modugno, F; Moysich, KB; Ness, RB; Edwards, RP; Schildkraut, JM; Berchuck, A; Olson, SH; Kiemeney, LA; Massuger, LFAG; Narod, SA; Phelan, CM; Anton-Culver, H; Ziogas, A; Wu, AH; Pearce, CL; Risch, HA; Jensen, A; , on behalf of the Ovarian Cancer Association Consortium,
MLA Citation
Rasmussen, CB, Kjaer, SK, Albieri, V, Bandera, EV, Doherty, JA, Høgdall, E, Webb, PM, Jordan, SJ, Rossing, MA, Wicklund, KG, Goodman, MT, Modugno, F, Moysich, KB, Ness, RB, Edwards, RP, Schildkraut, JM, Berchuck, A, Olson, SH, Kiemeney, LA, Massuger, LFAG, Narod, SA, Phelan, CM, Anton-Culver, H, Ziogas, A, Wu, AH, Pearce, CL, Risch, HA, Jensen, A, , and on behalf of the Ovarian Cancer Association Consortium, . "Pelvic Inflammatory Disease and the Risk of Ovarian Cancer and Borderline Ovarian Tumors: A Pooled Analysis of 13 Case-Control Studies." American journal of epidemiology 185.1 (January 2017): 8-20. (Review)
PMID
27941069
Source
epmc
Published In
American Journal of Epidemiology
Volume
185
Issue
1
Publish Date
2017
Start Page
8
End Page
20
DOI
10.1093/aje/kww161

Integration of Population-Level Genotype Data with Functional Annotation Reveals Over-Representation of Long Noncoding RNAs at Ovarian Cancer Susceptibility Loci.

Genome-wide association studies (GWAS) have identified multiple loci associated with epithelial ovarian cancer (EOC) susceptibility, but further progress requires integration of epidemiology and biology to illuminate true risk loci below genome-wide significance levels (P < 5 × 10-8). Most risk SNPs lie within non-protein-encoding regions, and we hypothesize that long noncoding RNA (lncRNA) genes are enriched at EOC risk regions and represent biologically relevant functional targets.Using imputed GWAS data from about 18,000 invasive EOC cases and 34,000 controls of European ancestry, the GENCODE (v19) lncRNA database was used to annotate SNPs from 13,442 lncRNAs for permutation-based enrichment analysis. Tumor expression quantitative trait locus (eQTL) analysis was performed for sub-genome-wide regions (1 × 10-5 > P > 5 × 10-8) overlapping lncRNAs.Of 5,294 EOC-associated SNPs (P < 1.0 × 10-5), 1,464 (28%) mapped within 53 unique lncRNAs and an additional 3,484 (66%) SNPs were correlated (r2 > 0.2) with SNPs within 115 lncRNAs. EOC-associated SNPs comprised 130 independent regions, of which 72 (55%) overlapped with lncRNAs, representing a significant enrichment (P = 5.0 × 10-4) that was more pronounced among a subset of 5,401 lncRNAs with active epigenetic regulation in normal ovarian tissue. EOC-associated lncRNAs and their putative promoters and transcription factors were enriched for biologically relevant pathways and eQTL analysis identified five novel putative risk regions with allele-specific effects on lncRNA gene expression.lncRNAs are significantly enriched at EOC risk regions, suggesting a mechanistic role for lncRNAs in driving predisposition to EOC.lncRNAs represent key candidates for integrative epidemiologic and functional studies. Further research on their biologic role in ovarian cancer is indicated. Cancer Epidemiol Biomarkers Prev; 26(1); 116-25. ©2016 AACR.

Authors
Reid, BM; Permuth, JB; Chen, YA; Teer, JK; Monteiro, ANA; Chen, Z; Tyrer, J; Berchuck, A; Chenevix-Trench, G; Doherty, JA; Goode, EL; Iverson, ES; Lawrenson, K; Pearce, CL; Pharoah, PD; Phelan, CM; Ramus, SJ; Rossing, MA; Schildkraut, JM; Cheng, JQ; Gayther, SA; Sellers, TA; Ovarian Cancer Association Consortium, ; Australian Ovarian Cancer Study Group and the Ovarian Cancer Association Consortium, ; Ovarian Cancer Association Consortium,
MLA Citation
Reid, BM, Permuth, JB, Chen, YA, Teer, JK, Monteiro, ANA, Chen, Z, Tyrer, J, Berchuck, A, Chenevix-Trench, G, Doherty, JA, Goode, EL, Iverson, ES, Lawrenson, K, Pearce, CL, Pharoah, PD, Phelan, CM, Ramus, SJ, Rossing, MA, Schildkraut, JM, Cheng, JQ, Gayther, SA, Sellers, TA, Ovarian Cancer Association Consortium, , Australian Ovarian Cancer Study Group and the Ovarian Cancer Association Consortium, , and Ovarian Cancer Association Consortium, . "Integration of Population-Level Genotype Data with Functional Annotation Reveals Over-Representation of Long Noncoding RNAs at Ovarian Cancer Susceptibility Loci." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 26.1 (January 2017): 116-125.
PMID
28035019
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
26
Issue
1
Publish Date
2017
Start Page
116
End Page
125
DOI
10.1158/1055-9965.epi-16-0341

Stress and burnout among gynecologic oncologists: A society of gynecologic oncology evidence-based review and recommendations

Authors
Cass, I; Duska, LR; Blank, SV; Cheng, G; Dupont, NC; Frederick, PJ; Hill, EK; Matthews, CM; Pua, TL; Rath, KS; Ruskin, R; Thaker, PH; Berchuck, A; Gostout, BS; Kushner, DM; Fowler, JM
MLA Citation
Cass, I, Duska, LR, Blank, SV, Cheng, G, Dupont, NC, Frederick, PJ, Hill, EK, Matthews, CM, Pua, TL, Rath, KS, Ruskin, R, Thaker, PH, Berchuck, A, Gostout, BS, Kushner, DM, and Fowler, JM. "Stress and burnout among gynecologic oncologists: A society of gynecologic oncology evidence-based review and recommendations." Obstetrical and Gynecological Survey 71.12 (December 1, 2016): 715-717.
Source
scopus
Published In
Obstetrical and Gynecological Survey
Volume
71
Issue
12
Publish Date
2016
Start Page
715
End Page
717
DOI
10.1097/OGX.0000000000000382

A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer.

Menopausal estrogen-alone therapy (ET) is a well-established risk factor for serous and endometrioid ovarian cancer. Genetics also plays a role in ovarian cancer, which is partly attributable to 18 confirmed ovarian cancer susceptibility loci identified by genome-wide association studies. The interplay among these loci, ET use and ovarian cancer risk has yet to be evaluated. We analyzed data from 1,414 serous cases, 337 endometrioid cases and 4,051 controls across 10 case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Conditional logistic regression was used to determine the association between the confirmed susceptibility variants and risk of serous and endometrioid ovarian cancer among ET users and non-users separately and to test for statistical interaction. A splicing variant in TERT, rs10069690, showed a statistically significant interaction with ET use for risk of serous ovarian cancer (pint  = 0.013). ET users carrying the T allele had a 51% increased risk of disease (OR = 1.51, 95% CI 1.19-1.91), which was stronger for long-term ET users of 10+ years (OR = 1.85, 95% CI 1.28-2.66, pint  = 0.034). Non-users showed essentially no association (OR = 1.08, 95% CI 0.96-1.21). Two additional genomic regions harboring rs7207826 (C allele) and rs56318008 (T allele) also had significant interactions with ET use for the endometrioid histotype (pint  = 0.021 and pint  = 0.037, respectively). Hence, three confirmed susceptibility variants were identified whose associations with ovarian cancer risk are modified by ET exposure; follow-up is warranted given that these interactions are not adjusted for multiple comparisons. These findings, if validated, may elucidate the mechanism of action of these loci.

Authors
Lee, AW; Bomkamp, A; Bandera, EV; Jensen, A; Ramus, SJ; Goodman, MT; Rossing, MA; Modugno, F; Moysich, KB; Chang-Claude, J; Rudolph, A; Gentry-Maharaj, A; Terry, KL; Gayther, SA; Cramer, DW; Doherty, JA; Schildkraut, JM; Kjaer, SK; Ness, RB; Menon, U; Berchuck, A; Mukherjee, B; Roman, L; Pharoah, PD; Chenevix-Trench, G; Olson, S; Hogdall, E; Wu, AH; Pike, MC; Stram, DO; Pearce, CL; Ovarian Cancer Association Consortium,
MLA Citation
Lee, AW, Bomkamp, A, Bandera, EV, Jensen, A, Ramus, SJ, Goodman, MT, Rossing, MA, Modugno, F, Moysich, KB, Chang-Claude, J, Rudolph, A, Gentry-Maharaj, A, Terry, KL, Gayther, SA, Cramer, DW, Doherty, JA, Schildkraut, JM, Kjaer, SK, Ness, RB, Menon, U, Berchuck, A, Mukherjee, B, Roman, L, Pharoah, PD, Chenevix-Trench, G, Olson, S, Hogdall, E, Wu, AH, Pike, MC, Stram, DO, Pearce, CL, and Ovarian Cancer Association Consortium, . "A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer." International journal of cancer 139.12 (December 2016): 2646-2654.
PMID
27420401
Source
epmc
Published In
International Journal of Cancer
Volume
139
Issue
12
Publish Date
2016
Start Page
2646
End Page
2654
DOI
10.1002/ijc.30274

Telomere structure and maintenance gene variants and risk of five cancer types.

Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs ≤3.08 × 10-5 ). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk.

Authors
Karami, S; Han, Y; Pande, M; Cheng, I; Rudd, J; Pierce, BL; Nutter, EL; Schumacher, FR; Kote-Jarai, Z; Lindstrom, S; Witte, JS; Fang, S; Han, J; Kraft, P; Hunter, DJ; Song, F; Hung, RJ; McKay, J; Gruber, SB; Chanock, SJ; Risch, A; Shen, H; Haiman, CA; Boardman, L; Ulrich, CM; Casey, G; Peters, U; Amin Al Olama, A; Berchuck, A; Berndt, SI; Bezieau, S; Brennan, P; Brenner, H; Brinton, L; Caporaso, N; Chan, AT; Chang-Claude, J; Christiani, DC; Cunningham, JM; Easton, D; Eeles, RA; Eisen, T et al.
MLA Citation
Karami, S, Han, Y, Pande, M, Cheng, I, Rudd, J, Pierce, BL, Nutter, EL, Schumacher, FR, Kote-Jarai, Z, Lindstrom, S, Witte, JS, Fang, S, Han, J, Kraft, P, Hunter, DJ, Song, F, Hung, RJ, McKay, J, Gruber, SB, Chanock, SJ, Risch, A, Shen, H, Haiman, CA, Boardman, L, Ulrich, CM, Casey, G, Peters, U, Amin Al Olama, A, Berchuck, A, Berndt, SI, Bezieau, S, Brennan, P, Brenner, H, Brinton, L, Caporaso, N, Chan, AT, Chang-Claude, J, Christiani, DC, Cunningham, JM, Easton, D, Eeles, RA, and Eisen, T et al. "Telomere structure and maintenance gene variants and risk of five cancer types." International journal of cancer 139.12 (December 2016): 2655-2670.
PMID
27459707
Source
epmc
Published In
International Journal of Cancer
Volume
139
Issue
12
Publish Date
2016
Start Page
2655
End Page
2670
DOI
10.1002/ijc.30288

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.

The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Authors
Southey, MC; Goldgar, DE; Winqvist, R; Pylkäs, K; Couch, F; Tischkowitz, M; Foulkes, WD; Dennis, J; Michailidou, K; van Rensburg, EJ; Heikkinen, T; Nevanlinna, H; Hopper, JL; Dörk, T; Claes, KB; Reis-Filho, J; Teo, ZL; Radice, P; Catucci, I; Peterlongo, P; Tsimiklis, H; Odefrey, FA; Dowty, JG; Schmidt, MK; Broeks, A; Hogervorst, FB; Verhoef, S; Carpenter, J; Clarke, C; Scott, RJ; Fasching, PA; Haeberle, L; Ekici, AB; Beckmann, MW; Peto, J; Dos-Santos-Silva, I; Fletcher, O; Johnson, N; Bolla, MK et al.
MLA Citation
Southey, MC, Goldgar, DE, Winqvist, R, Pylkäs, K, Couch, F, Tischkowitz, M, Foulkes, WD, Dennis, J, Michailidou, K, van Rensburg, EJ, Heikkinen, T, Nevanlinna, H, Hopper, JL, Dörk, T, Claes, KB, Reis-Filho, J, Teo, ZL, Radice, P, Catucci, I, Peterlongo, P, Tsimiklis, H, Odefrey, FA, Dowty, JG, Schmidt, MK, Broeks, A, Hogervorst, FB, Verhoef, S, Carpenter, J, Clarke, C, Scott, RJ, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Peto, J, Dos-Santos-Silva, I, Fletcher, O, Johnson, N, and Bolla, MK et al. "PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS." Journal of medical genetics 53.12 (December 2016): 800-811.
PMID
27595995
Source
epmc
Published In
Journal of medical genetics
Volume
53
Issue
12
Publish Date
2016
Start Page
800
End Page
811
DOI
10.1136/jmedgenet-2016-103839

Stress and burnout among gynecologic oncologists: A Society of Gynecologic Oncology Evidence-based Review and Recommendations.

Authors
Cass, I; Duska, LR; Blank, SV; Cheng, G; duPont, NC; Frederick, PJ; Hill, EK; Matthews, CM; Pua, TL; Rath, KS; Ruskin, R; Thaker, PH; Berchuck, A; Gostout, BS; Kushner, DM; Fowler, JM
MLA Citation
Cass, I, Duska, LR, Blank, SV, Cheng, G, duPont, NC, Frederick, PJ, Hill, EK, Matthews, CM, Pua, TL, Rath, KS, Ruskin, R, Thaker, PH, Berchuck, A, Gostout, BS, Kushner, DM, and Fowler, JM. "Stress and burnout among gynecologic oncologists: A Society of Gynecologic Oncology Evidence-based Review and Recommendations." Gynecologic oncology 143.2 (November 2016): 421-427. (Review)
PMID
27575910
Source
epmc
Published In
Gynecologic Oncology
Volume
143
Issue
2
Publish Date
2016
Start Page
421
End Page
427
DOI
10.1016/j.ygyno.2016.08.319

Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration.

RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10-4). Gene-level analyses revealed that variation in ADAR was associated (P<0.05) with EOC susceptibility, with PAML=0.022 and PSKAT-CR=0.020. Expression quantitative trait locus analysis in EOC tissue revealed significant associations (P<0.05) with ADAR expression for several SNPs in ADAR, including rs1127313 (G/A), a SNP in the 3' untranslated region. In summary, germline variation involving RNA editing genes may influence EOC susceptibility, warranting further investigation of inherited and acquired alterations affecting RNA editing.

Authors
Permuth, JB; Reid, B; Earp, M; Chen, YA; Monteiro, ANA; Chen, Z; AOCS Study Group, ; Chenevix-Trench, G; Fasching, PA; Beckmann, MW; Lambrechts, D; Vanderstichele, A; Van Niewenhuyse, E; Vergote, I; Rossing, MA; Doherty, JA; Chang-Claude, J; Moysich, K; Odunsi, K; Goodman, MT; Shvetsov, YB; Wilkens, LR; Thompson, PJ; Dörk, T; Bogdanova, N; Butzow, R; Nevanlinna, H; Pelttari, L; Leminen, A; Modugno, F; Edwards, RP; Ness, RB; Kelley, J; Heitz, F; Karlan, B; Lester, J; Kjaer, SK; Jensen, A et al.
MLA Citation
Permuth, JB, Reid, B, Earp, M, Chen, YA, Monteiro, ANA, Chen, Z, AOCS Study Group, , Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Lambrechts, D, Vanderstichele, A, Van Niewenhuyse, E, Vergote, I, Rossing, MA, Doherty, JA, Chang-Claude, J, Moysich, K, Odunsi, K, Goodman, MT, Shvetsov, YB, Wilkens, LR, Thompson, PJ, Dörk, T, Bogdanova, N, Butzow, R, Nevanlinna, H, Pelttari, L, Leminen, A, Modugno, F, Edwards, RP, Ness, RB, Kelley, J, Heitz, F, Karlan, B, Lester, J, Kjaer, SK, and Jensen, A et al. "Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration." Oncotarget 7.45 (November 2016): 72381-72394.
PMID
27911851
Source
epmc
Published In
Oncotarget
Volume
7
Issue
45
Publish Date
2016
Start Page
72381
End Page
72394
DOI
10.18632/oncotarget.10546

Risk Prediction for Epithelial Ovarian Cancer in 11 United States-Based Case-Control Studies: Incorporation of Epidemiologic Risk Factors and 17 Confirmed Genetic Loci

© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. Previously developed models for predicting absolute risk of invasive epithelial ovarian cancer have included a limited number of risk factors and have had low discriminatory power (area under the receiver operating characteristic curve (AUC)  < 0.60). Because of this, we developed and internally validated a relative risk prediction model that incorporates 17 established epidemiologic risk factors and 17 genome-wide significant single nucleotide polymorphisms (SNPs) using data from 11 case-control studies in the United States (5,793 cases; 9,512 controls) from the Ovarian Cancer Association Consortium (data accrued from 1992 to 2010). We developed a hierarchical logistic regression model for predicting case-control status that included imputation of missing data. We randomly divided the data into an 80% training sample and used the remaining 20% for model evaluation. The AUC for the full model was 0.664. A reduced model without SNPs performed similarly (AUC = 0.649). Both models performed better than a baseline model that included age and study site only (AUC = 0.563). The best predictive power was obtained in the full model among women younger than 50 years of age (AUC = 0.714); however, the addition of SNPs increased the AUC the most for women older than 50 years of age (AUC = 0.638 vs. 0.616). Adapting this improved model to estimate absolute risk and evaluating it in prospective data sets is warranted.

Authors
Clyde, MA; Palmieri Weber, R; Iversen, ES; Poole, EM; Doherty, JA; Goodman, MT; Ness, RB; Risch, HA; Rossing, MA; Terry, KL; Wentzensen, N; Whittemore, AS; Anton-Culver, H; Bandera, EV; Berchuck, A; Carney, ME; Cramer, DW; Cunningham, JM; Cushing-Haugen, KL; Edwards, RP; Fridley, BL; Goode, EL; Lurie, G; McGuire, V; Modugno, F; Moysich, KB; Olson, SH; Pearce, CL; Pike, MC; Rothstein, JH; Sellers, TA; Sieh, W; Stram, D; Thompson, PJ; Vierkant, RA; Wicklund, KG; Wu, AH; Ziogas, A; Tworoger, SS et al.
MLA Citation
Clyde, MA, Palmieri Weber, R, Iversen, ES, Poole, EM, Doherty, JA, Goodman, MT, Ness, RB, Risch, HA, Rossing, MA, Terry, KL, Wentzensen, N, Whittemore, AS, Anton-Culver, H, Bandera, EV, Berchuck, A, Carney, ME, Cramer, DW, Cunningham, JM, Cushing-Haugen, KL, Edwards, RP, Fridley, BL, Goode, EL, Lurie, G, McGuire, V, Modugno, F, Moysich, KB, Olson, SH, Pearce, CL, Pike, MC, Rothstein, JH, Sellers, TA, Sieh, W, Stram, D, Thompson, PJ, Vierkant, RA, Wicklund, KG, Wu, AH, Ziogas, A, and Tworoger, SS et al. "Risk Prediction for Epithelial Ovarian Cancer in 11 United States-Based Case-Control Studies: Incorporation of Epidemiologic Risk Factors and 17 Confirmed Genetic Loci." American journal of epidemiology 184.8 (October 15, 2016): 579-589.
Source
scopus
Published In
American Journal of Epidemiology
Volume
184
Issue
8
Publish Date
2016
Start Page
579
End Page
589

Risk Prediction for Epithelial Ovarian Cancer in 11 United States-Based Case-Control Studies: Incorporation of Epidemiologic Risk Factors and 17 Confirmed Genetic Loci.

Previously developed models for predicting absolute risk of invasive epithelial ovarian cancer have included a limited number of risk factors and have had low discriminatory power (area under the receiver operating characteristic curve (AUC) < 0.60). Because of this, we developed and internally validated a relative risk prediction model that incorporates 17 established epidemiologic risk factors and 17 genome-wide significant single nucleotide polymorphisms (SNPs) using data from 11 case-control studies in the United States (5,793 cases; 9,512 controls) from the Ovarian Cancer Association Consortium (data accrued from 1992 to 2010). We developed a hierarchical logistic regression model for predicting case-control status that included imputation of missing data. We randomly divided the data into an 80% training sample and used the remaining 20% for model evaluation. The AUC for the full model was 0.664. A reduced model without SNPs performed similarly (AUC = 0.649). Both models performed better than a baseline model that included age and study site only (AUC = 0.563). The best predictive power was obtained in the full model among women younger than 50 years of age (AUC = 0.714); however, the addition of SNPs increased the AUC the most for women older than 50 years of age (AUC = 0.638 vs. 0.616). Adapting this improved model to estimate absolute risk and evaluating it in prospective data sets is warranted.

Authors
Clyde, MA; Palmieri Weber, R; Iversen, ES; Poole, EM; Doherty, JA; Goodman, MT; Ness, RB; Risch, HA; Rossing, MA; Terry, KL; Wentzensen, N; Whittemore, AS; Anton-Culver, H; Bandera, EV; Berchuck, A; Carney, ME; Cramer, DW; Cunningham, JM; Cushing-Haugen, KL; Edwards, RP; Fridley, BL; Goode, EL; Lurie, G; McGuire, V; Modugno, F; Moysich, KB; Olson, SH; Pearce, CL; Pike, MC; Rothstein, JH; Sellers, TA; Sieh, W; Stram, D; Thompson, PJ; Vierkant, RA; Wicklund, KG; Wu, AH; Ziogas, A; Tworoger, SS et al.
MLA Citation
Clyde, MA, Palmieri Weber, R, Iversen, ES, Poole, EM, Doherty, JA, Goodman, MT, Ness, RB, Risch, HA, Rossing, MA, Terry, KL, Wentzensen, N, Whittemore, AS, Anton-Culver, H, Bandera, EV, Berchuck, A, Carney, ME, Cramer, DW, Cunningham, JM, Cushing-Haugen, KL, Edwards, RP, Fridley, BL, Goode, EL, Lurie, G, McGuire, V, Modugno, F, Moysich, KB, Olson, SH, Pearce, CL, Pike, MC, Rothstein, JH, Sellers, TA, Sieh, W, Stram, D, Thompson, PJ, Vierkant, RA, Wicklund, KG, Wu, AH, Ziogas, A, and Tworoger, SS et al. "Risk Prediction for Epithelial Ovarian Cancer in 11 United States-Based Case-Control Studies: Incorporation of Epidemiologic Risk Factors and 17 Confirmed Genetic Loci." American journal of epidemiology 184.8 (October 3, 2016): 579-589.
Website
http://hdl.handle.net/10161/12934
PMID
27698005
Source
epmc
Published In
American Journal of Epidemiology
Volume
184
Issue
8
Publish Date
2016
Start Page
579
End Page
589
DOI
10.1093/aje/kww091

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer.

Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer.In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients.The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively).Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Authors
Hampras, SS; Sucheston-Campbell, LE; Cannioto, R; Chang-Claude, J; Modugno, F; Dörk, T; Hillemanns, P; Preus, L; Knutson, KL; Wallace, PK; Hong, C-C; Friel, G; Davis, W; Nesline, M; Pearce, CL; Kelemen, LE; Goodman, MT; Bandera, EV; Terry, KL; Schoof, N; Eng, KH; Clay, A; Singh, PK; Joseph, JM; Aben, KKH; Anton-Culver, H; Antonenkova, N; Baker, H; Bean, Y; Beckmann, MW; Bisogna, M; Bjorge, L; Bogdanova, N; Brinton, LA; Brooks-Wilson, A; Bruinsma, F; Butzow, R; Campbell, IG; Carty, K; Cook, LS et al.
MLA Citation
Hampras, SS, Sucheston-Campbell, LE, Cannioto, R, Chang-Claude, J, Modugno, F, Dörk, T, Hillemanns, P, Preus, L, Knutson, KL, Wallace, PK, Hong, C-C, Friel, G, Davis, W, Nesline, M, Pearce, CL, Kelemen, LE, Goodman, MT, Bandera, EV, Terry, KL, Schoof, N, Eng, KH, Clay, A, Singh, PK, Joseph, JM, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, and Cook, LS et al. "Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer." Oncotarget 7.43 (October 2016): 69097-69110.
PMID
27533245
Source
epmc
Published In
Oncotarget
Volume
7
Issue
43
Publish Date
2016
Start Page
69097
End Page
69110
DOI
10.18632/oncotarget.10215

Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study.

In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer.We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases).The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01).Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.

Authors
Ong, J-S; Cuellar-Partida, G; Lu, Y; Australian Ovarian Cancer Study, ; Fasching, PA; Hein, A; Burghaus, S; Beckmann, MW; Lambrechts, D; Van Nieuwenhuysen, E; Vergote, I; Vanderstichele, A; Anne Doherty, J; Anne Rossing, M; Chang-Claude, J; Eilber, U; Rudolph, A; Wang-Gohrke, S; Goodman, MT; Bogdanova, N; Dörk, T; Dürst, M; Hillemanns, P; Runnebaum, IB; Antonenkova, N; Butzow, R; Leminen, A; Nevanlinna, H; Pelttari, LM; Edwards, RP; Kelley, JL; Modugno, F; Moysich, KB; Ness, RB; Cannioto, R et al.
MLA Citation
Ong, J-S, Cuellar-Partida, G, Lu, Y, Australian Ovarian Cancer Study, , Fasching, PA, Hein, A, Burghaus, S, Beckmann, MW, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Vanderstichele, A, Anne Doherty, J, Anne Rossing, M, Chang-Claude, J, Eilber, U, Rudolph, A, Wang-Gohrke, S, Goodman, MT, Bogdanova, N, Dörk, T, Dürst, M, Hillemanns, P, Runnebaum, IB, Antonenkova, N, Butzow, R, Leminen, A, Nevanlinna, H, Pelttari, LM, Edwards, RP, Kelley, JL, Modugno, F, Moysich, KB, Ness, RB, and Cannioto, R et al. "Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study." International journal of epidemiology 45.5 (October 2016): 1619-1630.
PMID
27594614
Source
epmc
Published In
International Journal of Epidemiology
Volume
45
Issue
5
Publish Date
2016
Start Page
1619
End Page
1630
DOI
10.1093/ije/dyw207

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.

Authors
Lawrenson, K; Kar, S; McCue, K; Kuchenbaeker, K; Michailidou, K; Tyrer, J; Beesley, J; Ramus, SJ; Li, Q; Delgado, MK; Lee, JM; Aittomäki, K; Andrulis, IL; Anton-Culver, H; Arndt, V; Arun, BK; Arver, B; Bandera, EV; Barile, M; Barkardottir, RB; Barrowdale, D; Beckmann, MW; Benitez, J; Berchuck, A; Bisogna, M; Bjorge, L; Blomqvist, C; Blot, W; Bogdanova, N; Bojesen, A; Bojesen, SE; Bolla, MK; Bonanni, B; Børresen-Dale, A-L; Brauch, H; Brennan, P; Brenner, H; Bruinsma, F; Brunet, J; Buhari, SA et al.
MLA Citation
Lawrenson, K, Kar, S, McCue, K, Kuchenbaeker, K, Michailidou, K, Tyrer, J, Beesley, J, Ramus, SJ, Li, Q, Delgado, MK, Lee, JM, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arun, BK, Arver, B, Bandera, EV, Barile, M, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Benitez, J, Berchuck, A, Bisogna, M, Bjorge, L, Blomqvist, C, Blot, W, Bogdanova, N, Bojesen, A, Bojesen, SE, Bolla, MK, Bonanni, B, Børresen-Dale, A-L, Brauch, H, Brennan, P, Brenner, H, Bruinsma, F, Brunet, J, and Buhari, SA et al. "Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus." Nature communications 7 (September 7, 2016): 12675-.
PMID
27601076
Source
epmc
Published In
Nature Communications
Volume
7
Publish Date
2016
Start Page
12675
DOI
10.1038/ncomms12675

Chronic Recreational Physical Inactivity and Epithelial Ovarian Cancer Risk: Evidence from the Ovarian Cancer Association Consortium

Authors
Cannioto, R; LaMonte, MJ; Risch, HA; Hong, CC; Sucheston-Campbell, LE; Eng, KH; Szender, JB; Chang-Claude, J; Schmalfeldt, B; Klapdor, R; Gower, E; Minlikeeva, AN; Zirpoli, G; Bandera, EV; Berchuck, A; Cramer, D; Doherty, JA; Edwards, RP; Fridley, BL; Goode, EL; Goodman, MT; Hogdall, E; Hosono, S; Jensen, A; Jordan, S; Kjaer, SK; Matsuo, K; Ness, RB; Olsen, CM; Olson, SH; Pearce, CL; Pike, MC; Rossing, MA; Szamreta, EA; Thompson, PJ; Tseng, CC; Vierkant, RA; Webb, PM; Wentzensen, N et al.
MLA Citation
Cannioto, R, LaMonte, MJ, Risch, HA, Hong, CC, Sucheston-Campbell, LE, Eng, KH, Szender, JB, Chang-Claude, J, Schmalfeldt, B, Klapdor, R, Gower, E, Minlikeeva, AN, Zirpoli, G, Bandera, EV, Berchuck, A, Cramer, D, Doherty, JA, Edwards, RP, Fridley, BL, Goode, EL, Goodman, MT, Hogdall, E, Hosono, S, Jensen, A, Jordan, S, Kjaer, SK, Matsuo, K, Ness, RB, Olsen, CM, Olson, SH, Pearce, CL, Pike, MC, Rossing, MA, Szamreta, EA, Thompson, PJ, Tseng, CC, Vierkant, RA, Webb, PM, and Wentzensen, N et al. "Chronic Recreational Physical Inactivity and Epithelial Ovarian Cancer Risk: Evidence from the Ovarian Cancer Association Consortium." Obstetrical and Gynecological Survey 71.9 (September 1, 2016): 528-530.
Source
scopus
Published In
Obstetrical and Gynecological Survey
Volume
71
Issue
9
Publish Date
2016
Start Page
528
End Page
530
DOI
10.1097/OGX.0000000000000357

Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types.

Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis.We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

Authors
Kar, SP; Beesley, J; Amin Al Olama, A; Michailidou, K; Tyrer, J; Kote-Jarai, Z; Lawrenson, K; Lindstrom, S; Ramus, SJ; Thompson, DJ; ABCTB Investigators, ; Kibel, AS; Dansonka-Mieszkowska, A; Michael, A; Dieffenbach, AK; Gentry-Maharaj, A; Whittemore, AS; Wolk, A; Monteiro, A; Peixoto, A; Kierzek, A; Cox, A; Rudolph, A; Gonzalez-Neira, A; Wu, AH; Lindblom, A; Swerdlow, A; AOCS Study Group & Australian Cancer Study (Ovarian Cancer), ; APCB BioResource, ; Ziogas, A; Ekici, AB; Burwinkel, B et al.
MLA Citation
Kar, SP, Beesley, J, Amin Al Olama, A, Michailidou, K, Tyrer, J, Kote-Jarai, Z, Lawrenson, K, Lindstrom, S, Ramus, SJ, Thompson, DJ, ABCTB Investigators, , Kibel, AS, Dansonka-Mieszkowska, A, Michael, A, Dieffenbach, AK, Gentry-Maharaj, A, Whittemore, AS, Wolk, A, Monteiro, A, Peixoto, A, Kierzek, A, Cox, A, Rudolph, A, Gonzalez-Neira, A, Wu, AH, Lindblom, A, Swerdlow, A, AOCS Study Group & Australian Cancer Study (Ovarian Cancer), , APCB BioResource, , Ziogas, A, Ekici, AB, and Burwinkel, B et al. "Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types." Cancer discovery 6.9 (September 2016): 1052-1067.
PMID
27432226
Source
epmc
Published In
Cancer Discovery
Volume
6
Issue
9
Publish Date
2016
Start Page
1052
End Page
1067
DOI
10.1158/2159-8290.cd-15-1227

Evaluating the Repertoire of Immune Checkpoint Markers Expressed Within Ovarian Cancers

Authors
Gaillard, S; Yi, J; Dumbauld, C; Ehrisman, J; Berchuck, A; Weinhold, K
MLA Citation
Gaillard, S, Yi, J, Dumbauld, C, Ehrisman, J, Berchuck, A, and Weinhold, K. "Evaluating the Repertoire of Immune Checkpoint Markers Expressed Within Ovarian Cancers." JOURNAL OF WOMENS HEALTH 25.9 (September 2016): 962-962.
Source
wos-lite
Published In
Journal of Women's Health
Volume
25
Issue
9
Publish Date
2016
Start Page
962
End Page
962

Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk.

Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P < 5.0 × 10 -  7). One of the most significant signals (Pall histologies = 1.01 × 10 -  13;Pserous = 3.54 × 10 -  14) occurred at 3q25.31 for rs62273959, a missense variant mapping to the LEKR1 gene that is in LD (r2 = 0.90) with a previously identified 'best hit' (rs7651446) mapping to an intron of TIPARP. Suggestive associations (5.0 × 10 -  5 > P≥5.0 ×10 -  7) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (PAML = 3.23 × 10 -  5; PSKAT-o = 9.23 × 10 -  4) and KRT13 (PAML = 1.67 × 10 -  4; PSKAT-o = 1.07 × 10 -  5), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further unravel the unexplained heritability and biology of this disease.

Authors
Permuth, JB; Pirie, A; Ann Chen, Y; Lin, H-Y; Reid, BM; Chen, Z; Monteiro, A; Dennis, J; Mendoza-Fandino, G; AOCS Study Group, ; Australian Cancer Study (Ovarian Cancer), ; Anton-Culver, H; Bandera, EV; Bisogna, M; Brinton, L; Brooks-Wilson, A; Carney, ME; Chenevix-Trench, G; Cook, LS; Cramer, DW; Cunningham, JM; Cybulski, C; D'Aloisio, AA; Anne Doherty, J; Earp, M; Edwards, RP; Fridley, BL; Gayther, SA; Gentry-Maharaj, A; Goodman, MT; Gronwald, J; Hogdall, E; Iversen, ES; Jakubowska, A et al.
MLA Citation
Permuth, JB, Pirie, A, Ann Chen, Y, Lin, H-Y, Reid, BM, Chen, Z, Monteiro, A, Dennis, J, Mendoza-Fandino, G, AOCS Study Group, , Australian Cancer Study (Ovarian Cancer), , Anton-Culver, H, Bandera, EV, Bisogna, M, Brinton, L, Brooks-Wilson, A, Carney, ME, Chenevix-Trench, G, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, D'Aloisio, AA, Anne Doherty, J, Earp, M, Edwards, RP, Fridley, BL, Gayther, SA, Gentry-Maharaj, A, Goodman, MT, Gronwald, J, Hogdall, E, Iversen, ES, and Jakubowska, A et al. "Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk." Human molecular genetics 25.16 (August 2016): 3600-3612.
PMID
27378695
Source
epmc
Published In
Human Molecular Genetics
Volume
25
Issue
16
Publish Date
2016
Start Page
3600
End Page
3612
DOI
10.1093/hmg/ddw196

Performance of sentinel lymph node biopsy in high-risk endometrial cancer.

To determine the rate and performance of sentinel lymph node (SLN) mapping among women with high-risk endometrial cancers.Patients diagnosed between 2012 and 2015 with uterine cancer of grade 3 endometrioid, clear cell, serous or carcinosarcoma histology and who underwent SLN mapping prior to full pelvic lymph node dissection were included. Subjects underwent methylene blue or ICG injection for laparoscopic (N = 16) or robotic-assisted laparoscopic (N = 20) staging. Outcomes included SLN mapping rates, SLN and non-SLN positive rates, false negative SLN algorithm rate, and the negative predictive value (NPV) of the SLN algorithm. Fisher's exact test was used to compare mapping and node positivity rates.9/36 (25%) patients with high-risk uterine cancer had at least one metastatic lymph node identified. Successful mapping occurred in 30/36 (83%) patients. SLN mapped to pelvic nodes bilaterally in 20 (56%), unilaterally in 9 (25%), and aortic nodes only in 1 (3%). Malignancy was identified in 14/95 (15%) of all sentinel nodes and 12/775 (1.5%) of all non-sentinel nodes (p < 0.001). The false negative rate of SLN mapping alone was 2/26 (7.7%); the NPV was 92.3%. When the SLN algorithm was applied retrospectively the false negative rate was 0/31 (0%); the NPV was 100%.SLN mapping rates for high-risk cancers are slightly lower than in prior reports of lower risk cancers. The NPV of the SLN mapping alone is 92% and rises to 100% when the SLN algorithm is applied. Such results are acceptable and consistent with larger subsets of lower risk endometrial cancers.

Authors
Ehrisman, J; Secord, AA; Berchuck, A; Lee, PS; Di Santo, N; Lopez-Acevedo, M; Broadwater, G; Valea, FA; Havrilesky, LJ
MLA Citation
Ehrisman, J, Secord, AA, Berchuck, A, Lee, PS, Di Santo, N, Lopez-Acevedo, M, Broadwater, G, Valea, FA, and Havrilesky, LJ. "Performance of sentinel lymph node biopsy in high-risk endometrial cancer." Gynecologic oncology reports 17 (August 2016): 69-71.
PMID
27453926
Source
epmc
Published In
Gynecologic Oncology Reports
Volume
17
Publish Date
2016
Start Page
69
End Page
71
DOI
10.1016/j.gore.2016.04.002

Association Between Menopausal Estrogen-Only Therapy and Ovarian Carcinoma Risk

Authors
Lee, AW; Ness, RB; Roman, LD; Terry, KL; Schildkraut, JM; Chang-Claude, J; Doherty, JA; Menon, U; Cramer, DW; Gayther, SA; Risch, H; Gentry-Maharaj, A; Goodman, MT; Modugno, F; Eilber, U; Moysich, KB; Berchuck, A; Rossing, MA; Jensen, A; Wicklund, KG; Cushing-Haugen, KL; Hogdall, E; Rudolph, A; Thompson, PJ; Wilkens, LR; Kjaer, SK; Carney, ME; Stram, DO; Ramus, SJ; Wu, AH; Pike, MC; Pearce, CL
MLA Citation
Lee, AW, Ness, RB, Roman, LD, Terry, KL, Schildkraut, JM, Chang-Claude, J, Doherty, JA, Menon, U, Cramer, DW, Gayther, SA, Risch, H, Gentry-Maharaj, A, Goodman, MT, Modugno, F, Eilber, U, Moysich, KB, Berchuck, A, Rossing, MA, Jensen, A, Wicklund, KG, Cushing-Haugen, KL, Hogdall, E, Rudolph, A, Thompson, PJ, Wilkens, LR, Kjaer, SK, Carney, ME, Stram, DO, Ramus, SJ, Wu, AH, Pike, MC, and Pearce, CL. "Association Between Menopausal Estrogen-Only Therapy and Ovarian Carcinoma Risk." Obstetrical & Gynecological Survey 71.8 (August 2016): 470-471.
Source
crossref
Published In
Obstetrical and Gynecological Survey
Volume
71
Issue
8
Publish Date
2016
Start Page
470
End Page
471
DOI
10.1097/01.ogx.0000489579.62561.b8

Abstract 3407: Gene expression subtypes of high grade serous ovarian cancer in African American women

Authors
Doherty, JA; Greene, CS; Rudd, JE; Tafe, LJ; Alberg, AJ; Bandera, EV; Barnholtz-Sloan, J; Bondy, M; Cote, ML; Funkhouser, E; Moorman, PG; Peters, ES; Schwartz, AG; Terry, P; Bentley, R; Berchuck, A; Marks, JR; Schildkraut, JM
MLA Citation
Doherty, JA, Greene, CS, Rudd, JE, Tafe, LJ, Alberg, AJ, Bandera, EV, Barnholtz-Sloan, J, Bondy, M, Cote, ML, Funkhouser, E, Moorman, PG, Peters, ES, Schwartz, AG, Terry, P, Bentley, R, Berchuck, A, Marks, JR, and Schildkraut, JM. "Abstract 3407: Gene expression subtypes of high grade serous ovarian cancer in African American women." July 15, 2016.
Source
crossref
Published In
Cancer Research
Volume
76
Issue
14 Supplement
Publish Date
2016
Start Page
3407
End Page
3407
DOI
10.1158/1538-7445.AM2016-3407

Abstract 797: A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer

Authors
Lee, AW; Bomkamp, A; Bandera, EV; Jensen, A; Ramus, SJ; Goodman, MT; Rossing, MA; Modugno, F; Moysich, KB; Chang-Claude, J; Rudolph, A; Gentry-Maharaj, A; Terry, KL; Gayther, SA; Cramer, DW; Doherty, JA; Schildkraut, JM; Kjaer, SK; Ness, RB; Menon, U; Berchuck, A; Mukherjee, B; Roman, L; Pharoah, PD; Chenevix-Trench, G; Wu, AH; Pike, MC; Pearce, CL
MLA Citation
Lee, AW, Bomkamp, A, Bandera, EV, Jensen, A, Ramus, SJ, Goodman, MT, Rossing, MA, Modugno, F, Moysich, KB, Chang-Claude, J, Rudolph, A, Gentry-Maharaj, A, Terry, KL, Gayther, SA, Cramer, DW, Doherty, JA, Schildkraut, JM, Kjaer, SK, Ness, RB, Menon, U, Berchuck, A, Mukherjee, B, Roman, L, Pharoah, PD, Chenevix-Trench, G, Wu, AH, Pike, MC, and Pearce, CL. "Abstract 797: A splicing variant of TERT identified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer." July 15, 2016.
Source
crossref
Published In
Cancer Research
Volume
76
Issue
14 Supplement
Publish Date
2016
Start Page
797
End Page
797
DOI
10.1158/1538-7445.AM2016-797

Assessing the genetic architecture of epithelial ovarian cancer histological subtypes.

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

Authors
Cuellar-Partida, G; Lu, Y; Dixon, SC; Australian Ovarian Cancer Study, ; Fasching, PA; Hein, A; Burghaus, S; Beckmann, MW; Lambrechts, D; Van Nieuwenhuysen, E; Vergote, I; Vanderstichele, A; Doherty, JA; Rossing, MA; Chang-Claude, J; Rudolph, A; Wang-Gohrke, S; Goodman, MT; Bogdanova, N; Dörk, T; Dürst, M; Hillemanns, P; Runnebaum, IB; Antonenkova, N; Butzow, R; Leminen, A; Nevanlinna, H; Pelttari, LM; Edwards, RP; Kelley, JL; Modugno, F; Moysich, KB; Ness, RB; Cannioto, R; Høgdall, E et al.
MLA Citation
Cuellar-Partida, G, Lu, Y, Dixon, SC, Australian Ovarian Cancer Study, , Fasching, PA, Hein, A, Burghaus, S, Beckmann, MW, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Vanderstichele, A, Doherty, JA, Rossing, MA, Chang-Claude, J, Rudolph, A, Wang-Gohrke, S, Goodman, MT, Bogdanova, N, Dörk, T, Dürst, M, Hillemanns, P, Runnebaum, IB, Antonenkova, N, Butzow, R, Leminen, A, Nevanlinna, H, Pelttari, LM, Edwards, RP, Kelley, JL, Modugno, F, Moysich, KB, Ness, RB, Cannioto, R, and Høgdall, E et al. "Assessing the genetic architecture of epithelial ovarian cancer histological subtypes." Human genetics 135.7 (July 2016): 741-756.
PMID
27075448
Source
epmc
Published In
Human Genetics
Volume
135
Issue
7
Publish Date
2016
Start Page
741
End Page
756
DOI
10.1007/s00439-016-1663-9

Chronic Recreational Physical Inactivity and Epithelial Ovarian Cancer Risk: Evidence from the Ovarian Cancer Association Consortium.

Despite a large body of literature evaluating the association between recreational physical activity and epithelial ovarian cancer (EOC) risk, the extant evidence is inconclusive, and little is known about the independent association between recreational physical inactivity and EOC risk. We conducted a pooled analysis of nine studies from the Ovarian Cancer Association Consortium to investigate the association between chronic recreational physical inactivity and EOC risk.In accordance with the 2008 Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. Multivariable logistic regression was utilized to estimate the ORs and 95% confidence intervals (CI) for the association between inactivity and EOC risk overall and by subgroups based upon histotype, menopausal status, race, and body mass index.The current analysis included data from 8,309 EOC patients and 12,612 controls. We observed a significant positive association between inactivity and EOC risk (OR = 1.34; 95% CI, 1.14-1.57), and similar associations were observed for each histotype.In this large pooled analysis examining the association between recreational physical inactivity and EOC risk, we observed consistent evidence of an association between chronic inactivity and all EOC histotypes.These data add to the growing body of evidence suggesting that inactivity is an independent risk factor for cancer. If the apparent association between inactivity and EOC risk is substantiated, additional work via targeted interventions should be pursued to characterize the dose of activity required to mitigate the risk of this highly fatal disease. Cancer Epidemiol Biomarkers Prev; 25(7); 1114-24. ©2016 AACR.

Authors
Cannioto, R; LaMonte, MJ; Risch, HA; Hong, C-C; Sucheston-Campbell, LE; Eng, KH; Brian Szender, J; Chang-Claude, J; Schmalfeldt, B; Klapdor, R; Gower, E; Minlikeeva, AN; Zirpoli, GR; Bandera, EV; Berchuck, A; Cramer, D; Doherty, JA; Edwards, RP; Fridley, BL; Goode, EL; Goodman, MT; Hogdall, E; Hosono, S; Jensen, A; Jordan, S; Australian Ovarian Cancer Study Group, ; Kjaer, SK; Matsuo, K; Ness, RB; Olsen, CM; Olson, SH; Leigh Pearce, C; Pike, MC; Anne Rossing, M; Szamreta, EA; Thompson, PJ et al.
MLA Citation
Cannioto, R, LaMonte, MJ, Risch, HA, Hong, C-C, Sucheston-Campbell, LE, Eng, KH, Brian Szender, J, Chang-Claude, J, Schmalfeldt, B, Klapdor, R, Gower, E, Minlikeeva, AN, Zirpoli, GR, Bandera, EV, Berchuck, A, Cramer, D, Doherty, JA, Edwards, RP, Fridley, BL, Goode, EL, Goodman, MT, Hogdall, E, Hosono, S, Jensen, A, Jordan, S, Australian Ovarian Cancer Study Group, , Kjaer, SK, Matsuo, K, Ness, RB, Olsen, CM, Olson, SH, Leigh Pearce, C, Pike, MC, Anne Rossing, M, Szamreta, EA, and Thompson, PJ et al. "Chronic Recreational Physical Inactivity and Epithelial Ovarian Cancer Risk: Evidence from the Ovarian Cancer Association Consortium." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 25.7 (July 2016): 1114-1124.
PMID
27197285
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
25
Issue
7
Publish Date
2016
Start Page
1114
End Page
1124
DOI
10.1158/1055-9965.epi-15-1330

Recreational physical inactivity and mortality in women with invasive epithelial ovarian cancer: evidence from the Ovarian Cancer Association Consortium.

Little is known about modifiable behaviours that may be associated with epithelial ovarian cancer (EOC) survival. We conducted a pooled analysis of 12 studies from the Ovarian Cancer Association Consortium to investigate the association between pre-diagnostic physical inactivity and mortality.Participants included 6806 women with a primary diagnosis of invasive EOC. In accordance with the Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. We utilised Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) representing the associations of inactivity with mortality censored at 5 years.In multivariate analysis, inactive women had significantly higher mortality risks, with (HR=1.34, 95% CI: 1.18-1.52) and without (HR=1.22, 95% CI: 1.12-1.33) further adjustment for residual disease, respectively.In this large pooled analysis, lack of recreational physical activity was associated with increased mortality among women with invasive EOC.

Authors
Cannioto, RA; LaMonte, MJ; Kelemen, LE; Risch, HA; Eng, KH; Minlikeeva, AN; Hong, C-C; Szender, JB; Sucheston-Campbell, L; Joseph, JM; Berchuck, A; Chang-Claude, J; Cramer, DW; DeFazio, A; Diergaarde, B; Dörk, T; Doherty, JA; Edwards, RP; Fridley, BL; Friel, G; Goode, EL; Goodman, MT; Hillemanns, P; Hogdall, E; Hosono, S; Kelley, JL; Kjaer, SK; Klapdor, R; Matsuo, K; Odunsi, K; Nagle, CM; Olsen, CM; Paddock, LE; Pearce, CL; Pike, MC; Rossing, MA; Schmalfeldt, B; Segal, BH; Szamreta, EA et al.
MLA Citation
Cannioto, RA, LaMonte, MJ, Kelemen, LE, Risch, HA, Eng, KH, Minlikeeva, AN, Hong, C-C, Szender, JB, Sucheston-Campbell, L, Joseph, JM, Berchuck, A, Chang-Claude, J, Cramer, DW, DeFazio, A, Diergaarde, B, Dörk, T, Doherty, JA, Edwards, RP, Fridley, BL, Friel, G, Goode, EL, Goodman, MT, Hillemanns, P, Hogdall, E, Hosono, S, Kelley, JL, Kjaer, SK, Klapdor, R, Matsuo, K, Odunsi, K, Nagle, CM, Olsen, CM, Paddock, LE, Pearce, CL, Pike, MC, Rossing, MA, Schmalfeldt, B, Segal, BH, and Szamreta, EA et al. "Recreational physical inactivity and mortality in women with invasive epithelial ovarian cancer: evidence from the Ovarian Cancer Association Consortium." British Journal of Cancer 115.1 (June 14, 2016): 95-101. (letter)
PMID
27299959
Source
epmc
Published In
British Journal of Cancer
Volume
115
Issue
1
Publish Date
2016
Start Page
95
End Page
101
DOI
10.1038/bjc.2016.153

The Association Between Body Mass Index and Presenting Symptoms in African American Women with Ovarian Cancer.

Ovarian cancer, the most lethal gynecologic malignancy, typically comes to clinical attention due to nonspecific gastrointestinal or pelvic symptoms. African Americans with ovarian cancer have a greater mortality burden than whites and are also much more likely to be obese. The objective of this study is to explore whether the presentation and duration of symptoms differ by body mass index (BMI) in African Americans with ovarian cancer.We conducted a case-only analysis using data from a multicenter population-based study of invasive epithelial ovarian cancer in African American women. Information on risk factors and symptoms leading to diagnosis was obtained in a telephone interview. Frequency and duration of symptoms by BMI categories were compared using logistic regression and linear regression analyses.Of the 326 women, ∼60% was obese (BMI ≥30), with 30.8% having a BMI ≥35 kg/m(2). Ninety-four percent of women reported ≥1 symptom during the year before diagnosis. We observed differences in frequency of symptoms by BMI categories, with most being reported more frequently by the heaviest women. The reported duration of symptoms was longer in women with higher BMI, with statistically significant trend tests for 6 of the 10 symptoms evaluated.BMI appears to impact ovarian cancer symptomatology. Women with higher BMI report having symptoms for a longer period of time before diagnosis of ovarian cancer. Healthcare providers should be vigilant and consider ovarian cancer in the differential diagnosis for obese women presenting with abdominal and pelvic symptoms.

Authors
Erondu, CO; Alberg, AJ; Bandera, EV; Barnholtz-Sloan, J; Bondy, M; Cote, ML; Funkhouser, E; Peters, E; Schwartz, AG; Terry, PD; Wallace, K; Akushevich, L; Wang, F; Crankshaw, S; Berchuck, A; Schildkraut, JM; Moorman, PG
MLA Citation
Erondu, CO, Alberg, AJ, Bandera, EV, Barnholtz-Sloan, J, Bondy, M, Cote, ML, Funkhouser, E, Peters, E, Schwartz, AG, Terry, PD, Wallace, K, Akushevich, L, Wang, F, Crankshaw, S, Berchuck, A, Schildkraut, JM, and Moorman, PG. "The Association Between Body Mass Index and Presenting Symptoms in African American Women with Ovarian Cancer." Journal of women's health (2002) 25.6 (June 2016): 571-578.
PMID
26886855
Source
epmc
Published In
Journal of Women's Health
Volume
25
Issue
6
Publish Date
2016
Start Page
571
End Page
578
DOI
10.1089/jwh.2015.5359

The influence of clinical and genetic factors on patient outcome in small cell carcinoma of the ovary, hypercalcemic type.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive tumor, with long term survival at ~30% in early stage disease. SCCOHT is caused by germline and somatic SMARCA4 mutations, but the effect of the mutation type on patients remains unknown. Furthermore, the rarity of SCCOHT has resulted in varied treatment, with no standardized protocols. We analyzed 293 cases to determine the effect of treatment modalities and SMARCA4 mutations on patient diagnosis and outcome.In 293 SCCOHT patients we collected information on age and stage at diagnosis, treatment modality (surgery, chemotherapy, radiotherapy, and/or high-dose chemotherapy with autologous stem cell rescue (HDC-aSCR)), SMARCA4 mutation origin (germline/somatic), and overall survival. Cox analysis and log-rank tests were performed on 257 cases with available survival data.The strongest prognostic factors were stage at diagnosis (p=2.72e-15) and treatment modality (p=3.87e-13). For FIGO stages II-IV, 5-year survival was 71% for patients who received HDC-aSCR, compared to 25% in patients who received conventional chemotherapy alone following surgery (p=0.002). Patients aged ≥40 had a worse outcome than younger patients (p=0.04). Twenty-six of 60 tested patients carried a germline SMARCA4 mutation, including all patients diagnosed <15years; carriers presented at a younger age than non-carriers (p=0.02).Stage at diagnosis is the most significant prognostic factor in SCCOHT and consolidation with HDC-aSCR may provide the best opportunity for long-term survival. The large fraction of SMARCA4 germline mutations carriers warrants genetic counseling for all patients.

Authors
Witkowski, L; Goudie, C; Ramos, P; Boshari, T; Brunet, J-S; Karnezis, AN; Longy, M; Knost, JA; Saloustros, E; McCluggage, WG; Stewart, CJR; Hendricks, WPD; Cunliffe, H; Huntsman, DG; Pautier, P; Levine, DA; Trent, JM; Berchuck, A; Hasselblatt, M; Foulkes, WD
MLA Citation
Witkowski, L, Goudie, C, Ramos, P, Boshari, T, Brunet, J-S, Karnezis, AN, Longy, M, Knost, JA, Saloustros, E, McCluggage, WG, Stewart, CJR, Hendricks, WPD, Cunliffe, H, Huntsman, DG, Pautier, P, Levine, DA, Trent, JM, Berchuck, A, Hasselblatt, M, and Foulkes, WD. "The influence of clinical and genetic factors on patient outcome in small cell carcinoma of the ovary, hypercalcemic type." Gynecologic oncology 141.3 (June 2016): 454-460.
PMID
26975901
Source
epmc
Published In
Gynecologic Oncology
Volume
141
Issue
3
Publish Date
2016
Start Page
454
End Page
460
DOI
10.1016/j.ygyno.2016.03.013

What Women and Their Physicians Need to Know About the UKCTOCS Study and Ovarian Cancer Screening.

MLA Citation
"What Women and Their Physicians Need to Know About the UKCTOCS Study and Ovarian Cancer Screening." American family physician 93.11 (June 2016): 903-904.
PMID
27331230
Source
epmc
Published In
American family physician
Volume
93
Issue
11
Publish Date
2016
Start Page
903
End Page
904

Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study.

Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC.We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis.Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81).Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.

Authors
Dixon, SC; Nagle, CM; Thrift, AP; Pharoah, PD; Pearce, CL; Zheng, W; Painter, JN; AOCS Group & Australian Cancer Study (Ovarian Cancer), ; Chenevix-Trench, G; Fasching, PA; Beckmann, MW; Lambrechts, D; Vergote, I; Lambrechts, S; Van Nieuwenhuysen, E; Rossing, MA; Doherty, JA; Wicklund, KG; Chang-Claude, J; Rudolph, A; Moysich, KB; Odunsi, K; Goodman, MT; Wilkens, LR; Thompson, PJ; Shvetsov, YB; Dörk, T; Park-Simon, T-W; Hillemanns, P; Bogdanova, N; Butzow, R; Nevanlinna, H; Pelttari, LM et al.
MLA Citation
Dixon, SC, Nagle, CM, Thrift, AP, Pharoah, PD, Pearce, CL, Zheng, W, Painter, JN, AOCS Group & Australian Cancer Study (Ovarian Cancer), , Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Lambrechts, S, Van Nieuwenhuysen, E, Rossing, MA, Doherty, JA, Wicklund, KG, Chang-Claude, J, Rudolph, A, Moysich, KB, Odunsi, K, Goodman, MT, Wilkens, LR, Thompson, PJ, Shvetsov, YB, Dörk, T, Park-Simon, T-W, Hillemanns, P, Bogdanova, N, Butzow, R, Nevanlinna, H, and Pelttari, LM et al. "Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study." International journal of epidemiology 45.3 (June 2016): 884-895.
PMID
27401727
Source
epmc
Published In
International Journal of Epidemiology
Volume
45
Issue
3
Publish Date
2016
Start Page
884
End Page
895
DOI
10.1093/ije/dyw158

No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer.

Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370.Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers).We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations.rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.

Authors
Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modifiers of BRCA1 and BRCA2, ; Hollestelle, A; van der Baan, FH; Berchuck, A; Johnatty, SE; Aben, KK; Agnarsson, BA; Aittomäki, K; Alducci, E; Andrulis, IL; Anton-Culver, H; Antonenkova, NN; Antoniou, AC; Apicella, C; Arndt, V; Arnold, N; Arun, BK; Arver, B; Ashworth, A; Australian Ovarian Cancer Study Group, ; Baglietto, L; Balleine, R; Bandera, EV; Barrowdale, D; Bean, YT; Beckmann, L; Beckmann, MW et al.
MLA Citation
Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modifiers of BRCA1 and BRCA2, , Hollestelle, A, van der Baan, FH, Berchuck, A, Johnatty, SE, Aben, KK, Agnarsson, BA, Aittomäki, K, Alducci, E, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Antoniou, AC, Apicella, C, Arndt, V, Arnold, N, Arun, BK, Arver, B, Ashworth, A, Australian Ovarian Cancer Study Group, , Baglietto, L, Balleine, R, Bandera, EV, Barrowdale, D, Bean, YT, Beckmann, L, and Beckmann, MW et al. "No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer." Gynecologic oncology 141.2 (May 2016): 386-401. (Review)
PMID
25940428
Source
epmc
Published In
Gynecologic Oncology
Volume
141
Issue
2
Publish Date
2016
Start Page
386
End Page
401
DOI
10.1016/j.ygyno.2015.04.034

Assessment of Multifactor Gene-Environment Interactions and Ovarian Cancer Risk: Candidate Genes, Obesity, and Hormone-Related Risk Factors.

Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene-environment interactions related to hormone-related risk factors could differ between obese and non-obese women.We considered interactions between 11,441 SNPs within 80 candidate genes related to hormone biosynthesis and metabolism and insulin-like growth factors with six hormone-related factors (oral contraceptive use, parity, endometriosis, tubal ligation, hormone replacement therapy, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case-control studies (6,247 cases; 10,379 controls). Histotype-specific analyses were also completed.SNPs in the following candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 × 10(-6)) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 × 10(-5)). The most notable obesity-gene-hormone risk factor interaction was within INSR (rs113759408, parity, histology = endometrioid, P = 8.8 × 10(-6)).We have demonstrated the feasibility of assessing multifactor interactions in large genetic epidemiology studies. Follow-up studies are necessary to assess the robustness of our findings for ESR1, CYP11A1, IGF1R, CYP11B1, INSR, and IGFBP2 Future work is needed to develop powerful statistical methods able to detect these complex interactions.Assessment of multifactor interaction is feasible, and, here, suggests that the relationship between genetic variants within candidate genes and hormone-related risk factors may vary EOC susceptibility. Cancer Epidemiol Biomarkers Prev; 25(5); 780-90. ©2016 AACR.

Authors
Usset, JL; Raghavan, R; Tyrer, JP; McGuire, V; Sieh, W; Webb, P; Chang-Claude, J; Rudolph, A; Anton-Culver, H; Berchuck, A; Brinton, L; Cunningham, JM; DeFazio, A; Doherty, JA; Edwards, RP; Gayther, SA; Gentry-Maharaj, A; Goodman, MT; Høgdall, E; Jensen, A; Johnatty, SE; Kiemeney, LA; Kjaer, SK; Larson, MC; Lurie, G; Massuger, L; Menon, U; Modugno, F; Moysich, KB; Ness, RB; Pike, MC; Ramus, SJ; Rossing, MA; Rothstein, J; Song, H; Thompson, PJ; van den Berg, DJ; Vierkant, RA; Wang-Gohrke, S et al.
MLA Citation
Usset, JL, Raghavan, R, Tyrer, JP, McGuire, V, Sieh, W, Webb, P, Chang-Claude, J, Rudolph, A, Anton-Culver, H, Berchuck, A, Brinton, L, Cunningham, JM, DeFazio, A, Doherty, JA, Edwards, RP, Gayther, SA, Gentry-Maharaj, A, Goodman, MT, Høgdall, E, Jensen, A, Johnatty, SE, Kiemeney, LA, Kjaer, SK, Larson, MC, Lurie, G, Massuger, L, Menon, U, Modugno, F, Moysich, KB, Ness, RB, Pike, MC, Ramus, SJ, Rossing, MA, Rothstein, J, Song, H, Thompson, PJ, van den Berg, DJ, Vierkant, RA, and Wang-Gohrke, S et al. "Assessment of Multifactor Gene-Environment Interactions and Ovarian Cancer Risk: Candidate Genes, Obesity, and Hormone-Related Risk Factors." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 25.5 (May 2016): 780-790.
PMID
26976855
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
25
Issue
5
Publish Date
2016
Start Page
780
End Page
790
DOI
10.1158/1055-9965.epi-15-1039

Association Between Menopausal Estrogen-Only Therapy and Ovarian Carcinoma Risk.

To describe the association between postmenopausal estrogen-only therapy use and risk of ovarian carcinoma, specifically with regard to disease histotype and duration and timing of use.We conducted a pooled analysis of 906 women with ovarian carcinoma and 1,220 women in a control group; all 2,126 women included reported having had a hysterectomy. Ten population-based case-control studies participating in the Ovarian Cancer Association Consortium, an international consortium whose goal is to combine data from many studies with similar methods so reliable assessments of risk factors can be determined, were included. Self-reported questionnaire data from each study were harmonized and conditional logistic regression was used to examine estrogen-only therapy's histotype-specific and duration and recency of use associations.Forty-three and a half percent of the women in the control group reported previous use of estrogen-only therapy. Compared with them, current or recent estrogen-only therapy use was associated with an increased risk for the serous (51.4%, odds ratio [OR] 1.63, 95% confidence interval [CI] 1.27-2.09) and endometrioid (48.6%, OR 2.00, 95% CI 1.17-3.41) histotypes. In addition, statistically significant trends in risk according to duration of use were seen among current or recent postmenopausal estrogen-only therapy users for both ovarian carcinoma histotypes (Ptrend<.001 for serous and endometrioid). Compared with women in the control group, current or recent users for 10 years or more had increased risks of serous ovarian carcinoma (36.8%, OR 1.73, 95% CI 1.26-2.38) and endometrioid ovarian carcinoma (34.9%, OR 4.03, 95% CI 1.91-8.49).We found evidence of an increased risk of serous and endometrioid ovarian carcinoma associated with postmenopausal estrogen-only therapy use, particularly of long duration. These findings emphasize that risk may be associated with extended estrogen-only therapy use.

Authors
Lee, AW; Ness, RB; Roman, LD; Terry, KL; Schildkraut, JM; Chang-Claude, J; Doherty, JA; Menon, U; Cramer, DW; Gayther, SA; Risch, H; Gentry-Maharaj, A; Goodman, MT; Modugno, F; Eilber, U; Moysich, KB; Berchuck, A; Rossing, MA; Jensen, A; Wicklund, KG; Cushing-Haugen, KL; Hogdall, E; Rudolph, A; Thompson, PJ; Wilkens, LR; Kjaer, SK; Carney, ME; Stram, DO; Ramus, SJ; Wu, AH; Pike, MC; Pearce, CL; Ovarian Cancer Association Consortium,
MLA Citation
Lee, AW, Ness, RB, Roman, LD, Terry, KL, Schildkraut, JM, Chang-Claude, J, Doherty, JA, Menon, U, Cramer, DW, Gayther, SA, Risch, H, Gentry-Maharaj, A, Goodman, MT, Modugno, F, Eilber, U, Moysich, KB, Berchuck, A, Rossing, MA, Jensen, A, Wicklund, KG, Cushing-Haugen, KL, Hogdall, E, Rudolph, A, Thompson, PJ, Wilkens, LR, Kjaer, SK, Carney, ME, Stram, DO, Ramus, SJ, Wu, AH, Pike, MC, Pearce, CL, and Ovarian Cancer Association Consortium, . "Association Between Menopausal Estrogen-Only Therapy and Ovarian Carcinoma Risk." Obstetrics and gynecology 127.5 (May 2016): 828-836.
PMID
27054934
Source
epmc
Published In
Obstetrics & Gynecology (Elsevier)
Volume
127
Issue
5
Publish Date
2016
Start Page
828
End Page
836
DOI
10.1097/aog.0000000000001387

The association between socioeconomic status and tumour stage at diagnosis of ovarian cancer: A pooled analysis of 18 case-control studies.

Socioeconomic status (SES) is a known predictor of survival for several cancers and it has been suggested that SES differences affecting tumour stage at diagnosis may be the most important explanatory factor for this. However, only a limited number of studies have investigated SES differences in tumour stage at diagnosis of ovarian cancer. In a pooled analysis, we investigated whether SES as represented by level of education is predictive for advanced tumour stage at diagnosis of ovarian cancer, overall and by histotype. The effect of cigarette smoking and body mass index (BMI) on the association was also evaluated.From 18 case-control studies, we obtained information on 10,601 women diagnosed with epithelial ovarian cancer. Study specific odds ratios (ORs) with corresponding 95% confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio (pOR) using a random effects model.Overall, women who completed ≤high school had an increased risk of advanced tumour stage at diagnosis compared with women who completed >high school (pOR 1.15; 95% CI 1.03-1.28). The risk estimates for the different histotypes of ovarian cancer resembled that observed for ovarian cancers combined but did not reach statistical significance. Our results were unchanged when we included BMI and cigarette smoking.Lower level of education was associated with an increased risk of advanced tumour stage at diagnosis of ovarian cancer. The observed socioeconomic difference in stage at diagnosis of ovarian cancer calls for further studies on how to reduce this diagnostic delay.

Authors
Præstegaard, C; Kjaer, SK; Nielsen, TSS; Jensen, SM; Webb, PM; Nagle, CM; Høgdall, E; Risch, HA; Rossing, MA; Doherty, JA; Wicklund, KG; Goodman, MT; Modugno, F; Moysich, K; Ness, RB; Edwards, RP; Goode, EL; Winham, SJ; Fridley, BL; Cramer, DW; Terry, KL; Schildkraut, JM; Berchuck, A; Bandera, EV; Paddock, L; Kiemeney, LA; Massuger, LF; Wentzensen, N; Pharoah, P; Song, H; Whittemore, AS; McGuire, V; Sieh, W; Rothstein, J; Anton-Culver, H; Ziogas, A; Menon, U; Gayther, SA; Ramus, SJ et al.
MLA Citation
Præstegaard, C, Kjaer, SK, Nielsen, TSS, Jensen, SM, Webb, PM, Nagle, CM, Høgdall, E, Risch, HA, Rossing, MA, Doherty, JA, Wicklund, KG, Goodman, MT, Modugno, F, Moysich, K, Ness, RB, Edwards, RP, Goode, EL, Winham, SJ, Fridley, BL, Cramer, DW, Terry, KL, Schildkraut, JM, Berchuck, A, Bandera, EV, Paddock, L, Kiemeney, LA, Massuger, LF, Wentzensen, N, Pharoah, P, Song, H, Whittemore, AS, McGuire, V, Sieh, W, Rothstein, J, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, and Ramus, SJ et al. "The association between socioeconomic status and tumour stage at diagnosis of ovarian cancer: A pooled analysis of 18 case-control studies." Cancer epidemiology 41 (April 2016): 71-79.
PMID
26851750
Source
epmc
Published In
Cancer Epidemiology: the international journal of cancer epidemiology, detection and prevention
Volume
41
Publish Date
2016
Start Page
71
End Page
79
DOI
10.1016/j.canep.2016.01.012

Subthreshold posttraumatic stress disorder: A meta-analytic review of DSM-IV prevalence and a proposed DSM-5 approach to measurement.

Subthreshold posttraumatic stress disorder (PTSD) is a chronic condition that is often ignored, the cumulative effects of which can negatively impact an individual's quality of life and overall health care costs. However, subthreshold PTSD prevalence rates and impairment remain unclear due to variations in research methodology. This study examined the existing literature in order to recommend approaches to standardize subthreshold PTSD assessment. We conducted (a) a meta-analysis of subthreshold PTSD prevalence rates and (b) compared functional impairment associated with the 3 most commonly studied subthreshold PTSD definitions. Meta-analytic results revealed that the average prevalence rate of subthreshold PTSD across studies was 14.7%, with a lower rate (12.6%) among the most methodologically rigorous studies and higher rate (15.6%) across less rigorous studies. There were significant methodological differences among reviewed studies with regard to definition, measurement, and population. Different definitions led to prevalence rates ranging between 13.7% and 16.4%. Variability in prevalence rates most related to population and sample composition, with trauma type and community (vs. epidemiological) samples significantly impacting heterogeneity. Qualitative information gathered from studies presenting functional correlates supported current evidence that psychological and behavioral parameters were worse among subthreshold PTSD groups compared with no-PTSD groups, but not as severe as impairment in PTSD groups. Several studies also reported significant increased risk of suicidality and hopelessness as well as higher health care utilization rates among those with subthreshold PTSD (compared with trauma exposed no-PTSD samples). Based on findings, we propose recommendations for developing a standard approach to evaluation of subthreshold PTSD.

Authors
Brancu, M; Mann-Wrobel, M; Beckham, JC; Wagner, HR; Elliott, A; Robbins, AT; Wong, M; Berchuck, AE; Runnals, JJ
MLA Citation
Brancu, M, Mann-Wrobel, M, Beckham, JC, Wagner, HR, Elliott, A, Robbins, AT, Wong, M, Berchuck, AE, and Runnals, JJ. "Subthreshold posttraumatic stress disorder: A meta-analytic review of DSM-IV prevalence and a proposed DSM-5 approach to measurement." Psychological trauma : theory, research, practice and policy 8.2 (March 2016): 222-232.
PMID
26390108
Source
epmc
Published In
Psychological Trauma: Theory, Research, Practice, and Policy
Volume
8
Issue
2
Publish Date
2016
Start Page
222
End Page
232
DOI
10.1037/tra0000078

Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer.

While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC).The primary patient set (Set 1) included 14 independent EOC studies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped).No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta = 1.1E-6, HRSet1 = 1.17, HRSet2 = 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E-6; Pcorrected = 0.01).Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed.This study represents the first exome-wide association study of EOC survival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study. Cancer Epidemiol Biomarkers Prev; 25(3); 446-54. ©2016 AACR.

Authors
Winham, SJ; Pirie, A; Chen, YA; Larson, MC; Fogarty, ZC; Earp, MA; Anton-Culver, H; Bandera, EV; Cramer, D; Doherty, JA; Goodman, MT; Gronwald, J; Karlan, BY; Kjaer, SK; Levine, DA; Menon, U; Ness, RB; Pearce, CL; Pejovic, T; Rossing, MA; Wentzensen, N; Bean, YT; Bisogna, M; Brinton, LA; Carney, ME; Cunningham, JM; Cybulski, C; deFazio, A; Dicks, EM; Edwards, RP; Gayther, SA; Gentry-Maharaj, A; Gore, M; Iversen, ES; Jensen, A; Johnatty, SE; Lester, J; Lin, H-Y; Lissowska, J; Lubinski, J et al.
MLA Citation
Winham, SJ, Pirie, A, Chen, YA, Larson, MC, Fogarty, ZC, Earp, MA, Anton-Culver, H, Bandera, EV, Cramer, D, Doherty, JA, Goodman, MT, Gronwald, J, Karlan, BY, Kjaer, SK, Levine, DA, Menon, U, Ness, RB, Pearce, CL, Pejovic, T, Rossing, MA, Wentzensen, N, Bean, YT, Bisogna, M, Brinton, LA, Carney, ME, Cunningham, JM, Cybulski, C, deFazio, A, Dicks, EM, Edwards, RP, Gayther, SA, Gentry-Maharaj, A, Gore, M, Iversen, ES, Jensen, A, Johnatty, SE, Lester, J, Lin, H-Y, Lissowska, J, and Lubinski, J et al. "Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 25.3 (March 2016): 446-454.
PMID
26747452
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
25
Issue
3
Publish Date
2016
Start Page
446
End Page
454
DOI
10.1158/1055-9965.epi-15-0240

A targeted genetic association study of epithelial ovarian cancer susceptibility.

Genome-wide association studies have identified several common susceptibility alleles for epithelial ovarian cancer (EOC). To further understand EOC susceptibility, we examined previously ungenotyped candidate variants, including uncommon variants and those residing within known susceptibility loci.At nine of eleven previously published EOC susceptibility regions (2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13), novel variants were identified that were more strongly associated with risk than previously reported variants. Beyond known susceptibility regions, no variants were found to be associated with EOC risk at genome-wide statistical significance (p <5x10(-8)), nor were any significant after Bonferroni correction for 17,000 variants (p< 3x10-6).A customized genotyping array was used to assess over 17,000 variants in coding, non-coding, regulatory, and known susceptibility regions in 4,973 EOC cases and 5,640 controls from 13 independent studies. Susceptibility for EOC overall and for select histotypes was evaluated using logistic regression adjusted for age, study site, and population substructure.Given the novel variants identified within the 2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13 regions, larger follow-up genotyping studies, using imputation where necessary, are needed for fine-mapping and confirmation of low frequency variants that fall below statistical significance.

Authors
Earp, M; Winham, SJ; Larson, N; Permuth, JB; Sicotte, H; Chien, J; Anton-Culver, H; Bandera, EV; Berchuck, A; Cook, LS; Cramer, D; Doherty, JA; Goodman, MT; Levine, DA; Monteiro, ANA; Ness, RB; Pearce, CL; Rossing, MA; Tworoger, SS; Wentzensen, N; Bisogna, M; Brinton, L; Brooks-Wilson, A; Carney, ME; Cunningham, JM; Edwards, RP; Fogarty, ZC; Iversen, ES; Kraft, P; Larson, MC; Le, ND; Lin, H-Y; Lissowska, J; Modugno, F; Moysich, KB; Olson, SH; Pike, MC; Poole, EM; Rider, DN; Terry, KL et al.
MLA Citation
Earp, M, Winham, SJ, Larson, N, Permuth, JB, Sicotte, H, Chien, J, Anton-Culver, H, Bandera, EV, Berchuck, A, Cook, LS, Cramer, D, Doherty, JA, Goodman, MT, Levine, DA, Monteiro, ANA, Ness, RB, Pearce, CL, Rossing, MA, Tworoger, SS, Wentzensen, N, Bisogna, M, Brinton, L, Brooks-Wilson, A, Carney, ME, Cunningham, JM, Edwards, RP, Fogarty, ZC, Iversen, ES, Kraft, P, Larson, MC, Le, ND, Lin, H-Y, Lissowska, J, Modugno, F, Moysich, KB, Olson, SH, Pike, MC, Poole, EM, Rider, DN, and Terry, KL et al. "A targeted genetic association study of epithelial ovarian cancer susceptibility." Oncotarget 7.7 (February 2016): 7381-7389.
PMID
26848776
Source
epmc
Published In
Oncotarget
Volume
7
Issue
7
Publish Date
2016
Start Page
7381
End Page
7389
DOI
10.18632/oncotarget.7121

Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer.

Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P=7x10-5, HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression.

Authors
French, JD; Johnatty, SE; Lu, Y; Beesley, J; Gao, B; Kalimutho, M; Henderson, MJ; Russell, AJ; Kar, S; Chen, X; Hillman, KM; Kaufmann, S; Sivakumaran, H; O'Reilly, M; Wang, C; Korbie, DJ; Australian Ovarian Cancer Study Group, ; Australian Ovarian Cancer Study, ; Lambrechts, D; Despierre, E; Van Nieuwenhuysen, E; Lambrechts, S; Vergote, I; Karlan, B; Lester, J; Orsulic, S; Walsh, C; Fasching, PA; Beckmann, MW; Ekici, AB; Hein, A; Matsuo, K; Hosono, S; Pisterer, J; Hillemanns, P; Nakanishi, T et al.
MLA Citation
French, JD, Johnatty, SE, Lu, Y, Beesley, J, Gao, B, Kalimutho, M, Henderson, MJ, Russell, AJ, Kar, S, Chen, X, Hillman, KM, Kaufmann, S, Sivakumaran, H, O'Reilly, M, Wang, C, Korbie, DJ, Australian Ovarian Cancer Study Group, , Australian Ovarian Cancer Study, , Lambrechts, D, Despierre, E, Van Nieuwenhuysen, E, Lambrechts, S, Vergote, I, Karlan, B, Lester, J, Orsulic, S, Walsh, C, Fasching, PA, Beckmann, MW, Ekici, AB, Hein, A, Matsuo, K, Hosono, S, Pisterer, J, Hillemanns, P, and Nakanishi, T et al. "Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer." Oncotarget 7.6 (February 2016): 6353-6368.
PMID
26840454
Source
epmc
Published In
Oncotarget
Volume
7
Issue
6
Publish Date
2016
Start Page
6353
End Page
6368
DOI
10.18632/oncotarget.7047

Prospective Evaluation of Lymph Node Processing at Staging Surgery for High-Grade Endometrial Cancer

Authors
Ehrisman, JA; Abbott, S; Harmon, Z; Secord, AA; Berchuck, A; Lee, PS; Valea, FA; Broadwater, G; Li, X; Havrilesky, LJ; Hall, A
MLA Citation
Ehrisman, JA, Abbott, S, Harmon, Z, Secord, AA, Berchuck, A, Lee, PS, Valea, FA, Broadwater, G, Li, X, Havrilesky, LJ, and Hall, A. "Prospective Evaluation of Lymph Node Processing at Staging Surgery for High-Grade Endometrial Cancer." February 2016.
Source
wos-lite
Published In
Modern Pathology
Volume
29
Publish Date
2016
Start Page
282A
End Page
282A

BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers.

The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers.Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided.The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed.Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.

Authors
Meeks, HD; Song, H; Michailidou, K; Bolla, MK; Dennis, J; Wang, Q; Barrowdale, D; Frost, D; EMBRACE, ; McGuffog, L; Ellis, S; Feng, B; Buys, SS; Hopper, JL; Southey, MC; Tesoriero, A; kConFab Investigators, ; James, PA; Bruinsma, F; Campbell, IG; Australia Ovarian Cancer Study Group, ; Broeks, A; Schmidt, MK; Hogervorst, FBL; HEBON, ; Beckman, MW; Fasching, PA; Fletcher, O; Johnson, N; Sawyer, EJ; Riboli, E; Banerjee, S; Menon, U; Tomlinson, I; Burwinkel, B; Hamann, U; Marme, F; Rudolph, A et al.
MLA Citation
Meeks, HD, Song, H, Michailidou, K, Bolla, MK, Dennis, J, Wang, Q, Barrowdale, D, Frost, D, EMBRACE, , McGuffog, L, Ellis, S, Feng, B, Buys, SS, Hopper, JL, Southey, MC, Tesoriero, A, kConFab Investigators, , James, PA, Bruinsma, F, Campbell, IG, Australia Ovarian Cancer Study Group, , Broeks, A, Schmidt, MK, Hogervorst, FBL, HEBON, , Beckman, MW, Fasching, PA, Fletcher, O, Johnson, N, Sawyer, EJ, Riboli, E, Banerjee, S, Menon, U, Tomlinson, I, Burwinkel, B, Hamann, U, Marme, F, and Rudolph, A et al. "BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers." Journal of the National Cancer Institute 108.2 (February 2016).
PMID
26586665
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
108
Issue
2
Publish Date
2016
DOI
10.1093/jnci/djv315

Investigation of small GTPase genes in epithelial ovarian cancer.

Authors
Lin, H-Y; Xiong, Y; Tyrer, J; Marchion, DC; Monteiro, ANA; Berchuck, A; Schildkraut, JM; Goode, EL; Ramus, SJ; Gayther, SA; Pharoah, PDP; Narod, SA; Sellers, TA; Phelan, CM
MLA Citation
Lin, H-Y, Xiong, Y, Tyrer, J, Marchion, DC, Monteiro, ANA, Berchuck, A, Schildkraut, JM, Goode, EL, Ramus, SJ, Gayther, SA, Pharoah, PDP, Narod, SA, Sellers, TA, and Phelan, CM. "Investigation of small GTPase genes in epithelial ovarian cancer." CLINICAL CANCER RESEARCH 22 (January 15, 2016).
Source
wos-lite
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
22
Publish Date
2016

Evidence of a genetic link between endometriosis and ovarian cancer.

To evaluate whether endometriosis-associated genetic variation affects risk of ovarian cancer.Pooled genetic analysis.University hospital.Genetic data from 46,176 participants (15,361 ovarian cancer cases and 30,815 controls) from 41 ovarian cancer studies.None.Endometriosis-associated genetic variation and ovarian cancer.There was significant evidence of an association between endometriosis-related genetic variation and ovarian cancer risk, especially for the high-grade serous and clear cell histotypes. Overall we observed 15 significant burden statistics, which was three times more than expected.By focusing on candidate regions from a phenotype associated with ovarian cancer, we have shown a clear genetic link between endometriosis and ovarian cancer that warrants further follow-up. The functional significance of the identified regions and SNPs is presently uncertain, though future fine mapping and histotype-specific functional analyses may shed light on the etiologies of both gynecologic conditions.

Authors
Lee, AW; Templeman, C; Stram, DA; Beesley, J; Tyrer, J; Berchuck, A; Pharoah, PP; Chenevix-Trench, G; Pearce, CL; Ovarian Cancer Association Consortium,
MLA Citation
Lee, AW, Templeman, C, Stram, DA, Beesley, J, Tyrer, J, Berchuck, A, Pharoah, PP, Chenevix-Trench, G, Pearce, CL, and Ovarian Cancer Association Consortium, . "Evidence of a genetic link between endometriosis and ovarian cancer." Fertility and sterility 105.1 (January 2016): 35-43.e1-10-.
PMID
26477498
Source
epmc
Published In
Fertility and Sterility
Volume
105
Issue
1
Publish Date
2016
Start Page
35-43.e1-10
DOI
10.1016/j.fertnstert.2015.09.023

Corrigendum: Common variants at 19p13 are associated with susceptibility to ovarian cancer

Authors
Bolton, KL; Tyrer, J; Song, H; Ramus, SJ; Notaridou, M; Jones, C; Sher, T; Gentry-Maharaj, A; Wozniak, E; Tsai, Y-Y; Weidhaas, J; Paik, D; Van Den Berg, DJ; Stram, DO; Pearce, CL; Wu, AH; Brewster, W; Anton-Culver, H; Ziogas, A; Narod, SA; Levine, DA; Kaye, SB; Brown, R; Paul, J; Flanagan, J; Sieh, W; McGuire, V; Whittemore, AS; Campbell, I; Gore, ME; Lissowska, J; Yang, HP; Medrek, K; Gronwald, J; Lubinski, J; Jakubowska, A; Le, ND; Cook, LS; Kelemen, LE; Brooks-Wilson, A; Massuger, LFAG et al.
MLA Citation
Bolton, KL, Tyrer, J, Song, H, Ramus, SJ, Notaridou, M, Jones, C, Sher, T, Gentry-Maharaj, A, Wozniak, E, Tsai, Y-Y, Weidhaas, J, Paik, D, Van Den Berg, DJ, Stram, DO, Pearce, CL, Wu, AH, Brewster, W, Anton-Culver, H, Ziogas, A, Narod, SA, Levine, DA, Kaye, SB, Brown, R, Paul, J, Flanagan, J, Sieh, W, McGuire, V, Whittemore, AS, Campbell, I, Gore, ME, Lissowska, J, Yang, HP, Medrek, K, Gronwald, J, Lubinski, J, Jakubowska, A, Le, ND, Cook, LS, Kelemen, LE, Brooks-Wilson, A, and Massuger, LFAG et al. "Corrigendum: Common variants at 19p13 are associated with susceptibility to ovarian cancer." Nature Genetics 48.1 (December 29, 2015): 101-101.
Source
crossref
Published In
Nature Genetics
Volume
48
Issue
1
Publish Date
2015
Start Page
101
End Page
101
DOI
10.1038/ng0116-101b

Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium.

Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome.We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥ 4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis.Five SNPs were significantly associated (P ≤ 1.0 × 10(-5)) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10(-6)). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤ 6 × 10(-3)).We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies.

Authors
Johnatty, SE; Tyrer, JP; Kar, S; Beesley, J; Lu, Y; Gao, B; Fasching, PA; Hein, A; Ekici, AB; Beckmann, MW; Lambrechts, D; Van Nieuwenhuysen, E; Vergote, I; Lambrechts, S; Rossing, MA; Doherty, JA; Chang-Claude, J; Modugno, F; Ness, RB; Moysich, KB; Levine, DA; Kiemeney, LA; Massuger, LFAG; Gronwald, J; Lubiński, J; Jakubowska, A; Cybulski, C; Brinton, L; Lissowska, J; Wentzensen, N; Song, H; Rhenius, V; Campbell, I; Eccles, D; Sieh, W; Whittemore, AS; McGuire, V; Rothstein, JH; Sutphen, R et al.
MLA Citation
Johnatty, SE, Tyrer, JP, Kar, S, Beesley, J, Lu, Y, Gao, B, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambrechts, S, Rossing, MA, Doherty, JA, Chang-Claude, J, Modugno, F, Ness, RB, Moysich, KB, Levine, DA, Kiemeney, LA, Massuger, LFAG, Gronwald, J, Lubiński, J, Jakubowska, A, Cybulski, C, Brinton, L, Lissowska, J, Wentzensen, N, Song, H, Rhenius, V, Campbell, I, Eccles, D, Sieh, W, Whittemore, AS, McGuire, V, Rothstein, JH, and Sutphen, R et al. "Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium." Clinical cancer research : an official journal of the American Association for Cancer Research 21.23 (December 2015): 5264-5276.
PMID
26152742
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
21
Issue
23
Publish Date
2015
Start Page
5264
End Page
5276
DOI
10.1158/1078-0432.ccr-15-0632

Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk.

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.

Authors
Amankwah, EK; Lin, H-Y; Tyrer, JP; Lawrenson, K; Dennis, J; Chornokur, G; Aben, KKH; Anton-Culver, H; Antonenkova, N; Bruinsma, F; Bandera, EV; Bean, YT; Beckmann, MW; Bisogna, M; Bjorge, L; Bogdanova, N; Brinton, LA; Brooks-Wilson, A; Bunker, CH; Butzow, R; Campbell, IG; Carty, K; Chen, Z; Chen, YA; Chang-Claude, J; Cook, LS; Cramer, DW; Cunningham, JM; Cybulski, C; Dansonka-Mieszkowska, A; du Bois, A; Despierre, E; Dicks, E; Doherty, JA; Dörk, T; Dürst, M; Easton, DF; Eccles, DM; Edwards, RP et al.
MLA Citation
Amankwah, EK, Lin, H-Y, Tyrer, JP, Lawrenson, K, Dennis, J, Chornokur, G, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chen, Z, Chen, YA, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Dicks, E, Doherty, JA, Dörk, T, Dürst, M, Easton, DF, Eccles, DM, and Edwards, RP et al. "Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk." Genetic epidemiology 39.8 (December 2015): 689-697.
PMID
26399219
Source
epmc
Published In
Genetic Epidemiology
Volume
39
Issue
8
Publish Date
2015
Start Page
689
End Page
697
DOI
10.1002/gepi.21921

Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer.

Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.

Authors
Lawrenson, K; Iversen, ES; Tyrer, J; Weber, RP; Concannon, P; Hazelett, DJ; Li, Q; Marks, JR; Berchuck, A; Lee, JM; Aben, KKH; Anton-Culver, H; Antonenkova, N; Australian Cancer Study (Ovarian Cancer), ; Australian Ovarian Cancer Study Group, ; Bandera, EV; Bean, Y; Beckmann, MW; Bisogna, M; Bjorge, L; Bogdanova, N; Brinton, LA; Brooks-Wilson, A; Bruinsma, F; Butzow, R; Campbell, IG; Carty, K; Chang-Claude, J; Chenevix-Trench, G; Chen, A; Chen, Z; Cook, LS; Cramer, DW; Cunningham, JM et al.
MLA Citation
Lawrenson, K, Iversen, ES, Tyrer, J, Weber, RP, Concannon, P, Hazelett, DJ, Li, Q, Marks, JR, Berchuck, A, Lee, JM, Aben, KKH, Anton-Culver, H, Antonenkova, N, Australian Cancer Study (Ovarian Cancer), , Australian Ovarian Cancer Study Group, , Bandera, EV, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chenevix-Trench, G, Chen, A, Chen, Z, Cook, LS, Cramer, DW, and Cunningham, JM et al. "Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer." Carcinogenesis 36.11 (November 2015): 1341-1353.
PMID
26424751
Source
epmc
Published In
Carcinogenesis
Volume
36
Issue
11
Publish Date
2015
Start Page
1341
End Page
1353
DOI
10.1093/carcin/bgv138

Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma.

To identify angiogenic biomarkers associated with tumor angiogenesis and clinical outcome in high-grade serous ovarian cancer (HGSC).51 HGSC samples were analyzed using Affymetrix HG-U133A microarray. Microvessel density (MVD) counts were determined using CD31 and CD105. Associations between mRNA expression levels and overall survival were assessed using rank score statistic. Effect size was estimated as a hazard ratio (HR) under a proportional hazard model. The Storey q-value method was used to account for multiple testing within the false-discovery rate (FDR) framework. Publicly available databases including TCGA and GSE were used for external confirmation.Thirty-one angiogenic-related genes were significantly associated with survival (q≤0.05). Of these 31 genes, 4 were also associated with outcome in the TCGA data: AKT1 (q=0.02; TCGA p=0.01, HR=0.8), CD44 (q=0.003; TCGA p=0.05, HR=0.9), EPHB2 (q=0.01; TCGA p=0.05, HR=1.2), and ERBB2 (q=0.02; TCGA p=0.05, HR=1.2). While 5 were associated with outcome in the GSE database: FLT1 (q=0.03; GSE26712 p=0.01, HR=3.1); PF4 (q=0.02; GSE26712 p=0.01, HR=3.0); NRP1 (q=0.02; GSE26712 p<0.04, HR>1.4); COL4A3 (q=0.04; GSE26712 p=0.03, HR=1.3); and ANGPTL3 (q=0.02; GSE14764 p=0.02, HR=1.5). High AKT1 and CD44 were associated with longer survival. In contrast, high expression of EPHB2, ERBB2, FLT1; PF4, NRP1, COL4A3, and ANGPTL3 were associated with shorter survival. CD105-MVD and CD31-MVD were not significantly associated with angiogenic gene expression.Thirty-one angiogenic-related genes were associated with survival in advanced HGSC and nine of these genes were confirmed in independent publicly available databases.

Authors
Siamakpour-Reihani, S; Owzar, K; Jiang, C; Turner, T; Deng, Y; Bean, SM; Horton, JK; Berchuck, A; Marks, JR; Dewhirst, MW; Alvarez Secord, A
MLA Citation
Siamakpour-Reihani, S, Owzar, K, Jiang, C, Turner, T, Deng, Y, Bean, SM, Horton, JK, Berchuck, A, Marks, JR, Dewhirst, MW, and Alvarez Secord, A. "Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma." Gynecologic oncology 139.1 (October 2015): 23-29.
PMID
26260910
Source
epmc
Published In
Gynecologic Oncology
Volume
139
Issue
1
Publish Date
2015
Start Page
23
End Page
29
DOI
10.1016/j.ygyno.2015.08.001

Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk.

Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations.We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls).Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network.We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development.Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.

Authors
Kar, SP; Tyrer, JP; Li, Q; Lawrenson, K; Aben, KKH; Anton-Culver, H; Antonenkova, N; Chenevix-Trench, G; Australian Cancer Study, ; Australian Ovarian Cancer Study Group, ; Baker, H; Bandera, EV; Bean, YT; Beckmann, MW; Berchuck, A; Bisogna, M; Bjørge, L; Bogdanova, N; Brinton, L; Brooks-Wilson, A; Butzow, R; Campbell, I; Carty, K; Chang-Claude, J; Chen, YA; Chen, Z; Cook, LS; Cramer, D; Cunningham, JM; Cybulski, C; Dansonka-Mieszkowska, A; Dennis, J; Dicks, E; Doherty, JA; Dörk, T; du Bois, A et al.
MLA Citation
Kar, SP, Tyrer, JP, Li, Q, Lawrenson, K, Aben, KKH, Anton-Culver, H, Antonenkova, N, Chenevix-Trench, G, Australian Cancer Study, , Australian Ovarian Cancer Study Group, , Baker, H, Bandera, EV, Bean, YT, Beckmann, MW, Berchuck, A, Bisogna, M, Bjørge, L, Bogdanova, N, Brinton, L, Brooks-Wilson, A, Butzow, R, Campbell, I, Carty, K, Chang-Claude, J, Chen, YA, Chen, Z, Cook, LS, Cramer, D, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, and du Bois, A et al. "Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 24.10 (October 2015): 1574-1584. (Review)
PMID
26209509
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
24
Issue
10
Publish Date
2015
Start Page
1574
End Page
1584
DOI
10.1158/1055-9965.epi-14-1270

Shared genetics underlying epidemiological association between endometriosis and ovarian cancer.

Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07-0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.

Authors
Lu, Y; Cuellar-Partida, G; Painter, JN; Nyholt, DR; Australian Ovarian Cancer Study, ; International Endogene Consortium (IEC), ; Morris, AP; Fasching, PA; Hein, A; Burghaus, S; Beckmann, MW; Lambrechts, D; Van Nieuwenhuysen, E; Vergote, I; Vanderstichele, A; Doherty, JA; Rossing, MA; Wicklund, KG; Chang-Claude, J; Eilber, U; Rudolph, A; Wang-Gohrke, S; Goodman, MT; Bogdanova, N; Dörk, T; Dürst, M; Hillemanns, P; Runnebaum, IB; Antonenkova, N; Butzow, R; Leminen, A; Nevanlinna, H; Pelttari, LM et al.
MLA Citation
Lu, Y, Cuellar-Partida, G, Painter, JN, Nyholt, DR, Australian Ovarian Cancer Study, , International Endogene Consortium (IEC), , Morris, AP, Fasching, PA, Hein, A, Burghaus, S, Beckmann, MW, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Vanderstichele, A, Doherty, JA, Rossing, MA, Wicklund, KG, Chang-Claude, J, Eilber, U, Rudolph, A, Wang-Gohrke, S, Goodman, MT, Bogdanova, N, Dörk, T, Dürst, M, Hillemanns, P, Runnebaum, IB, Antonenkova, N, Butzow, R, Leminen, A, Nevanlinna, H, and Pelttari, LM et al. "Shared genetics underlying epidemiological association between endometriosis and ovarian cancer." Human molecular genetics 24.20 (October 2015): 5955-5964.
PMID
26231222
Source
epmc
Published In
Human Molecular Genetics
Volume
24
Issue
20
Publish Date
2015
Start Page
5955
End Page
5964
DOI
10.1093/hmg/ddv306

A functional variant in HOXA11-AS, a novel long non-coding RNA, inhibits the oncogenic phenotype of epithelial ovarian cancer.

The homeobox A (HOXA) region of protein-coding genes impacts female reproductive system embryogenesis and ovarian carcinogenesis. The 5-prime end of HOXA includes three long non-coding RNAs (lncRNAs) (HOXA10-AS, HOXA11-AS, and HOTTIP) that are underexplored in epithelial ovarian cancer (EOC). We evaluated whether common genetic variants in these lncRNAs are associated with EOC risk and/or have functional roles in EOC development. Using genome-wide association study data from 1,201 serous EOC cases and 2,009 controls, an exonic variant within HOXA11-AS, rs17427875 (A>T), was marginally associated with reduced serous EOC risk (OR = 0.88 (95% CI: 0.78-1.01, p = 0.06). Functional studies of ectopic expression of HOXA11-AS minor allele T in EOC cells showed decreased survival, proliferation, migration, and invasion compared to common allele A expression. Additionally, stable expression of HOXA11-AS minor allele T reduced primary tumor growth in mouse xenograft models to a greater extent than common allele A. Furthermore, HOXA11-AS expression levels were significantly lower in human EOC tumors than normal ovarian tissues (p < 0.05), suggesting that HOXA11-AS has a tumor suppressor function in EOC which may be enhanced by the T allele. These findings demonstrate for the first time a role for HOXA11-AS in EOC with effects that could be modified by germline variants.

Authors
Richards, EJ; Permuth-Wey, J; Li, Y; Chen, YA; Coppola, D; Reid, BM; Lin, H-Y; Teer, JK; Berchuck, A; Birrer, MJ; Lawrenson, K; Monteiro, ANA; Schildkraut, JM; Goode, EL; Gayther, SA; Sellers, TA; Cheng, JQ
MLA Citation
Richards, EJ, Permuth-Wey, J, Li, Y, Chen, YA, Coppola, D, Reid, BM, Lin, H-Y, Teer, JK, Berchuck, A, Birrer, MJ, Lawrenson, K, Monteiro, ANA, Schildkraut, JM, Goode, EL, Gayther, SA, Sellers, TA, and Cheng, JQ. "A functional variant in HOXA11-AS, a novel long non-coding RNA, inhibits the oncogenic phenotype of epithelial ovarian cancer." Oncotarget 6.33 (October 2015): 34745-34757.
PMID
26430965
Source
epmc
Published In
Oncotarget
Volume
6
Issue
33
Publish Date
2015
Start Page
34745
End Page
34757
DOI
10.18632/oncotarget.5784

Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.

Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.

Authors
Lawrenson, K; Li, Q; Kar, S; Seo, J-H; Tyrer, J; Spindler, TJ; Lee, J; Chen, Y; Karst, A; Drapkin, R; Aben, KKH; Anton-Culver, H; Antonenkova, N; Australian Ovarian Cancer Study Group, ; Baker, H; Bandera, EV; Bean, Y; Beckmann, MW; Berchuck, A; Bisogna, M; Bjorge, L; Bogdanova, N; Brinton, LA; Brooks-Wilson, A; Bruinsma, F; Butzow, R; Campbell, IG; Carty, K; Chang-Claude, J; Chenevix-Trench, G; Chen, A; Chen, Z; Cook, LS; Cramer, DW; Cunningham, JM; Cybulski, C; Dansonka-Mieszkowska, A et al.
MLA Citation
Lawrenson, K, Li, Q, Kar, S, Seo, J-H, Tyrer, J, Spindler, TJ, Lee, J, Chen, Y, Karst, A, Drapkin, R, Aben, KKH, Anton-Culver, H, Antonenkova, N, Australian Ovarian Cancer Study Group, , Baker, H, Bandera, EV, Bean, Y, Beckmann, MW, Berchuck, A, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chenevix-Trench, G, Chen, A, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, and Dansonka-Mieszkowska, A et al. "Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer." Nature communications 6 (September 22, 2015): 8234-.
PMID
26391404
Source
epmc
Published In
Nature Communications
Volume
6
Publish Date
2015
Start Page
8234
DOI
10.1038/ncomms9234

Abstract POSTER-THER-1420: Ascites drives ovarian cancer stem-like cell growth: therapeutic opportunities

Authors
Mo, L; Kennedy, M; Berchuck, A; Cianciolo, G; Bachelder, RE; Pizzo, SV
MLA Citation
Mo, L, Kennedy, M, Berchuck, A, Cianciolo, G, Bachelder, RE, and Pizzo, SV. "Abstract POSTER-THER-1420: Ascites drives ovarian cancer stem-like cell growth: therapeutic opportunities." August 15, 2015.
Source
crossref
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
21
Issue
16 Supplement
Publish Date
2015
Start Page
POSTER-THER-1420
End Page
POSTER-THER-1420
DOI
10.1158/1557-3265.OVCASYMP14-POSTER-THER-1420

Abstract POSTER-BIOL-1319: Temporal shifts in the epigenetic regulation of tight junctions from primary to recurrent ovarian cancer

Authors
Huang, Z; Visco, Z; Sfakianos, G; Whitaker, R; Berchuck, A; Murphy, S
MLA Citation
Huang, Z, Visco, Z, Sfakianos, G, Whitaker, R, Berchuck, A, and Murphy, S. "Abstract POSTER-BIOL-1319: Temporal shifts in the epigenetic regulation of tight junctions from primary to recurrent ovarian cancer." August 15, 2015.
Source
crossref
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
21
Issue
16 Supplement
Publish Date
2015
Start Page
POSTER-BIOL-1319
End Page
POSTER-BIOL-1319
DOI
10.1158/1557-3265.OVCASYMP14-POSTER-BIOL-1319

Abstract 2236: Emergence of epigenetic regulation of tight junction genes in recurrent serous epithelial ovarian cancer

Authors
Huang, Z; Visco, Z; Sfakianos, G; Whitaker, R; Berchuck, A; Murphy, SK
MLA Citation
Huang, Z, Visco, Z, Sfakianos, G, Whitaker, R, Berchuck, A, and Murphy, SK. "Abstract 2236: Emergence of epigenetic regulation of tight junction genes in recurrent serous epithelial ovarian cancer." August 1, 2015.
Source
crossref
Published In
Cancer Research
Volume
75
Issue
15 Supplement
Publish Date
2015
Start Page
2236
End Page
2236
DOI
10.1158/1538-7445.AM2015-2236

Abstract 4635: Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility

Authors
Permuth-Wey, J; Reid, BM; Chen, YA; Lin, H-Y; Monteiro, A; Chen, Z; Berchuck, A; Chenevix-Trench, G; Doherty, J; Gayther, S; Goode, E; Iversen, E; Pearce, L; Pharoah, PDP; Phelan, C; Ramus, S; Rossing, MA; Schildkraut, J; Sellers, T
MLA Citation
Permuth-Wey, J, Reid, BM, Chen, YA, Lin, H-Y, Monteiro, A, Chen, Z, Berchuck, A, Chenevix-Trench, G, Doherty, J, Gayther, S, Goode, E, Iversen, E, Pearce, L, Pharoah, PDP, Phelan, C, Ramus, S, Rossing, MA, Schildkraut, J, and Sellers, T. "Abstract 4635: Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility." August 1, 2015.
Source
crossref
Published In
Cancer Research
Volume
75
Issue
15 Supplement
Publish Date
2015
Start Page
4635
End Page
4635
DOI
10.1158/1538-7445.AM2015-4635

Abstract 4633: Evidence that long non-coding RNA variants associate with epithelial ovarian cancer risk

Authors
Sellers, TA; Reid, BM; Chen, YA; Lin, H-Y; Richards, E; Teer, J; Monteiro, A; Chen, Z; Berchuck, A; Chenevix-Trench, G; Doherty, J; Goode, E; Iverson, E; Pearce, L; Pharoah, P; Phelan, C; Ramus, S; Rossing, MA; Schildkraut, J; Cheng, J; Gayther, S; Permuth-Wey, J
MLA Citation
Sellers, TA, Reid, BM, Chen, YA, Lin, H-Y, Richards, E, Teer, J, Monteiro, A, Chen, Z, Berchuck, A, Chenevix-Trench, G, Doherty, J, Goode, E, Iverson, E, Pearce, L, Pharoah, P, Phelan, C, Ramus, S, Rossing, MA, Schildkraut, J, Cheng, J, Gayther, S, and Permuth-Wey, J. "Abstract 4633: Evidence that long non-coding RNA variants associate with epithelial ovarian cancer risk." August 1, 2015.
Source
crossref
Published In
Cancer Research
Volume
75
Issue
15 Supplement
Publish Date
2015
Start Page
4633
End Page
4633
DOI
10.1158/1538-7445.AM2015-4633

Abstract 4634: Variants within super-enhancer regulatory elements associate with epithelial ovarian cancer risk

Authors
Reid, BM; Permuth-Wey, J; Chen, YA; Lin, H-Y; Monteiro, A; Chen, Z; Berchuck, A; Chenevix-Trench, G; Doherty, J; Gayther, S; Goode, EL; Iversen, E; Pearce, L; Pharoah, P; Phelan, C; Ramus, S; Rossing, MA; Schildkraut, J; Sellers, T
MLA Citation
Reid, BM, Permuth-Wey, J, Chen, YA, Lin, H-Y, Monteiro, A, Chen, Z, Berchuck, A, Chenevix-Trench, G, Doherty, J, Gayther, S, Goode, EL, Iversen, E, Pearce, L, Pharoah, P, Phelan, C, Ramus, S, Rossing, MA, Schildkraut, J, and Sellers, T. "Abstract 4634: Variants within super-enhancer regulatory elements associate with epithelial ovarian cancer risk." August 1, 2015.
Source
crossref
Published In
Cancer Research
Volume
75
Issue
15 Supplement
Publish Date
2015
Start Page
4634
End Page
4634
DOI
10.1158/1538-7445.AM2015-4634

Abstract 4636: Investigation of exome variants associated with overall survival in ovarian cancer

Authors
Winham, SJ; Fridley, BL; Larson, MC; Fogarty, Z; Berchuck, A; Chen, YA; Lin, H-Y; Chenevix-Trench, G; Permuth-Wey, J; Sellers, TA; Pirie, A; Goode, EL
MLA Citation
Winham, SJ, Fridley, BL, Larson, MC, Fogarty, Z, Berchuck, A, Chen, YA, Lin, H-Y, Chenevix-Trench, G, Permuth-Wey, J, Sellers, TA, Pirie, A, and Goode, EL. "Abstract 4636: Investigation of exome variants associated with overall survival in ovarian cancer." August 1, 2015.
Source
crossref
Published In
Cancer Research
Volume
75
Issue
15 Supplement
Publish Date
2015
Start Page
4636
End Page
4636
DOI
10.1158/1538-7445.AM2015-4636

Genome-wide significant risk associations for mucinous ovarian carcinoma.

Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2q31.1 (P = 7.5 × 10(-12)) and rs688187 at 19q13.2 (P = 6.8 × 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

Authors
Kelemen, LE; Lawrenson, K; Tyrer, J; Li, Q; Lee, JM; Seo, J-H; Phelan, CM; Beesley, J; Chen, X; Spindler, TJ; Aben, KKH; Anton-Culver, H; Antonenkova, N; Australian Cancer Study, ; Australian Ovarian Cancer Study Group, ; Ovarian Cancer Association Consortium,
MLA Citation
Kelemen, LE, Lawrenson, K, Tyrer, J, Li, Q, Lee, JM, Seo, J-H, Phelan, CM, Beesley, J, Chen, X, Spindler, TJ, Aben, KKH, Anton-Culver, H, Antonenkova, N, Australian Cancer Study, , Australian Ovarian Cancer Study Group, , and Ovarian Cancer Association Consortium, . "Genome-wide significant risk associations for mucinous ovarian carcinoma." Nature genetics 47.8 (August 2015): 888-897.
PMID
26075790
Source
epmc
Published In
Nature Genetics
Volume
47
Issue
8
Publish Date
2015
Start Page
888
End Page
897
DOI
10.1038/ng.3336

Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci.

Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most single-nucleotide polymorphisms (SNPs) associated with cancer risk lie in non-protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs) and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared with normal human mammary epithelial cells and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissue-specific regulatory signatures compared to non-gynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P = 3.8 × 10(-30)), OSECs (P = 2.4 × 10(-23)) and HMECs (P = 6.7 × 10(-15)) but not for EECs (P = 0.45) or LNCaP cells (P = 0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) suggesting both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets of germline genetic susceptibility variants for ovarian cancer.

Authors
Coetzee, SG; Shen, HC; Hazelett, DJ; Lawrenson, K; Kuchenbaecker, K; Tyrer, J; Rhie, SK; Levanon, K; Karst, A; Drapkin, R; Ramus, SJ; Ovarian Cancer Association Consortium, The Consortium of Investigators of Modifiers of BRCA1/2, ; Couch, FJ; Offit, K; Chenevix-Trench, G; Monteiro, ANA; Antoniou, A; Freedman, M; Coetzee, GA; Pharoah, PDP; Noushmehr, H; Gayther, SA; Ovarian Cancer Association Consortium The Consortium of Investigators of Modifiers of BRCA1/2,
MLA Citation
Coetzee, SG, Shen, HC, Hazelett, DJ, Lawrenson, K, Kuchenbaecker, K, Tyrer, J, Rhie, SK, Levanon, K, Karst, A, Drapkin, R, Ramus, SJ, Ovarian Cancer Association Consortium, The Consortium of Investigators of Modifiers of BRCA1/2, , Couch, FJ, Offit, K, Chenevix-Trench, G, Monteiro, ANA, Antoniou, A, Freedman, M, Coetzee, GA, Pharoah, PDP, Noushmehr, H, Gayther, SA, and Ovarian Cancer Association Consortium The Consortium of Investigators of Modifiers of BRCA1/2, . "Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci." Human molecular genetics 24.13 (July 2015): 3595-3607.
PMID
25804953
Source
epmc
Published In
Human Molecular Genetics
Volume
24
Issue
13
Publish Date
2015
Start Page
3595
End Page
3607
DOI
10.1093/hmg/ddv101

LIFETIME RISK OF OVARIAN CANCER BASED ON ENDOMETRIOSIS AND OTHER RISK FACTORS: IGCS-0014 06. Ovarian Cancer.

Authors
Ness, R; Pearce, C; Stram, D; Berchuck, A; Pike, M; Pharoah, P
MLA Citation
Ness, R, Pearce, C, Stram, D, Berchuck, A, Pike, M, and Pharoah, P. "LIFETIME RISK OF OVARIAN CANCER BASED ON ENDOMETRIOSIS AND OTHER RISK FACTORS: IGCS-0014 06. Ovarian Cancer." International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 25 Suppl 1 (May 2015): 50-.
PMID
25955930
Source
epmc
Published In
International Journal of Gynecological Cancer
Volume
25 Suppl 1
Publish Date
2015
Start Page
50
DOI
10.1097/00009577-201505001-00039

LIFETIME RISK OF OVARIAN CANCER BASED ON ENDOMETRIOSIS AND OTHER RISK FACTORS

Authors
Ness, R; Pearce, C; Stram, D; Berchuck, A; Pike, M; Pharoah, P
MLA Citation
Ness, R, Pearce, C, Stram, D, Berchuck, A, Pike, M, and Pharoah, P. "LIFETIME RISK OF OVARIAN CANCER BASED ON ENDOMETRIOSIS AND OTHER RISK FACTORS." INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 25 (May 2015): 50-51.
Source
wos-lite
Published In
International Journal of Gynecological Cancer
Volume
25
Publish Date
2015
Start Page
50
End Page
51

Population distribution of lifetime risk of ovarian cancer in the United States.

In U.S. women, lifetime risk of ovarian cancer is 1.37%, but some women are at a substantially lower or higher risk than this average.We have characterized the distribution of lifetime risk in the general population. Published data on the relative risks and their variances for five well-accepted risk and protective factors for ovarian cancer, oral contraceptive use, parity, tubal ligation, endometriosis, and first-degree family history of ovarian cancer in conjunction with a genetic risk score using genome-wide significant common, low penetrance variants were used. The joint distribution of these factors (i.e., risk/protective factor profiles) was derived using control data from four U.S. population-based studies, providing a broad representation of women in the United States.A total of 214 combinations of risk/protective factors were observed, and the lifetime risk estimates ranged from 0.35% [95% confidence interval (CI), 0.29-0.42] to 8.78% (95% CI, 7.10-10.9). Among women with lifetime risk ranging from 4% to 9%, 73% had no family history of ovarian cancer; most of these women had a self-reported history of endometriosis.Profiles including the known modifiable protective factors of oral contraceptive use and tubal ligation were associated with a lower lifetime risk of ovarian cancer. Oral contraceptive use and tubal ligation were essentially absent among the women at 4% to 9% lifetime risk.This work demonstrates that there are women in the general population who have a much higher than average lifetime risk of ovarian cancer. Preventive strategies are available. Should effective screening become available, higher than average risk women can be identified.

Authors
Pearce, CL; Stram, DO; Ness, RB; Stram, DA; Roman, LD; Templeman, C; Lee, AW; Menon, U; Fasching, PA; McAlpine, JN; Doherty, JA; Modugno, F; Schildkraut, JM; Rossing, MA; Huntsman, DG; Wu, AH; Berchuck, A; Pike, MC; Pharoah, PDP
MLA Citation
Pearce, CL, Stram, DO, Ness, RB, Stram, DA, Roman, LD, Templeman, C, Lee, AW, Menon, U, Fasching, PA, McAlpine, JN, Doherty, JA, Modugno, F, Schildkraut, JM, Rossing, MA, Huntsman, DG, Wu, AH, Berchuck, A, Pike, MC, and Pharoah, PDP. "Population distribution of lifetime risk of ovarian cancer in the United States." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 24.4 (April 2015): 671-676.
PMID
25623732
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
24
Issue
4
Publish Date
2015
Start Page
671
End Page
676
DOI
10.1158/1055-9965.epi-14-1128

Prophylactic oophorectomy for hereditary small cell carcinoma of the ovary, hypercalcemic type.

•Prophylactic oophorectomy can prevent small cell carcinoma of the ovary, hypercalcemic type in carriers of germline SMARCA4 mutations.•Unaffected SMARCA4 mutation carriers who desire children may be best served by oocyte cryopreservation prior to prophylactic oophorectomy.

Authors
Berchuck, A; Witkowski, L; Hasselblatt, M; Foulkes, WD
MLA Citation
Berchuck, A, Witkowski, L, Hasselblatt, M, and Foulkes, WD. "Prophylactic oophorectomy for hereditary small cell carcinoma of the ovary, hypercalcemic type." Gynecologic oncology reports 12 (April 2015): 20-22.
PMID
26076152
Source
epmc
Published In
Gynecologic Oncology Reports
Volume
12
Publish Date
2015
Start Page
20
End Page
22
DOI
10.1016/j.gore.2015.02.002

Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study.

Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted.Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations.We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive).Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.

Authors
Lee, AW; Tyrer, JP; Doherty, JA; Stram, DA; Kupryjanczyk, J; Dansonka-Mieszkowska, A; Plisiecka-Halasa, J; Spiewankiewicz, B; Myers, EJ; Australian Cancer Study (Ovarian Cancer), ; Australian Ovarian Cancer Study Group, ; Chenevix-Trench, G; Fasching, PA; Beckmann, MW; Ekici, AB; Hein, A; Vergote, I; Van Nieuwenhuysen, E; Lambrechts, D; Wicklund, KG; Eilber, U; Wang-Gohrke, S; Chang-Claude, J; Rudolph, A; Sucheston-Campbell, L; Odunsi, K; Moysich, KB; Shvetsov, YB; Thompson, PJ; Goodman, MT et al.
MLA Citation
Lee, AW, Tyrer, JP, Doherty, JA, Stram, DA, Kupryjanczyk, J, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Spiewankiewicz, B, Myers, EJ, Australian Cancer Study (Ovarian Cancer), , Australian Ovarian Cancer Study Group, , Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Ekici, AB, Hein, A, Vergote, I, Van Nieuwenhuysen, E, Lambrechts, D, Wicklund, KG, Eilber, U, Wang-Gohrke, S, Chang-Claude, J, Rudolph, A, Sucheston-Campbell, L, Odunsi, K, Moysich, KB, Shvetsov, YB, Thompson, PJ, and Goodman, MT et al. "Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study." Gynecologic oncology 136.3 (March 2015): 542-548.
PMID
25528498
Source
epmc
Published In
Gynecologic Oncology
Volume
136
Issue
3
Publish Date
2015
Start Page
542
End Page
548
DOI
10.1016/j.ygyno.2014.12.017

Syngeneic Murine Ovarian Cancer Model Reveals That Ascites Enriches for Ovarian Cancer Stem-Like Cells Expressing Membrane GRP78.

Patients with ovarian cancer are generally diagnosed at FIGO (International Federation of Gynecology and Obstetrics) stage III/IV, when ascites is common. The volume of ascites correlates positively with the extent of metastasis and negatively with prognosis. Membrane GRP78, a stress-inducible endoplasmic reticulum chaperone that is also expressed on the plasma membrane ((mem)GRP78) of aggressive cancer cells, plays a crucial role in the embryonic stem cell maintenance. We studied the effects of ascites on ovarian cancer stem-like cells using a syngeneic mouse model. Our study demonstrates that ascites-derived tumor cells from mice injected intraperitoneally with murine ovarian cancer cells (ID8) express increased (mem)GRP78 levels compared with ID8 cells from normal culture. We hypothesized that these ascites-associated (mem)GRP78(+) cells are cancer stem-like cells (CSC). Supporting this hypothesis, we show that (mem)GRP78(+) cells isolated from murine ascites exhibit increased sphere forming and tumor initiating abilities compared with (mem)GRP78(-) cells. When the tumor microenvironment is recapitulated by adding ascites fluid to cell culture, ID8 cells express more (mem)GRP78 and increased self-renewing ability compared with those cultured in medium alone. Moreover, compared with their counterparts cultured in normal medium, ID8 cells cultured in ascites, or isolated from ascites, show increased stem cell marker expression. Antibodies directed against the carboxy-terminal domain of GRP78: (i) reduce self-renewing ability of murine and human ovarian cancer cells preincubated with ascites and (ii) suppress a GSK3α-AKT/SNAI1 signaling axis in these cells. Based on these data, we suggest that (mem)GRP78 is a logical therapeutic target for late-stage ovarian cancer.

Authors
Mo, L; Bachelder, RE; Kennedy, M; Chen, P-H; Chi, J-T; Berchuck, A; Cianciolo, G; Pizzo, SV
MLA Citation
Mo, L, Bachelder, RE, Kennedy, M, Chen, P-H, Chi, J-T, Berchuck, A, Cianciolo, G, and Pizzo, SV. "Syngeneic Murine Ovarian Cancer Model Reveals That Ascites Enriches for Ovarian Cancer Stem-Like Cells Expressing Membrane GRP78." Molecular cancer therapeutics 14.3 (March 2015): 747-756.
PMID
25589495
Source
epmc
Published In
Molecular cancer therapeutics
Volume
14
Issue
3
Publish Date
2015
Start Page
747
End Page
756
DOI
10.1158/1535-7163.mct-14-0579

MicroRNAs in endometrial cancers from black and white patients

Copyright © 2015 Elsevier Inc. All rights reserved. OBJECTIVE: Previous studies have identified differences in gene mutations among endometrial cancers from whites and blacks suggesting that differences in tumor biology may explain racial disparities in patient outcome. Micro RNAs (miRNAs) have emerged as regulators of transcript expression and their aberrant expression has been discovered in many diseases, including endometrial cancer. We performed quantitative polymerase chain reaction-based analysis in a set of endometrial cancers to identify whether there are racial differences in miRNA expression. STUDY DESIGN: Tumor cells from 50 stage-I endometrioid endometrial cancer specimens from 41 white and 9 black patients were prepared by laser microdissection and miRNA extracts were analyzed using TaqMan (Life Technologies, Carlsbad, CA) low-density arrays. Statistically significant, differentially expressed miRNAs between blacks and whites were identified using multidimensional scaling, Wilcoxon testing, and analysis of variance. RESULTS: There were no global differences in miRNA expression between endometrial cancers from 41 white and 9 black patients. To minimize potential bias introduced by unbalanced sample size, we performed a subset analysis with stage- and histology-matched specimens from 9 whites and 9 blacks that identified 18 differentially abundant miRNAs ( > 2-fold at P < .005). Quantitative polymerase chain reaction validated miRNA-337-3p in an independent set of endometrial cancer specimens from 23 white and 24 black women. There were no racial differences in hsa-miR-337-3p expression in normal endometrium. CONCLUSION: These data indicate that hsa-mir-337-3p is more frequently down-regulated in endometrial cancers from whites compared to blacks. Future studies are focused on determining the phenotypic impact of miR-337-3p and whether its differential expression is associated with clinical outcome.

Authors
Maxwell, GL; Shoji, Y; Darcy, K; Litzi, T; Berchuck, A; Hamilton, CA; Conrads, TP; Risinger, JI
MLA Citation
Maxwell, GL, Shoji, Y, Darcy, K, Litzi, T, Berchuck, A, Hamilton, CA, Conrads, TP, and Risinger, JI. "MicroRNAs in endometrial cancers from black and white patients." American journal of obstetrics and gynecology 212.2 (February 1, 2015).
Source
scopus
Published In
American Journal of Obstetrics & Gynecology
Volume
212
Issue
2
Publish Date
2015
DOI
10.1016/j.ajog.2014.08.028

MicroRNAs in endometrial cancers from black and white patients.

OBJECTIVE: Previous studies have identified differences in gene mutations among endometrial cancers from whites and blacks suggesting that differences in tumor biology may explain racial disparities in patient outcome. Micro RNAs (miRNAs) have emerged as regulators of transcript expression and their aberrant expression has been discovered in many diseases, including endometrial cancer. We performed quantitative polymerase chain reaction-based analysis in a set of endometrial cancers to identify whether there are racial differences in miRNA expression. STUDY DESIGN: Tumor cells from 50 stage-I endometrioid endometrial cancer specimens from 41 white and 9 black patients were prepared by laser microdissection and miRNA extracts were analyzed using TaqMan (Life Technologies, Carlsbad, CA) low-density arrays. Statistically significant, differentially expressed miRNAs between blacks and whites were identified using multidimensional scaling, Wilcoxon testing, and analysis of variance. RESULTS: There were no global differences in miRNA expression between endometrial cancers from 41 white and 9 black patients. To minimize potential bias introduced by unbalanced sample size, we performed a subset analysis with stage- and histology-matched specimens from 9 whites and 9 blacks that identified 18 differentially abundant miRNAs (>2-fold at P < .005). Quantitative polymerase chain reaction validated miRNA-337-3p in an independent set of endometrial cancer specimens from 23 white and 24 black women. There were no racial differences in hsa-miR-337-3p expression in normal endometrium. CONCLUSION: These data indicate that hsa-mir-337-3p is more frequently down-regulated in endometrial cancers from whites compared to blacks. Future studies are focused on determining the phenotypic impact of miR-337-3p and whether its differential expression is associated with clinical outcome.

Authors
Maxwell, GL; Shoji, Y; Darcy, K; Litzi, T; Berchuck, A; Hamilton, CA; Conrads, TP; Risinger, JI
MLA Citation
Maxwell, GL, Shoji, Y, Darcy, K, Litzi, T, Berchuck, A, Hamilton, CA, Conrads, TP, and Risinger, JI. "MicroRNAs in endometrial cancers from black and white patients." American journal of obstetrics and gynecology 212.2 (February 2015): 191.e1-191.10.
PMID
25174797
Source
epmc
Published In
American Journal of Obstetrics & Gynecology
Volume
212
Issue
2
Publish Date
2015
Start Page
191.e1
End Page
191.10
DOI
10.1016/j.ajog.2014.08.028

Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

Authors
Kuchenbaecker, KB; Ramus, SJ; Tyrer, J; Lee, A; Shen, HC; Beesley, J; Lawrenson, K; McGuffog, L; Healey, S; Lee, JM; Spindler, TJ; Lin, YG; Pejovic, T; Bean, Y; Li, Q; Coetzee, S; Hazelett, D; Miron, A; Southey, M; Terry, MB; Goldgar, DE; Buys, SS; Janavicius, R; Dorfling, CM; van Rensburg, EJ; Neuhausen, SL; Ding, YC; Hansen, TVO; Jønson, L; Gerdes, A-M; Ejlertsen, B; Barrowdale, D; Dennis, J; Benitez, J; Osorio, A; Garcia, MJ; Komenaka, I; Weitzel, JN; Ganschow, P; Peterlongo, P; Bernard, L et al.
MLA Citation
Kuchenbaecker, KB, Ramus, SJ, Tyrer, J, Lee, A, Shen, HC, Beesley, J, Lawrenson, K, McGuffog, L, Healey, S, Lee, JM, Spindler, TJ, Lin, YG, Pejovic, T, Bean, Y, Li, Q, Coetzee, S, Hazelett, D, Miron, A, Southey, M, Terry, MB, Goldgar, DE, Buys, SS, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Hansen, TVO, Jønson, L, Gerdes, A-M, Ejlertsen, B, Barrowdale, D, Dennis, J, Benitez, J, Osorio, A, Garcia, MJ, Komenaka, I, Weitzel, JN, Ganschow, P, Peterlongo, P, and Bernard, L et al. "Identification of six new susceptibility loci for invasive epithelial ovarian cancer." Nature genetics 47.2 (February 2015): 164-171.
PMID
25581431
Source
epmc
Published In
Nature Genetics
Volume
47
Issue
2
Publish Date
2015
Start Page
164
End Page
171
DOI
10.1038/ng.3185

Vaginal Cuff Thermal Injury by Mode of Colpotomy at Total Laparoscopic Hysterectomy: A Randomized Clinical Trial

Authors
Teoh, D; Lowery, WJ; Jiang, X; Ehrisman, J; Halvorson, P; Broadwater, G; Bentley, R; Secord, AA; Sobolewski, C; Berchuck, A; Havrilesky, LJ; Valea, FA; Lee, PS
MLA Citation
Teoh, D, Lowery, WJ, Jiang, X, Ehrisman, J, Halvorson, P, Broadwater, G, Bentley, R, Secord, AA, Sobolewski, C, Berchuck, A, Havrilesky, LJ, Valea, FA, and Lee, PS. "Vaginal Cuff Thermal Injury by Mode of Colpotomy at Total Laparoscopic Hysterectomy: A Randomized Clinical Trial." JOURNAL OF MINIMALLY INVASIVE GYNECOLOGY 22.2 (February 2015): 227-233.
Source
wos-lite
Published In
Journal of Minimally Invasive Gynecology
Volume
22
Issue
2
Publish Date
2015
Start Page
227
End Page
233
DOI
10.1016/j.jmig.2014.10.002

Role of surgery in cancer prevention

Authors
Guillem, JG; Berchuck, A; Moley, JF; Norton, JA; Gabram-Mendola, SGA; Hui, VW
MLA Citation
Guillem, JG, Berchuck, A, Moley, JF, Norton, JA, Gabram-Mendola, SGA, and Hui, VW. "Role of surgery in cancer prevention." DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology: Tenth Edition. January 7, 2015.
Source
scopus
Publish Date
2015

Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.

Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4).These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.

Authors
Chornokur, G; Lin, H-Y; Tyrer, JP; Lawrenson, K; Dennis, J; Amankwah, EK; Qu, X; Tsai, Y-Y; Jim, HSL; Chen, Z; Chen, AY; Permuth-Wey, J; Aben, KKH; Anton-Culver, H; Antonenkova, N; Bruinsma, F; Bandera, EV; Bean, YT; Beckmann, MW; Bisogna, M; Bjorge, L; Bogdanova, N; Brinton, LA; Brooks-Wilson, A; Bunker, CH; Butzow, R; Campbell, IG; Carty, K; Chang-Claude, J; Cook, LS; Cramer, DW; Cunningham, JM; Cybulski, C; Dansonka-Mieszkowska, A; du Bois, A; Despierre, E; Dicks, E; Doherty, JA; Dörk, T et al.
MLA Citation
Chornokur, G, Lin, H-Y, Tyrer, JP, Lawrenson, K, Dennis, J, Amankwah, EK, Qu, X, Tsai, Y-Y, Jim, HSL, Chen, Z, Chen, AY, Permuth-Wey, J, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Dicks, E, Doherty, JA, and Dörk, T et al. "Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk." PloS one 10.6 (January 2015): e0128106-.
PMID
26091520
Source
epmc
Published In
PloS one
Volume
10
Issue
6
Publish Date
2015
Start Page
e0128106
DOI
10.1371/journal.pone.0128106

Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC).

Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10(-4)]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.

Authors
Jim, HSL; Lin, H-Y; Tyrer, JP; Lawrenson, K; Dennis, J; Chornokur, G; Chen, Z; Chen, AY; Permuth-Wey, J; Aben, KK; Anton-Culver, H; Antonenkova, N; Bruinsma, F; Bandera, EV; Bean, YT; Beckmann, MW; Bisogna, M; Bjorge, L; Bogdanova, N; Brinton, LA; Brooks-Wilson, A; Bunker, CH; Butzow, R; Campbell, IG; Carty, K; Chang-Claude, J; Cook, LS; Cramer, DW; Cunningham, JM; Cybulski, C; Dansonka-Mieszkowska, A; du Bois, A; Despierre, E; Sieh, W; Doherty, JA; Dörk, T; Dürst, M; Easton, DF; Eccles, DM et al.
MLA Citation
Jim, HSL, Lin, H-Y, Tyrer, JP, Lawrenson, K, Dennis, J, Chornokur, G, Chen, Z, Chen, AY, Permuth-Wey, J, Aben, KK, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Sieh, W, Doherty, JA, Dörk, T, Dürst, M, Easton, DF, and Eccles, DM et al. "Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)." Journal of genetics and genome research 2.2 (January 2015).
PMID
26807442
Source
epmc
Published In
Journal of Genetics and Genome Research
Volume
2
Issue
2
Publish Date
2015

Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma

© 2015 Elsevier Inc. All rights reserved.Objectives To identify angiogenic biomarkers associated with tumor angiogenesis and clinical outcome in high-grade serous ovarian cancer (HGSC). Methods 51 HGSC samples were analyzed using Affymetrix HG-U133A microarray. Microvessel density (MVD) counts were determined using CD31 and CD105. Associations between mRNA expression levels and overall survival were assessed using rank score statistic. Effect size was estimated as a hazard ratio (HR) under a proportional hazard model. The Storey q-value method was used to account for multiple testing within the false-discovery rate (FDR) framework. Publicly available databases including TCGA and GSE were used for external confirmation. Results Thirty-one angiogenic-related genes were significantly associated with survival (q 0.05). Of these 31 genes, 4 were also associated with outcome in the TCGA data: AKT1 (q = 0.02; TCGA p = 0.01, HR = 0.8), CD44 (q = 0.003; TCGA p = 0.05, HR = 0.9), EPHB2 (q = 0.01; TCGA p = 0.05, HR = 1.2), and ERBB2 (q = 0.02; TCGA p = 0.05, HR = 1.2). While 5 were associated with outcome in the GSE database: FLT1 (q = 0.03; GSE26712 p = 0.01, HR = 3.1); PF4 (q = 0.02; GSE26712 p = 0.01, HR = 3.0); NRP1 (q = 0.02; GSE26712 p 0.04, HR 1.4); COL4A3 (q = 0.04; GSE26712 p = 0.03, HR = 1.3); and ANGPTL3 (q = 0.02; GSE14764 p = 0.02, HR = 1.5). High AKT1 and CD44 were associated with longer survival. In contrast, high expression of EPHB2, ERBB2, FLT1; PF4, NRP1, COL4A3, and ANGPTL3 were associated with shorter survival. CD105-MVD and CD31-MVD were not significantly associated with angiogenic gene expression. Conclusions Thirty-one angiogenic-related genes were associated with survival in advanced HGSC and nine of these genes were confirmed in independent publicly available databases.

Authors
Siamakpour-Reihani, S; Owzar, K; Jiang, C; Turner, T; Deng, Y; Bean, SM; Horton, JK; Berchuck, A; Marks, JR; Dewhirst, MW; Secord, AA
MLA Citation
Siamakpour-Reihani, S, Owzar, K, Jiang, C, Turner, T, Deng, Y, Bean, SM, Horton, JK, Berchuck, A, Marks, JR, Dewhirst, MW, and Secord, AA. "Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma." Gynecologic Oncology 139.1 (2015): 23-29.
Source
scival
Published In
Gynecologic Oncology
Volume
139
Issue
1
Publish Date
2015
Start Page
23
End Page
29
DOI
10.1016/j.ygyno.2015.08.001

Patient preferences in advanced or recurrent ovarian cancer.

The objective of this study was to elucidate relative preferences of women with ovarian cancer for symptoms, treatment-related side effects, and progression-free survival (PFS) relevant to choosing a treatment regimen.Women with advanced or recurrent ovarian cancer participated in a survey that included 3 methods to measure patient preferences (ratings, rankings, and a discrete-choice experiment) for 7 attributes: mode of administration, visit frequency, peripheral neuropathy, nausea and vomiting, fatigue, abdominal discomfort, and PFS. Participants were asked to choose between 2 unlabeled treatment scenarios that were characterized using the 7 attributes. Each participant completed 12 choice questions in which attribute levels were assigned according to an experimental design and a fixed-choice question representing 2 chemotherapy regimens for ovarian cancer.In total, 95 women completed the survey. Participants' ratings and rankings revealed greater concern and importance for PFS than for any other attribute (P < .0001 for all). The discrete-choice experiment revealed that the relative odds that a participant would choose a scenario with 18 months, 21 months, and 24 months of PFS versus 15 months of PFS were 1.5 (P = .01), 3.4 (P < .001), and 7.5 (P < .001), respectively. However, participants' choices indicated that they were willing to accept a shorter PFS to avoid severe side effects: 6.7 months to reduce nausea and vomiting from severe to mild, 5.0 months to reduce neuropathy from severe to mild, and 3.7 months to reduce abdominal symptoms from severe to moderate.PFS is the predominant driver of patient preferences for chemotherapy regimens. However, women in the current study were willing to trade significant PFS time for reductions in treatment-related toxicity.

Authors
Havrilesky, LJ; Alvarez Secord, A; Ehrisman, JA; Berchuck, A; Valea, FA; Lee, PS; Gaillard, SL; Samsa, GP; Cella, D; Weinfurt, KP; Abernethy, AP; Reed, SD
MLA Citation
Havrilesky, LJ, Alvarez Secord, A, Ehrisman, JA, Berchuck, A, Valea, FA, Lee, PS, Gaillard, SL, Samsa, GP, Cella, D, Weinfurt, KP, Abernethy, AP, and Reed, SD. "Patient preferences in advanced or recurrent ovarian cancer." Cancer 120.23 (December 2014): 3651-3659.
PMID
25091693
Source
epmc
Published In
Cancer
Volume
120
Issue
23
Publish Date
2014
Start Page
3651
End Page
3659
DOI
10.1002/cncr.28940

Biology and genetics

Authors
Gaillard, S; Maxwell, GL; Sood, AK; Berchuck, A
MLA Citation
Gaillard, S, Maxwell, GL, Sood, AK, and Berchuck, A. "Biology and genetics." Berek and Hacker's Gynecologic Oncology: Sixth Edition. November 11, 2014. 2-38.
Source
scopus
Publish Date
2014
Start Page
2
End Page
38

LIFETIME RISK OF OVARIAN CANCER BASED ON ENDOMETRIOSIS AND OTHER RISK FACTORS

Authors
Ness, R; Pearce, CPC; Stram, DSD; Berchuck, ABA; Pike, MPM; Pharoah, PPP; OCAC,
MLA Citation
Ness, R, Pearce, CPC, Stram, DSD, Berchuck, ABA, Pike, MPM, Pharoah, PPP, and OCAC, . "LIFETIME RISK OF OVARIAN CANCER BASED ON ENDOMETRIOSIS AND OTHER RISK FACTORS." INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 24.9 (November 2014): 441-442.
Source
wos-lite
Published In
International Journal of Gynecological Cancer
Volume
24
Issue
9
Publish Date
2014
Start Page
441
End Page
442

PROPHYLACTIC OOPHORECTOMY FOR HEREDITARY SMALL-CELL CARCINOMA OF THE OVARY, HYPERCALCEMIC TYPE

Authors
Berchuck, A; Witkowski, L; Hasselblatt, M; Wallace, A; Clarke, BA; Foulkes, WD
MLA Citation
Berchuck, A, Witkowski, L, Hasselblatt, M, Wallace, A, Clarke, BA, and Foulkes, WD. "PROPHYLACTIC OOPHORECTOMY FOR HEREDITARY SMALL-CELL CARCINOMA OF THE OVARY, HYPERCALCEMIC TYPE." INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 24.9 (November 2014): 961-962.
Source
wos-lite
Published In
International Journal of Gynecological Cancer
Volume
24
Issue
9
Publish Date
2014
Start Page
961
End Page
962

ENDOMETRIOSIS AND OVARIAN CANCER: AN INTERNATIONAL POOLED ANALYSIS

Authors
Ness, R; Pearce, CPC; Templeman, CTC; Wu, AWA; Berchuck, ABA; OCAC,
MLA Citation
Ness, R, Pearce, CPC, Templeman, CTC, Wu, AWA, Berchuck, ABA, and OCAC, . "ENDOMETRIOSIS AND OVARIAN CANCER: AN INTERNATIONAL POOLED ANALYSIS." INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 24.9 (November 2014): 439-440.
Source
wos-lite
Published In
International Journal of Gynecological Cancer
Volume
24
Issue
9
Publish Date
2014
Start Page
439
End Page
440

IDENTIFICATION OF SIX NOVEL, COMMON VARIANT GENETIC SUSCEPTIBILITY LOCI FOR INVASIVE EPITHELIAL OVARIAN CANCER

Authors
Berchuck, A; Kuchenbaecker, K; Ramus, SJ; Tyrer, JP; Gayther, SA; Pharoah, PDP; Antoniou, AC; Chenevix-Trench, G
MLA Citation
Berchuck, A, Kuchenbaecker, K, Ramus, SJ, Tyrer, JP, Gayther, SA, Pharoah, PDP, Antoniou, AC, and Chenevix-Trench, G. "IDENTIFICATION OF SIX NOVEL, COMMON VARIANT GENETIC SUSCEPTIBILITY LOCI FOR INVASIVE EPITHELIAL OVARIAN CANCER." INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER 24.9 (November 2014): 13-13.
Source
wos-lite
Published In
International Journal of Gynecological Cancer
Volume
24
Issue
9
Publish Date
2014
Start Page
13
End Page
13

Abstract 4570: Role of ERRalpha in ovarian cancer

Authors
Stevens, EV; Whitaker, R; Guinet, A; Chang, C-Y; Grenier, C; Marks, J; McDonnell, DP; Murphy, SK; Berchuck, A; Gaillard, S
MLA Citation
Stevens, EV, Whitaker, R, Guinet, A, Chang, C-Y, Grenier, C, Marks, J, McDonnell, DP, Murphy, SK, Berchuck, A, and Gaillard, S. "Abstract 4570: Role of ERRalpha in ovarian cancer." October 1, 2014.
Source
crossref
Published In
Cancer Research
Volume
74
Issue
19 Supplement
Publish Date
2014
Start Page
4570
End Page
4570
DOI
10.1158/1538-7445.AM2014-4570

Abstract 3283: GWAS identifies risk variants for mucinous ovarian carcinoma

Authors
Kelemen, LE; Tyrer, J; Phelan, CM; Ramus, SJ; Berchuck, A; Gayther, SA; Goode, EL; Pearce, CL; Schildkraut, JM; Chenevix-Trench, G; Monteiro, AN; Goodman, MT; Sellers, TA; Pharoah, PP
MLA Citation
Kelemen, LE, Tyrer, J, Phelan, CM, Ramus, SJ, Berchuck, A, Gayther, SA, Goode, EL, Pearce, CL, Schildkraut, JM, Chenevix-Trench, G, Monteiro, AN, Goodman, MT, Sellers, TA, and Pharoah, PP. "Abstract 3283: GWAS identifies risk variants for mucinous ovarian carcinoma." October 1, 2014.
Source
crossref
Published In
Cancer Research
Volume
74
Issue
19 Supplement
Publish Date
2014
Start Page
3283
End Page
3283
DOI
10.1158/1538-7445.AM2014-3283

Abstract 946: Exome genotyping array identifies rare and low-frequency variants that may be associated with ovarian cancer risk

Authors
Permuth-Wey, J; Chen, YA; Chen, Z; Berchuck, A; Chenevix-Trench, G; Doherty, J; Gayther, S; Goode, EL; Iversen, E; Monteiro, ANA; Pearce, L; Pharoah, PDP; Phelan, CM; Pirie, A; Ramus, S; Rossing, MA; Schildkraut, JM
MLA Citation
Permuth-Wey, J, Chen, YA, Chen, Z, Berchuck, A, Chenevix-Trench, G, Doherty, J, Gayther, S, Goode, EL, Iversen, E, Monteiro, ANA, Pearce, L, Pharoah, PDP, Phelan, CM, Pirie, A, Ramus, S, Rossing, MA, and Schildkraut, JM. "Abstract 946: Exome genotyping array identifies rare and low-frequency variants that may be associated with ovarian cancer risk." October 1, 2014.
Source
crossref
Published In
Cancer Research
Volume
74
Issue
19 Supplement
Publish Date
2014
Start Page
946
End Page
946
DOI
10.1158/1538-7445.AM2014-946

Abstract LB-89: Germ-line and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type

Authors
Witkowski, L; Carrot-Zhang, J; Albrecht, S; Hamel, N; Tomiak, E; Grynspan, D; Saloustros, E; Gilpin, C; Silva-Smith, R; Plourde, F; Rivera, B; Castellsagué, E; Wu, M; Fahiminiya, S; Nadaf, J; Saskin, A; Arseneault, M; Karabakhtsian, RG; Reilly, EA; Ueland, FR; Margiolaki, A; Pavlakis, K; Castellino, SM; Lamovec, J; Roth, LM; Ulbright, TM; Bender, T; Longy, M; Berchuck, A; Tischkowitz, M; Siebert, R; Nagel, I; Georgoulias, V; Stewart, CJR; McCluggage, G; Arseneau, J; Clarke, BA et al.
MLA Citation
Witkowski, L, Carrot-Zhang, J, Albrecht, S, Hamel, N, Tomiak, E, Grynspan, D, Saloustros, E, Gilpin, C, Silva-Smith, R, Plourde, F, Rivera, B, Castellsagué, E, Wu, M, Fahiminiya, S, Nadaf, J, Saskin, A, Arseneault, M, Karabakhtsian, RG, Reilly, EA, Ueland, FR, Margiolaki, A, Pavlakis, K, Castellino, SM, Lamovec, J, Roth, LM, Ulbright, TM, Bender, T, Longy, M, Berchuck, A, Tischkowitz, M, Siebert, R, Nagel, I, Georgoulias, V, Stewart, CJR, McCluggage, G, Arseneau, J, and Clarke, BA et al. "Abstract LB-89: Germ-line and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type." October 1, 2014.
Source
crossref
Published In
Cancer Research
Volume
74
Issue
19 Supplement
Publish Date
2014
Start Page
LB-89
End Page
LB-89
DOI
10.1158/1538-7445.AM2014-LB-89

Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk.

We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10⁻⁵) and rs828054 (OR = 1.06; p = 1 × 10⁻⁴). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10⁻⁶) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (p(interaction) = 0.03-0.006).Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Authors
Kelemen, LE; Terry, KL; Goodman, MT; Webb, PM; Bandera, EV; McGuire, V; Rossing, MA; Wang, Q; Dicks, E; Tyrer, JP; Song, H; Kupryjanczyk, J; Dansonka-Mieszkowska, A; Plisiecka-Halasa, J; Timorek, A; Menon, U; Gentry-Maharaj, A; Gayther, SA; Ramus, SJ; Narod, SA; Risch, HA; McLaughlin, JR; Siddiqui, N; Glasspool, R; Paul, J; Carty, K; Gronwald, J; Lubiński, J; Jakubowska, A; Cybulski, C; Kiemeney, LA; Massuger, LFAG; van Altena, AM; Aben, KKH; Olson, SH; Orlow, I; Cramer, DW; Levine, DA et al.
MLA Citation
Kelemen, LE, Terry, KL, Goodman, MT, Webb, PM, Bandera, EV, McGuire, V, Rossing, MA, Wang, Q, Dicks, E, Tyrer, JP, Song, H, Kupryjanczyk, J, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Timorek, A, Menon, U, Gentry-Maharaj, A, Gayther, SA, Ramus, SJ, Narod, SA, Risch, HA, McLaughlin, JR, Siddiqui, N, Glasspool, R, Paul, J, Carty, K, Gronwald, J, Lubiński, J, Jakubowska, A, Cybulski, C, Kiemeney, LA, Massuger, LFAG, van Altena, AM, Aben, KKH, Olson, SH, Orlow, I, Cramer, DW, and Levine, DA et al. "Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk." Molecular nutrition & food research 58.10 (October 2014): 2023-2035.
PMID
25066213
Source
epmc
Published In
Molecular Nutrition & Food Research
Volume
58
Issue
10
Publish Date
2014
Start Page
2023
End Page
2035
DOI
10.1002/mnfr.201400068

Modifizierter doppelt gestielter VRAM-Lappen zur simultanen Rekonstruktion eines Perineum- und posterioren vaginalen Defekts

Authors
Kokosis, G; Schmitz, R; Secord, AA; Havrilesky, LJ; Berchuck, A; Mantyh, CR; Erdmann, D
MLA Citation
Kokosis, G, Schmitz, R, Secord, AA, Havrilesky, LJ, Berchuck, A, Mantyh, CR, and Erdmann, D. "Modifizierter doppelt gestielter VRAM-Lappen zur simultanen Rekonstruktion eines Perineum- und posterioren vaginalen Defekts." Der Gynäkologe 47.10 (October 2014): 784-787.
Source
crossref
Published In
Der Gynäkologe
Volume
47
Issue
10
Publish Date
2014
Start Page
784
End Page
787
DOI
10.1007/s00129-014-3448-3

Epigenetic determinants of ovarian clear cell carcinoma biology.

Targeted approaches have revealed frequent epigenetic alterations in ovarian cancer, but the scope and relation of these changes to histologic subtype of disease is unclear. Genome-wide methylation and expression data for 14 clear cell carcinoma (CCC), 32 non-CCC and four corresponding normal cell lines were generated to determine how methylation profiles differ between cells of different histological derivations of ovarian cancer. Consensus clustering showed that CCC is epigenetically distinct. Inverse relationships between expression and methylation in CCC were identified, suggesting functional regulation by methylation, and included 22 hypomethylated (UM) genes and 276 hypermethylated (HM) genes. Categorical and pathway analyses indicated that the CCC-specific UM genes were involved in response to stress and many contain hepatocyte nuclear factor (HNF) 1-binding sites, while the CCC-specific HM genes included members of the estrogen receptor alpha (ERalpha) network and genes involved in tumor development. We independently validated the methylation status of 17 of these pathway-specific genes, and confirmed increased expression of HNF1 network genes and repression of ERalpha pathway genes in CCC cell lines and primary cancer tissues relative to non-CCC specimens. Treatment of three CCC cell lines with the demethylating agent Decitabine significantly induced expression for all five genes analyzed. Coordinate changes in pathway expression were confirmed using two primary ovarian cancer datasets (p < 0.0001 for both). Our results suggest that methylation regulates specific pathways and biological functions in CCC, with hypomethylation influencing the characteristic biology of the disease while hypermethylation contributes to the carcinogenic process.

Authors
Yamaguchi, K; Huang, Z; Matsumura, N; Mandai, M; Okamoto, T; Baba, T; Konishi, I; Berchuck, A; Murphy, SK
MLA Citation
Yamaguchi, K, Huang, Z, Matsumura, N, Mandai, M, Okamoto, T, Baba, T, Konishi, I, Berchuck, A, and Murphy, SK. "Epigenetic determinants of ovarian clear cell carcinoma biology." Int J Cancer 135.3 (August 1, 2014): 585-597.
PMID
24382740
Source
pubmed
Published In
International Journal of Cancer
Volume
135
Issue
3
Publish Date
2014
Start Page
585
End Page
597
DOI
10.1002/ijc.28701

Epigenetic determinants of ovarian clear cell carcinoma biology

Targeted approaches have revealed frequent epigenetic alterations in ovarian cancer, but the scope and relation of these changes to histologic subtype of disease is unclear. Genome-wide methylation and expression data for 14 clear cell carcinoma (CCC), 32 non-CCC and four corresponding normal cell lines were generated to determine how methylation profiles differ between cells of different histological derivations of ovarian cancer. Consensus clustering showed that CCC is epigenetically distinct. Inverse relationships between expression and methylation in CCC were identified, suggesting functional regulation by methylation, and included 22 hypomethylated (UM) genes and 276 hypermethylated (HM) genes. Categorical and pathway analyses indicated that the CCC-specific UM genes were involved in response to stress and many contain hepatocyte nuclear factor (HNF) 1-binding sites, while the CCC-specific HM genes included members of the estrogen receptor alpha (ERalpha) network and genes involved in tumor development. We independently validated the methylation status of 17 of these pathway-specific genes, and confirmed increased expression of HNF1 network genes and repression of ERalpha pathway genes in CCC cell lines and primary cancer tissues relative to non-CCC specimens. Treatment of three CCC cell lines with the demethylating agent Decitabine significantly induced expression for all five genes analyzed. Coordinate changes in pathway expression were confirmed using two primary ovarian cancer datasets (p < 0.0001 for both). Our results suggest that methylation regulates specific pathways and biological functions in CCC, with hypomethylation influencing the characteristic biology of the disease while hypermethylation contributes to the carcinogenic process. What's new? Ovarian cancer has several subtypes, and although different genetic mutations have been associated with particular subtypes, the molecular characteristics of ovarian clear cell carcinoma remain hazy. Aberrant DNA methylation can turn cells cancerous, and this study compared patterns of gene methylation in ovarian clear cell carcinomas, other ovarian cancer cells, and normal cells. They found that the clear cell carcinomas could indeed be identified by their distinctive pattern of DNA methylation. They found that this methylation pattern increased expression of certain stress response genes, while other genes, with tumor suppressive functions, were stifled. © 2013 UICC.

Authors
Yamaguchi, K; Huang, Z; Matsumura, N; Mandai, M; Okamoto, T; Baba, T; Konishi, I; Berchuck, A; Murphy, SK
MLA Citation
Yamaguchi, K, Huang, Z, Matsumura, N, Mandai, M, Okamoto, T, Baba, T, Konishi, I, Berchuck, A, and Murphy, SK. "Epigenetic determinants of ovarian clear cell carcinoma biology." International Journal of Cancer 135.3 (August 1, 2014): 585-597.
Source
scopus
Published In
International Journal of Cancer
Volume
135
Issue
3
Publish Date
2014
Start Page
585
End Page
597
DOI
10.1002/ijc.28701

Variation in NF-κB signaling pathways and survival in invasive epithelial ovarian cancer.

Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10(-5)). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41-2.35; P = 4.13 × 10(-6)] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56-0.82; P = 2.33 × 10(-5)). Other associations of note included TNF receptor-associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77-0.92; P = 6.49 × 10(-5)) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26-0.73; P = 4.56 × 10(-4)). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.

Authors
Block, MS; Charbonneau, B; Vierkant, RA; Fogarty, Z; Bamlet, WR; Pharoah, PDP; Georgia Chenevix-Trench, ; for AOCS, ; /ACS Group, ; Rossing, MA; Cramer, D; Pearce, CL; Schildkraut, J; Menon, U; Kjaer, SK; Levine, DA; Gronwald, J; Culver, HA; Whittemore, AS; Karlan, BY; Lambrechts, D; Wentzensen, N; Kupryjanczyk, J; Chang-Claude, J; Bandera, EV; Hogdall, E; Heitz, F; Kaye, SB; Fasching, PA; Campbell, I; Goodman, MT; Pejovic, T; Bean, YT; Hays, LE; Lurie, G; Eccles, D; Hein, A; Beckmann, MW et al.
MLA Citation
Block, MS, Charbonneau, B, Vierkant, RA, Fogarty, Z, Bamlet, WR, Pharoah, PDP, Georgia Chenevix-Trench, , for AOCS, , /ACS Group, , Rossing, MA, Cramer, D, Pearce, CL, Schildkraut, J, Menon, U, Kjaer, SK, Levine, DA, Gronwald, J, Culver, HA, Whittemore, AS, Karlan, BY, Lambrechts, D, Wentzensen, N, Kupryjanczyk, J, Chang-Claude, J, Bandera, EV, Hogdall, E, Heitz, F, Kaye, SB, Fasching, PA, Campbell, I, Goodman, MT, Pejovic, T, Bean, YT, Hays, LE, Lurie, G, Eccles, D, Hein, A, and Beckmann, MW et al. "Variation in NF-κB signaling pathways and survival in invasive epithelial ovarian cancer." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 23.7 (July 2014): 1421-1427.
PMID
24740199
Source
epmc
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
23
Issue
7
Publish Date
2014
Start Page
1421
End Page
1427
DOI
10.1158/1055-9965.epi-13-0962

ABCA transporter gene expression and poor outcome in epithelial ovarian cancer.

ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown.The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA-mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan-Meier analysis and log-rank tests. All statistical tests were two-sided.Associations with outcome were observed with ABC transporters of the "A" subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e-6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration.Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid trafficking as a potentially important process in EOC.

Authors
Hedditch, EL; Gao, B; Russell, AJ; Lu, Y; Emmanuel, C; Beesley, J; Johnatty, SE; Chen, X; Harnett, P; George, J; Australian Ovarian Cancer Study Group, ; Williams, RT; Flemming, C; Lambrechts, D; Despierre, E; Lambrechts, S; Vergote, I; Karlan, B; Lester, J; Orsulic, S; Walsh, C; Fasching, P; Beckmann, MW; Ekici, AB; Hein, A; Matsuo, K; Hosono, S; Nakanishi, T; Yatabe, Y; Pejovic, T; Bean, Y; Heitz, F; Harter, P; du Bois, A; Schwaab, I; Hogdall, E; Kjaer, SK; Jensen, A; Hogdall, C; Lundvall, L et al.
MLA Citation
Hedditch, EL, Gao, B, Russell, AJ, Lu, Y, Emmanuel, C, Beesley, J, Johnatty, SE, Chen, X, Harnett, P, George, J, Australian Ovarian Cancer Study Group, , Williams, RT, Flemming, C, Lambrechts, D, Despierre, E, Lambrechts, S, Vergote, I, Karlan, B, Lester, J, Orsulic, S, Walsh, C, Fasching, P, Beckmann, MW, Ekici, AB, Hein, A, Matsuo, K, Hosono, S, Nakanishi, T, Yatabe, Y, Pejovic, T, Bean, Y, Heitz, F, Harter, P, du Bois, A, Schwaab, I, Hogdall, E, Kjaer, SK, Jensen, A, Hogdall, C, and Lundvall, L et al. "ABCA transporter gene expression and poor outcome in epithelial ovarian cancer." Journal of the National Cancer Institute 106.7 (July 2014).
PMID
24957074
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
106
Issue
7
Publish Date
2014
DOI
10.1093/jnci/dju149

Relative influence of factors determining a woman's preference for treatment options in ovarian cancer.

Authors
Havrilesky, LJ; Secord, AA; Ehrisman, JA; Berchuck, A; Valea, FA; Lee, PS; Gaillard, S; Celia, D; Weinfurt, K; Abernethy, AP; Reed, SD
MLA Citation
Havrilesky, LJ, Secord, AA, Ehrisman, JA, Berchuck, A, Valea, FA, Lee, PS, Gaillard, S, Celia, D, Weinfurt, K, Abernethy, AP, and Reed, SD. "Relative influence of factors determining a woman's preference for treatment options in ovarian cancer." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Relationship between minimally invasive hysterectomy, pelvic cytology, and lymph vascular space invasion: a single institution study of 458 patients.

The aim of this study is to determine whether a minimally invasive approach to hysterectomy is associated with an increased rate of lymph vascular space invasion (LVSI) and/or malignant pelvic peritoneal cytology in endometrial cancer.We performed a single institution analysis of 458 women with endometrial cancer who underwent either total abdominal hysterectomy (TAH) or minimally invasive hysterectomy (MIH) with use of a disposable uterine manipulator. All patients had endometrial cancer diagnosed by endometrial biopsy at a single academic institution between 2002 and 2012. Exclusion criteria were pre-operative D&C and/or hysteroscopy, uterine perforation or morcellation, and conversion to laparotomy. Multivariate logistic regression models to determine if type of hysterectomy predicts either LVSI or presence of abnormal cytology were controlled for grade, stage, depth of invasion, tumor size, cervical and adnexal involvement.LVSI was identified in 39/214 (18%) MIH and 44/242 (18%) TAH (p=0.99). Pelvic washings were malignant in 14/203 (7%) MIH and 16/241 (7%) TAH (p=1.0). Washings were atypical or inconclusive in 16/203 (8%) MIH and 6/241 (2.5%) TAH (p=0.014). In multivariate analyses, type of hysterectomy was not a significant predictor of either LVSI (p=0.29) or presence of malignant washings (p=0.66), but was a predictor of atypical or inconclusive washings (p=0.03).Minimally invasive hysterectomy with use of a uterine manipulator for endometrial cancer is not associated with LVSI or malignant cytology. Algorithms that better determine the etiology and implications of inconclusive or atypical pelvic cytology are needed to inform the possible additional risk associated with a minimally invasive approach to endometrial cancer.

Authors
Zhang, C; Havrilesky, LJ; Broadwater, G; Di Santo, N; Ehrisman, JA; Lee, PS; Berchuck, A; Alvarez Secord, A; Bean, S; Bentley, RC; Valea, FA
MLA Citation
Zhang, C, Havrilesky, LJ, Broadwater, G, Di Santo, N, Ehrisman, JA, Lee, PS, Berchuck, A, Alvarez Secord, A, Bean, S, Bentley, RC, and Valea, FA. "Relationship between minimally invasive hysterectomy, pelvic cytology, and lymph vascular space invasion: a single institution study of 458 patients." Gynecologic oncology 133.2 (May 2014): 211-215.
PMID
24582867
Source
epmc
Published In
Gynecologic Oncology
Volume
133
Issue
2
Publish Date
2014
Start Page
211
End Page
215
DOI
10.1016/j.ygyno.2014.02.025

Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.

Authors
Witkowski, L; Carrot-Zhang, J; Albrecht, S; Fahiminiya, S; Hamel, N; Tomiak, E; Grynspan, D; Saloustros, E; Nadaf, J; Rivera, B; Gilpin, C; Castellsagué, E; Silva-Smith, R; Plourde, F; Wu, M; Saskin, A; Arseneault, M; Karabakhtsian, RG; Reilly, EA; Ueland, FR; Margiolaki, A; Pavlakis, K; Castellino, SM; Lamovec, J; Mackay, HJ; Roth, LM; Ulbright, TM; Bender, TA; Georgoulias, V; Longy, M; Berchuck, A; Tischkowitz, M; Nagel, I; Siebert, R; Stewart, CJR; Arseneau, J; McCluggage, WG; Clarke, BA et al.
MLA Citation
Witkowski, L, Carrot-Zhang, J, Albrecht, S, Fahiminiya, S, Hamel, N, Tomiak, E, Grynspan, D, Saloustros, E, Nadaf, J, Rivera, B, Gilpin, C, Castellsagué, E, Silva-Smith, R, Plourde, F, Wu, M, Saskin, A, Arseneault, M, Karabakhtsian, RG, Reilly, EA, Ueland, FR, Margiolaki, A, Pavlakis, K, Castellino, SM, Lamovec, J, Mackay, HJ, Roth, LM, Ulbright, TM, Bender, TA, Georgoulias, V, Longy, M, Berchuck, A, Tischkowitz, M, Nagel, I, Siebert, R, Stewart, CJR, Arseneau, J, McCluggage, WG, and Clarke, BA et al. "Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type." Nature genetics 46.5 (May 2014): 438-443.
PMID
24658002
Source
epmc
Published In
Nature Genetics
Volume
46
Issue
5
Publish Date
2014
Start Page
438
End Page
443
DOI
10.1038/ng.2931

Relationship between minimally invasive hysterectomy, pelvic cytology, and lymph vascular space invasion: A single institution study of 458 patients

Authors
Zhang, C; Havrilesky, LJ; Broadwater, G; Di Santo, N; Ehrisman, JA; Lee, PS; Berchuck, A; Alvarez Secord, A; Bean, S; Bentley, RC; Valea, FA
MLA Citation
Zhang, C, Havrilesky, LJ, Broadwater, G, Di Santo, N, Ehrisman, JA, Lee, PS, Berchuck, A, Alvarez Secord, A, Bean, S, Bentley, RC, and Valea, FA. "Relationship between minimally invasive hysterectomy, pelvic cytology, and lymph vascular space invasion: A single institution study of 458 patients." Gynecologic Oncology 133.2 (May 2014): 211-215.
Source
crossref
Published In
Gynecologic Oncology
Volume
133
Issue
2
Publish Date
2014
Start Page
211
End Page
215
DOI
10.1016/j.ygyno.2014.02.025

RELATIVE INFLUENCE OF FACTORS DETERMINING A WOMAN'S PREFERENCE FOR TREATMENT OPTIONS IN OVARIAN CANCER: A DISCRETE CHOICE EXPERIMENT

Authors
Havrilesky, LJ; Secord, AA; Ehrisman, J; Berchuck, A; Valea, FA; Lee, PS; Cella, D; Weinfurt, K; Abernethy, AP; Reed, SD
MLA Citation
Havrilesky, LJ, Secord, AA, Ehrisman, J, Berchuck, A, Valea, FA, Lee, PS, Cella, D, Weinfurt, K, Abernethy, AP, and Reed, SD. "RELATIVE INFLUENCE OF FACTORS DETERMINING A WOMAN'S PREFERENCE FOR TREATMENT OPTIONS IN OVARIAN CANCER: A DISCRETE CHOICE EXPERIMENT." VALUE IN HEALTH 17.3 (May 2014): A93-A93.
Source
wos-lite
Published In
Value in Health
Volume
17
Issue
3
Publish Date
2014
Start Page
A93
End Page
A93

Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA.

Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.

Authors
Earp, MA; Kelemen, LE; Magliocco, AM; Swenerton, KD; Chenevix-Trench, G; Australian Cancer Study, ; Australian Ovarian Cancer Study Group, ; Lu, Y; Hein, A; Ekici, AB; Beckmann, MW; Fasching, PA; Lambrechts, D; Despierre, E; Vergote, I; Lambrechts, S; Doherty, JA; Rossing, MA; Chang-Claude, J; Rudolph, A; Friel, G; Moysich, KB; Odunsi, K; Sucheston-Campbell, L; Lurie, G; Goodman, MT; Carney, ME; Thompson, PJ; Runnebaum, IB; Dürst, M; Hillemanns, P; Dörk, T; Antonenkova, N; Bogdanova, N et al.
MLA Citation
Earp, MA, Kelemen, LE, Magliocco, AM, Swenerton, KD, Chenevix-Trench, G, Australian Cancer Study, , Australian Ovarian Cancer Study Group, , Lu, Y, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Despierre, E, Vergote, I, Lambrechts, S, Doherty, JA, Rossing, MA, Chang-Claude, J, Rudolph, A, Friel, G, Moysich, KB, Odunsi, K, Sucheston-Campbell, L, Lurie, G, Goodman, MT, Carney, ME, Thompson, PJ, Runnebaum, IB, Dürst, M, Hillemanns, P, Dörk, T, Antonenkova, N, and Bogdanova, N et al. "Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA." Hum Genet 133.5 (May 2014): 481-497.
PMID
24190013
Source
pubmed
Published In
Human Genetics
Volume
133
Issue
5
Publish Date
2014
Start Page
481
End Page
497
DOI
10.1007/s00439-013-1383-3

Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome.

The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 × 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 × 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 × 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 × 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 × 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer.

Authors
Charbonneau, B; Moysich, KB; Kalli, KR; Oberg, AL; Vierkant, RA; Fogarty, ZC; Block, MS; Maurer, MJ; Goergen, KM; Fridley, BL; Cunningham, JM; Rider, DN; Preston, C; Hartmann, LC; Lawrenson, K; Wang, C; Tyrer, J; Song, H; deFazio, A; Johnatty, SE; Doherty, JA; Phelan, CM; Sellers, TA; Ramirez, SM; Vitonis, AF; Terry, KL; Van Den Berg, D; Pike, MC; Wu, AH; Berchuck, A; Gentry-Maharaj, A; Ramus, SJ; Diergaarde, B; Shen, H; Jensen, A; Menkiszak, J; Cybulski, C; Lubiłski, J; Ziogas, A et al.
MLA Citation
Charbonneau, B, Moysich, KB, Kalli, KR, Oberg, AL, Vierkant, RA, Fogarty, ZC, Block, MS, Maurer, MJ, Goergen, KM, Fridley, BL, Cunningham, JM, Rider, DN, Preston, C, Hartmann, LC, Lawrenson, K, Wang, C, Tyrer, J, Song, H, deFazio, A, Johnatty, SE, Doherty, JA, Phelan, CM, Sellers, TA, Ramirez, SM, Vitonis, AF, Terry, KL, Van Den Berg, D, Pike, MC, Wu, AH, Berchuck, A, Gentry-Maharaj, A, Ramus, SJ, Diergaarde, B, Shen, H, Jensen, A, Menkiszak, J, Cybulski, C, Lubiłski, J, and Ziogas, A et al. "Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome." Cancer immunology research 2.4 (April 2014): 332-340.
PMID
24764580
Source
epmc
Published In
Cancer Immunology Research
Volume
2
Issue
4
Publish Date
2014
Start Page
332
End Page
340
DOI
10.1158/2326-6066.cir-13-0136

Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type

Authors
Witkowski, L; Carrot-Zhang, J; Albrecht, S; Fahiminiya, S; Hamel, N; Tomiak, E; Grynspan, D; Saloustros, E; Nadaf, J; Rivera, B; Gilpin, C; Castellsagué, E; Silva-Smith, R; Plourde, F; Wu, M; Saskin, A; Arseneault, M; Karabakhtsian, RG; Reilly, EA; Ueland, FR; Margiolaki, A; Pavlakis, K; Castellino, SM; Lamovec, J; Mackay, HJ; Roth, LM; Ulbright, TM; Bender, TA; Georgoulias, V; Longy, M; Berchuck, A; Tischkowitz, M; Nagel, I; Siebert, R; Stewart, CJR; Arseneau, J; McCluggage, WG; Clarke, BA et al.
MLA Citation
Witkowski, L, Carrot-Zhang, J, Albrecht, S, Fahiminiya, S, Hamel, N, Tomiak, E, Grynspan, D, Saloustros, E, Nadaf, J, Rivera, B, Gilpin, C, Castellsagué, E, Silva-Smith, R, Plourde, F, Wu, M, Saskin, A, Arseneault, M, Karabakhtsian, RG, Reilly, EA, Ueland, FR, Margiolaki, A, Pavlakis, K, Castellino, SM, Lamovec, J, Mackay, HJ, Roth, LM, Ulbright, TM, Bender, TA, Georgoulias, V, Longy, M, Berchuck, A, Tischkowitz, M, Nagel, I, Siebert, R, Stewart, CJR, Arseneau, J, McCluggage, WG, and Clarke, BA et al. "Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type." Nature Genetics 46.5 (March 23, 2014): 438-443.
Source
crossref
Published In
Nature Genetics
Volume
46
Issue
5
Publish Date
2014
Start Page
438
End Page
443
DOI
10.1038/ng.2931

Risk of ovarian cancer and the NF-κB pathway: genetic association with IL1A and TNFSF10.

A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 × 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted.

Authors
Charbonneau, B; Block, MS; Bamlet, WR; Vierkant, RA; Kalli, KR; Fogarty, Z; Rider, DN; Sellers, TA; Tworoger, SS; Poole, E; Risch, HA; Salvesen, HB; Kiemeney, LA; Baglietto, L; Giles, GG; Severi, G; Trabert, B; Wentzensen, N; Chenevix-Trench, G; for AOCS/ACS group, ; Whittemore, AS; Sieh, W; Chang-Claude, J; Bandera, EV; Orlow, I; Terry, K; Goodman, MT; Thompson, PJ; Cook, LS; Rossing, MA; Ness, RB; Narod, SA; Kupryjanczyk, J; Lu, K; Butzow, R; Dörk, T; Pejovic, T; Campbell, I; Le, ND et al.
MLA Citation
Charbonneau, B, Block, MS, Bamlet, WR, Vierkant, RA, Kalli, KR, Fogarty, Z, Rider, DN, Sellers, TA, Tworoger, SS, Poole, E, Risch, HA, Salvesen, HB, Kiemeney, LA, Baglietto, L, Giles, GG, Severi, G, Trabert, B, Wentzensen, N, Chenevix-Trench, G, for AOCS/ACS group, , Whittemore, AS, Sieh, W, Chang-Claude, J, Bandera, EV, Orlow, I, Terry, K, Goodman, MT, Thompson, PJ, Cook, LS, Rossing, MA, Ness, RB, Narod, SA, Kupryjanczyk, J, Lu, K, Butzow, R, Dörk, T, Pejovic, T, Campbell, I, and Le, ND et al. "Risk of ovarian cancer and the NF-κB pathway: genetic association with IL1A and TNFSF10." Cancer Res 74.3 (February 1, 2014): 852-861.
PMID
24272484
Source
pubmed
Published In
Cancer Research
Volume
74
Issue
3
Publish Date
2014
Start Page
852
End Page
861
DOI
10.1158/0008-5472.CAN-13-1051

Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer: a pooled analysis in the Ovarian Cancer Association Consortium.

Regular aspirin use is associated with reduced risk of several malignancies. Epidemiologic studies analyzing aspirin, nonaspirin nonsteroidal anti-inflammatory drug (NSAID), and acetaminophen use and ovarian cancer risk have been inconclusive.We analyzed pooled data from 12 population-based case-control studies of ovarian cancer, including 7776 case patients and 11843 control subjects accrued between 1992 and 2007. Odds ratios (ORs) for associations of medication use with invasive epithelial ovarian cancer were estimated in individual studies using logistic regression and combined using random effects meta-analysis. Associations between frequency, dose, and duration of analgesic use and risk of ovarian cancer were also assessed. All statistical tests were two-sided.Aspirin use was associated with a reduced risk of ovarian cancer (OR = 0.91; 95% confidence interval [CI] = 0.84 to 0.99). Results were similar but not statistically significant for nonaspirin NSAIDs, and there was no association with acetaminophen. In seven studies with frequency data, the reduced risk was strongest among daily aspirin users (OR = 0.80; 95% CI = 0.67 to 0.96). In three studies with dose information, the reduced risk was strongest among users of low dose (<100 mg) aspirin (OR = 0.66; 95% CI = 0.53 to 0.83), whereas for nonaspirin NSAIDs, the reduced risk was strongest for high dose (≥500 mg) usage (OR = 0.76; 95% CI = 0.64 to 0.91).Aspirin use was associated with a reduced risk of ovarian cancer, especially among daily users of low-dose aspirin. These findings suggest that the same aspirin regimen proven to protect against cardiovascular events and several cancers could reduce the risk of ovarian cancer 20% to 34% depending on frequency and dose of use.

Authors
Trabert, B; Ness, RB; Lo-Ciganic, W-H; Murphy, MA; Goode, EL; Poole, EM; Brinton, LA; Webb, PM; Nagle, CM; Jordan, SJ; Australian Ovarian Cancer Study Group, Australian Cancer Study (Ovarian Cancer), ; Risch, HA; Rossing, MA; Doherty, JA; Goodman, MT; Lurie, G; Kjær, SK; Hogdall, E; Jensen, A; Cramer, DW; Terry, KL; Vitonis, A; Bandera, EV; Olson, S; King, MG; Chandran, U; Anton-Culver, H; Ziogas, A; Menon, U; Gayther, SA; Ramus, SJ; Gentry-Maharaj, A; Wu, AH; Pearce, CL; Pike, MC; Berchuck, A et al.
MLA Citation
Trabert, B, Ness, RB, Lo-Ciganic, W-H, Murphy, MA, Goode, EL, Poole, EM, Brinton, LA, Webb, PM, Nagle, CM, Jordan, SJ, Australian Ovarian Cancer Study Group, Australian Cancer Study (Ovarian Cancer), , Risch, HA, Rossing, MA, Doherty, JA, Goodman, MT, Lurie, G, Kjær, SK, Hogdall, E, Jensen, A, Cramer, DW, Terry, KL, Vitonis, A, Bandera, EV, Olson, S, King, MG, Chandran, U, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Wu, AH, Pearce, CL, Pike, MC, and Berchuck, A et al. "Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer: a pooled analysis in the Ovarian Cancer Association Consortium." Journal of the National Cancer Institute 106.2 (February 2014): djt431-.
PMID
24503200
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
106
Issue
2
Publish Date
2014
Start Page
djt431
DOI
10.1093/jnci/djt431

Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer: a pooled analysis in the Ovarian Cancer Association Consortium.

Regular aspirin use is associated with reduced risk of several malignancies. Epidemiologic studies analyzing aspirin, nonaspirin nonsteroidal anti-inflammatory drug (NSAID), and acetaminophen use and ovarian cancer risk have been inconclusive. We analyzed pooled data from 12 population-based case-control studies of ovarian cancer, including 7776 case patients and 11843 control subjects accrued between 1992 and 2007. Odds ratios (ORs) for associations of medication use with invasive epithelial ovarian cancer were estimated in individual studies using logistic regression and combined using random effects meta-analysis. Associations between frequency, dose, and duration of analgesic use and risk of ovarian cancer were also assessed. All statistical tests were two-sided. Aspirin use was associated with a reduced risk of ovarian cancer (OR = 0.91; 95% confidence interval [CI] = 0.84 to 0.99). Results were similar but not statistically significant for nonaspirin NSAIDs, and there was no association with acetaminophen. In seven studies with frequency data, the reduced risk was strongest among daily aspirin users (OR = 0.80; 95% CI = 0.67 to 0.96). In three studies with dose information, the reduced risk was strongest among users of low dose (<100 mg) aspirin (OR = 0.66; 95% CI = 0.53 to 0.83), whereas for nonaspirin NSAIDs, the reduced risk was strongest for high dose (≥500 mg) usage (OR = 0.76; 95% CI = 0.64 to 0.91). Aspirin use was associated with a reduced risk of ovarian cancer, especially among daily users of low-dose aspirin. These findings suggest that the same aspirin regimen proven to protect against cardiovascular events and several cancers could reduce the risk of ovarian cancer 20% to 34% depending on frequency and dose of use.

Authors
Trabert, B; Ness, RB; Lo-Ciganic, WH; Murphy, MA; Goode, EL; Poole, EM; Brinton, LA; Webb, PM; Nagle, CM; Jordan, SJ; Australian Ovarian Cancer Study Group, ACSOC; Risch, HA; Rossing, MA; Doherty, JA; Goodman, MT; Lurie, G; Kjær, SK; Hogdall, E; Jensen, A; Cramer, DW; Terry, KL; Vitonis, A; Bandera, EV; Olson, S; King, MG; Chandran, U; Anton-Culver, H; Ziogas, A; Menon, U; Gayther, SA; Ramus, SJ; Gentry-Maharaj, A; Wu, AH; Pearce, CL; Pike, MC; Berchuck, A; Schildkraut, JM; Wentzensen, N et al.
MLA Citation
Trabert, B, Ness, RB, Lo-Ciganic, WH, Murphy, MA, Goode, EL, Poole, EM, Brinton, LA, Webb, PM, Nagle, CM, Jordan, SJ, Australian Ovarian Cancer Study Group, ACSOC, Risch, HA, Rossing, MA, Doherty, JA, Goodman, MT, Lurie, G, Kjær, SK, Hogdall, E, Jensen, A, Cramer, DW, Terry, KL, Vitonis, A, Bandera, EV, Olson, S, King, MG, Chandran, U, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, SA, Ramus, SJ, Gentry-Maharaj, A, Wu, AH, Pearce, CL, Pike, MC, Berchuck, A, Schildkraut, JM, and Wentzensen, N et al. "Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer: a pooled analysis in the Ovarian Cancer Association Consortium." Journal of the National Cancer Institute 106.2 (January 1, 2014).
Source
scopus
Published In
Journal of the National Cancer Institute
Volume
106
Issue
2
Publish Date
2014
DOI
10.1093/jnci/djt431

Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes. © 2013 Springer-Verlag Berlin Heidelberg.

Authors
Earp, MA; Kelemen, LE; Magliocco, AM; Swenerton, KD; Chenevix-Trench, G; Lu, Y; Hein, A; Ekici, AB; Beckmann, MW; Fasching, PA; Lambrechts, D; Despierre, E; Vergote, I; Lambrechts, S; Doherty, JA; Rossing, MA; Chang-Claude, J; Rudolph, A; Friel, G; Moysich, KB; Odunsi, K; Sucheston-Campbell, L; Lurie, G; Goodman, MT; Carney, ME; Thompson, PJ; Runnebaum, IB; Dürst, M; Hillemanns, P; Dörk, T; Antonenkova, N; Bogdanova, N; Leminen, A; Nevanlinna, H; Pelttari, LM; Butzow, R; Bunker, CH; Modugno, F et al.
MLA Citation
Earp, MA, Kelemen, LE, Magliocco, AM, Swenerton, KD, Chenevix-Trench, G, Lu, Y, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Despierre, E, Vergote, I, Lambrechts, S, Doherty, JA, Rossing, MA, Chang-Claude, J, Rudolph, A, Friel, G, Moysich, KB, Odunsi, K, Sucheston-Campbell, L, Lurie, G, Goodman, MT, Carney, ME, Thompson, PJ, Runnebaum, IB, Dürst, M, Hillemanns, P, Dörk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Nevanlinna, H, Pelttari, LM, Butzow, R, Bunker, CH, and Modugno, F et al. "Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA." Human Genetics 133.5 (January 1, 2014): 481-497.
Source
scopus
Published In
Human Genetics
Volume
133
Issue
5
Publish Date
2014
Start Page
481
End Page
497
DOI
10.1007/s00439-013-1383-3

A modified bipedicle VRAM flap for simultaneous reconstruction of a perineal and posterior vaginal defect

© 2014, Springer-Verlag Berlin Heidelberg. The management of locally advanced pelvic tumors regularly requires radical surgical resection. The resection results in significant intrinsic and extrinsic pelvic defects. The advent of composite flaps has revolutionized vaginal and perineal reconstruction. Flaps provide bulky tissue to obliterate dead space, recruit vascularized tissue to an irradiated area and facilitate the skin closure. The authors present a modified vertical rectus abdominis myocutaneous (VRAM) flap for simultaneous reconstruction of a perineal and posterior vaginal defect following radical pelvic and abdominoperineal resection, based on two individual perforators off the inferior epigastric artery and vein with an excellent outcome. The English full-text version of this article is available at SpringerLink (under supplemental).

Authors
Kokosis, G; Schmitz, R; Secord, AA; Havrilesky, LJ; Berchuck, A; Mantyh, CR; Erdmann, D
MLA Citation
Kokosis, G, Schmitz, R, Secord, AA, Havrilesky, LJ, Berchuck, A, Mantyh, CR, and Erdmann, D. "A modified bipedicle VRAM flap for simultaneous reconstruction of a perineal and posterior vaginal defect." Gynakologe 47.10 (January 1, 2014): 784-787.
Source
scopus
Published In
Der Gynäkologe
Volume
47
Issue
10
Publish Date
2014
Start Page
784
End Page
787
DOI
10.1007/s00129-014-3448-3

Patient preferences in advanced or recurrent ovarian cancer

© 2014 American Cancer Society. BACKGROUND: The objective of this study was to elucidate relative preferences of women with ovarian cancer for symptoms, treatment-related side effects, and progression-free survival (PFS) relevant to choosing a treatment regimen. METHODS: Women with advanced or recurrent ovarian cancer participated in a survey that included 3 methods to measure patient preferences (ratings, rankings, and a discrete-choice experiment) for 7 attributes: mode of administration, visit frequency, peripheral neuropathy, nausea and vomiting, fatigue, abdominal discomfort, and PFS. Participants were asked to choose between 2 unlabeled treatment scenarios that were characterized using the 7 attributes. Each participant completed 12 choice questions in which attribute levels were assigned according to an experimental design and a fixed-choice question representing 2 chemotherapy regimens for ovarian cancer. RESULTS: In total, 95 women completed the survey. Participants' ratings and rankings revealed greater concern and importance for PFS than for any other attribute (P < .0001 for all). The discrete-choice experiment revealed that the relative odds that a participant would choose a scenario with 18 months, 21 months, a nd 24 months of PFS versus 15 months of PFS were 1.5 (P5.01), 3.4 (P < .001), and 7.5 (P < .001), respectively. However, participants' choices indicated that they were willing to accept a shorter PFS to avoid severe side effects: 6.7 months to reduce nausea and vomiting from severe to mild, 5.0 months to reduce neuropathy from severe to mild, and 3.7 months to reduce abdominal symptoms from severe to moderate. CONCLUSIONS: PFS is the predominant driver of patient preferences for chemotherapy regimens. However, women in the current study were willing to trade significant PFS time for reductions in treatment-related toxicity.

Authors
Havrilesky, LJ; Secord, AA; Ehrisman, JA; Berchuck, A; Valea, FA; Lee, PS; Gaillard, SL; Samsa, GP; Cella, D; Weinfurt, KP; Abernethy, AP; Reed, SD
MLA Citation
Havrilesky, LJ, Secord, AA, Ehrisman, JA, Berchuck, A, Valea, FA, Lee, PS, Gaillard, SL, Samsa, GP, Cella, D, Weinfurt, KP, Abernethy, AP, and Reed, SD. "Patient preferences in advanced or recurrent ovarian cancer." Cancer 120.23 (January 1, 2014): 3651-3659.
Source
scopus
Published In
Cancer
Volume
120
Issue
23
Publish Date
2014
Start Page
3651
End Page
3659
DOI
10.1002/cncr.28940

Differential Angiogenic Gene Expression in TP53 Wild-Type and Mutant Ovarian Cancer Cell Lines.

Underlying mechanisms regulating angiogenesis in ovarian cancer have not been completely elucidated. Evidence suggests that the TP53 tumor suppressor pathway and tumor microenvironment play integral roles. We utilized microarray technology to study the interaction between TP53 mutational status and hypoxia on angiogenic gene expression.Affymetrix U133A arrays were analyzed for angiogenic gene expression in 19 ovarian cancer cell lines stratified both by TP53 mutation status and A2780 wild-type (wt) TP53 vs. mutated (m) TP53 cell lines after treatment under hypoxic conditions or with ionizing radiation.Twenty-eight differentially expressed angiogenic genes were identified in the mTP53 cell lines compared to wtTP53 lines. Five genes were upregulated in mTP53 cells: 40% involved in extracellular matrix (ECM) degradation [matrix metalloproteinase 10 (MMP10)/15] and 60% in angiogenesis (fibroblast growth factor receptor 3/VEGFA/ephrin receptor-B4). Twenty-three genes were upregulated in wtTP53: nearly 22% were ECM constituents or involved in ECM degradation; over 40% were growth factors or mediators of angiogenesis. Five genes were upregulated in the A2780mTP53 cells: 40% involved in ECM remodeling (MMP10, ADAMTS1), 40% with pro-angiogenic activity (EFNB2, factor 2 receptor), and 20% with anti-angiogenic properties (ADAMTS1). Three genes were upregulated in hypoxia treated cells compared to controls: one with anti-angiogenic activity (angiopoietin-like 4) and two with pro-angiogenic activity (VEGFA, EFNA3). No significant gene fold changes were noted after exposure to radiation. Four genes continued to demonstrate significant differential expression (p ≤ 0.05) after adjusting for multiple comparisons. These genes included endoglin upregulation in wt lines (pro-angiogenesis) and upregulation of FGF20 (growth factor), ADAMTS1 (anti-angiogenesis) and MMP10 (ECM degradation) in mTP53 cell lines.Our exploratory findings indicate that non-overlapping angiogenic pathways may be altered by TP53 mutations and hypoxic conditions in the tumor microenvironment. Further evaluation is needed for confirmation.

Authors
Davidson, BA; Rubatt, JM; Corcoran, DL; Teoh, DK; Bernardini, MQ; Grace, LA; Soper, WJ; Berchuck, A; Siamakpour-Reihani, S; Chen, W; Owzar, K; Murphy, SK; Secord, AA
MLA Citation
Davidson, BA, Rubatt, JM, Corcoran, DL, Teoh, DK, Bernardini, MQ, Grace, LA, Soper, WJ, Berchuck, A, Siamakpour-Reihani, S, Chen, W, Owzar, K, Murphy, SK, and Secord, AA. "Differential Angiogenic Gene Expression in TP53 Wild-Type and Mutant Ovarian Cancer Cell Lines." Frontiers in oncology 4 (January 2014): 163-.
PMID
24999452
Source
epmc
Published In
Frontiers in Oncology
Volume
4
Publish Date
2014
Start Page
163
DOI
10.3389/fonc.2014.00163

A genome-wide association scan (GWAS) for mean telomere length within the COGS project: identified loci show little association with hormone-related cancer risk.

Mean telomere length (TL) in blood cells is heritable and has been reported to be associated with risks of several diseases, including cancer. We conducted a meta-analysis of three GWAS for TL (total n=2240) and selected 1629 variants for replication via the "iCOGS" custom genotyping array. All ∼200 000 iCOGS variants were analysed with TL, and those displaying associations in healthy controls (n = 15 065) were further tested in breast cancer cases (n = 11 024). We found a novel TL association (Ptrend < 4 × 10(-10)) at 3p14.4 close to PXK and evidence (Ptrend < 7 × 10(-7)) for TL loci at 6p22.1 (ZNF311) and 20q11.2 (BCL2L1). We additionally confirmed (Ptrend < 5 × 10(-14)) the previously reported loci at 3q26.2 (TERC), 5p15.3 (TERT) and 10q24.3 (OBFC1) and found supportive evidence (Ptrend < 5 × 10(-4)) for the published loci at 2p16.2 (ACYP2), 4q32.2 (NAF1) and 20q13.3 (RTEL1). SNPs tagging these loci explain TL differences of up to 731 bp (corresponding to 18% of total TL in healthy individuals), however, they display little direct evidence for association with breast, ovarian or prostate cancer risks.

Authors
Pooley, KA; Bojesen, SE; Weischer, M; Nielsen, SF; Thompson, D; Amin Al Olama, A; Michailidou, K; Tyrer, JP; Benlloch, S; Brown, J; Audley, T; Luben, R; Khaw, K-T; Neal, DE; Hamdy, FC; Donovan, JL; Kote-Jarai, Z; Baynes, C; Shah, M; Bolla, MK; Wang, Q; Dennis, J; Dicks, E; Yang, R; Rudolph, A; Schildkraut, J; Chang-Claude, J; Burwinkel, B; Chenevix-Trench, G; Pharoah, PDP; Berchuck, A; Eeles, RA; Easton, DF; Dunning, AM; Nordestgaard, BG
MLA Citation
Pooley, KA, Bojesen, SE, Weischer, M, Nielsen, SF, Thompson, D, Amin Al Olama, A, Michailidou, K, Tyrer, JP, Benlloch, S, Brown, J, Audley, T, Luben, R, Khaw, K-T, Neal, DE, Hamdy, FC, Donovan, JL, Kote-Jarai, Z, Baynes, C, Shah, M, Bolla, MK, Wang, Q, Dennis, J, Dicks, E, Yang, R, Rudolph, A, Schildkraut, J, Chang-Claude, J, Burwinkel, B, Chenevix-Trench, G, Pharoah, PDP, Berchuck, A, Eeles, RA, Easton, DF, Dunning, AM, and Nordestgaard, BG. "A genome-wide association scan (GWAS) for mean telomere length within the COGS project: identified loci show little association with hormone-related cancer risk." Hum Mol Genet 22.24 (December 15, 2013): 5056-5064.
PMID
23900074
Source
pubmed
Published In
Human Molecular Genetics
Volume
22
Issue
24
Publish Date
2013
Start Page
5056
End Page
5064
DOI
10.1093/hmg/ddt355

Evidence of a chemopreventive effect of progestin unrelated to ovulation on reproductive tract cancers in the egg-laying hen.

Epidemiologic, laboratory, and animal evidence suggests that progestins and vitamin D may be potent ovarian cancer preventives. Our objectives were to evaluate progestins as reproductive tract cancer chemopreventives in the chicken, determine whether restricted ovulation affected the incidence of reproductive tract tumors, and assess whether vitamin D would confer cancer protection either alone or in addition to progestin. A total of 2,400 two-year-old Single Comb White Leghorns were randomized into six groups (400 each) with hormonal and dietary manipulation for 2 years as follows: (i) no intervention, regular feed/caloric intake, (ii) control, (iii) vitamin D, (iv) the progestin levonorgestrel, (v) vitamin D plus levonorgestrel, and (vi) the progestin Provera (medroxyprogesterone acetate). Groups 2 to 6 were caloric restricted to inhibit ovulation. Our results indicated that caloric restriction decreased egg production by more than 60%, and was associated with a greater than 70% decrease in reproductive tract cancers. Ovulatory events did not differ among the caloric-restricted groups (groups 2-6), except for the group receiving levonorgestrel, which had fewer ovulatory events than controls (P = 0.046). After correcting for egg production, birds receiving progestins had significantly fewer reproductive tract cancers [OR, 0.61; confidence interval (CI), 0.39-0.95; P = 0.03], with similar proportionate reductions in tumors arising in either the ovary or oviduct. Vitamin D did not significantly affect cancer incidence overall, or add to the cancer preventive effect of progestins. This study suggests a protective effect of progestins against ovarian and oviductal cancers. These data support the concept that progestins provide a chemopreventive effect unrelated to ovulation.

Authors
Rodriguez, GC; Barnes, HJ; Anderson, KE; Whitaker, RS; Berchuck, A; Petitte, JN; Lancaster, JM; Wenham, RM; Turbov, JM; Day, R; Maxwell, GL; Carver, DK
MLA Citation
Rodriguez, GC, Barnes, HJ, Anderson, KE, Whitaker, RS, Berchuck, A, Petitte, JN, Lancaster, JM, Wenham, RM, Turbov, JM, Day, R, Maxwell, GL, and Carver, DK. "Evidence of a chemopreventive effect of progestin unrelated to ovulation on reproductive tract cancers in the egg-laying hen." Cancer Prev Res (Phila) 6.12 (December 2013): 1283-1292.
PMID
24136864
Source
pubmed
Published In
Cancer Prevention Research
Volume
6
Issue
12
Publish Date
2013
Start Page
1283
End Page
1292
DOI
10.1158/1940-6207.CAPR-12-0426

Molecular signatures of epithelial ovarian cancer: analysis of associations with tumor characteristics and epidemiologic risk factors.

BACKGROUND: Six gene expression subtypes of invasive epithelial ovarian cancer were recently defined using microarrays by Tothill and colleagues. The Cancer Genome Atlas (TCGA) project subsequently replicated these subtypes and identified a signature predictive of survival in high-grade serous (HGS) cancers. We previously validated these signatures for use in formalin-fixed paraffin-embedded tissues. The aim of the present study was to determine whether these signatures are associated with specific ovarian cancer risk factors, which would add to the evidence that they reflect the heterogeneous etiology of this disease. METHODS: We modeled signature-specific tumor characteristics and epidemiologic risk factor relationships using multiple regression and multivariate response multiple regression models in 193 patients from a case-control study of epithelial ovarian cancer. RESULTS: We observed associations between the Tothill gene expression subtype signatures and both age at diagnosis (P = 0.0008) and race (P = 0.008). Although most established epidemiologic risk factors were not associated with molecular signatures, there was an association between breast feeding (P = 0.024) and first-degree family history of breast or ovarian cancer (P = 0.034) among the 106 HGS cases. Some of the above associations were validated using gene expression microarray data from the TCGA project. Weak associations were seen with age at menarche and duration of oral contraceptive use and the TCGA survival signature. CONCLUSIONS: These data support the potential for genomic characterization to elucidate the etiologic heterogeneity of epithelial ovarian cancer. IMPACT: This study suggests that molecular signatures may augment the ability to define etiologic subtypes of epithelial ovarian cancer.

Authors
Schildkraut, JM; Iversen, ES; Akushevich, L; Whitaker, R; Bentley, RC; Berchuck, A; Marks, JR
MLA Citation
Schildkraut, JM, Iversen, ES, Akushevich, L, Whitaker, R, Bentley, RC, Berchuck, A, and Marks, JR. "Molecular signatures of epithelial ovarian cancer: analysis of associations with tumor characteristics and epidemiologic risk factors." Cancer Epidemiol Biomarkers Prev 22.10 (October 2013): 1709-1721.
PMID
23917454
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
22
Issue
10
Publish Date
2013
Start Page
1709
End Page
1721
DOI
10.1158/1055-9965.EPI-13-0192

ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: a comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas.

OBJECTIVE: ABCB1 encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance. We comprehensively evaluated this gene and flanking regions for an association with clinical outcome in epithelial ovarian cancer (EOC). METHODS: The best candidates from fine-mapping analysis of 21 ABCB1 SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium (OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either 'standard' first-line paclitaxel-carboplatin chemotherapy (n=1158) or any first-line chemotherapy regimen (n=2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients. RESULT: Fine-mapping revealed that rs1128503, rs2032582, and rs1045642 were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survival or overall survival in analysis of data from 14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77-1.01; p=0.07). In contrast, ABCB1 expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours. CONCLUSION: Our study represents the largest analysis of ABCB1 SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival.

Authors
Johnatty, SE; Beesley, J; Gao, B; Chen, X; Lu, Y; Law, MH; Henderson, MJ; Russell, AJ; Hedditch, EL; Emmanuel, C; Fereday, S; Webb, PM; Australian Ovarian Cancer Study Group, ; Goode, EL; Vierkant, RA; Fridley, BL; Cunningham, JM; Fasching, PA; Beckmann, MW; Ekici, AB; Hogdall, E; Kjaer, SK; Jensen, A; Hogdall, C; Brown, R; Paul, J; Lambrechts, S; Despierre, E; Vergote, I; Lester, J; Karlan, BY; Heitz, F; du Bois, A; Harter, P; Schwaab, I; Bean, Y; Pejovic, T; Levine, DA; Goodman, MT; Camey, ME et al.
MLA Citation
Johnatty, SE, Beesley, J, Gao, B, Chen, X, Lu, Y, Law, MH, Henderson, MJ, Russell, AJ, Hedditch, EL, Emmanuel, C, Fereday, S, Webb, PM, Australian Ovarian Cancer Study Group, , Goode, EL, Vierkant, RA, Fridley, BL, Cunningham, JM, Fasching, PA, Beckmann, MW, Ekici, AB, Hogdall, E, Kjaer, SK, Jensen, A, Hogdall, C, Brown, R, Paul, J, Lambrechts, S, Despierre, E, Vergote, I, Lester, J, Karlan, BY, Heitz, F, du Bois, A, Harter, P, Schwaab, I, Bean, Y, Pejovic, T, Levine, DA, Goodman, MT, and Camey, ME et al. "ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: a comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas." Gynecol Oncol 131.1 (October 2013): 8-14.
PMID
23917080
Source
pubmed
Published In
Gynecologic Oncology
Volume
131
Issue
1
Publish Date
2013
Start Page
8
End Page
14
DOI
10.1016/j.ygyno.2013.07.107

Vaginal cuff thermal injury and healing based on mode of colpotomy incision at total laparoscopic hysterectomy: a randomized clinical trial

Authors
Teoh, D; Lowery, WJ; Walter, PJ; Secord, AA; Valea, FA; Berchuck, A; Havrilesky, LJ; Lee, PS
MLA Citation
Teoh, D, Lowery, WJ, Walter, PJ, Secord, AA, Valea, FA, Berchuck, A, Havrilesky, LJ, and Lee, PS. "Vaginal cuff thermal injury and healing based on mode of colpotomy incision at total laparoscopic hysterectomy: a randomized clinical trial." September 2013.
PMID
25305572
Source
wos-lite
Published In
Journal of The American College of Surgeons
Volume
217
Issue
3
Publish Date
2013
Start Page
S71
End Page
S72

Genital powder use and risk of ovarian cancer: a pooled analysis of 8,525 cases and 9,859 controls.

Genital powder use has been associated with risk of epithelial ovarian cancer in some, but not all, epidemiologic investigations, possibly reflecting the carcinogenic effects of talc particles found in most of these products. Whether risk increases with number of genital powder applications and for all histologic types of ovarian cancer also remains uncertain. Therefore, we estimated the association between self-reported genital powder use and epithelial ovarian cancer risk in eight population-based case-control studies. Individual data from each study were collected and harmonized. Lifetime number of genital powder applications was estimated from duration and frequency of use. Pooled ORs were calculated using conditional logistic regression matched on study and age and adjusted for potential confounders. Subtype-specific risks were estimated according to tumor behavior and histology. 8,525 cases and 9,859 controls were included in the analyses. Genital powder use was associated with a modest increased risk of epithelial ovarian cancer [OR, 1.24; 95% confidence interval (CI), 1.15-1.33] relative to women who never used powder. Risk was elevated for invasive serous (OR, 1.20; 95% CI, 1.09-1.32), endometrioid (OR, 1.22; 95% CI, 1.04-1.43), and clear cell (OR, 1.24; 95% CI, 1.01-1.52) tumors, and for borderline serous tumors (OR, 1.46; 95% CI, 1.24-1.72). Among genital powder users, we observed no significant trend (P = 0.17) in risk with increasing number of lifetime applications (assessed in quartiles). We noted no increase in risk among women who only reported nongenital powder use. In summary, genital powder use is a modifiable exposure associated with small-to-moderate increases in risk of most histologic subtypes of epithelial ovarian cancer.

Authors
Terry, KL; Karageorgi, S; Shvetsov, YB; Merritt, MA; Lurie, G; Thompson, PJ; Carney, ME; Weber, RP; Akushevich, L; Lo-Ciganic, W-H; Cushing-Haugen, K; Sieh, W; Moysich, K; Doherty, JA; Nagle, CM; Berchuck, A; Pearce, CL; Pike, M; Ness, RB; Webb, PM; Australian Cancer Study (Ovarian Cancer), ; Australian Ovarian Cancer Study Group, ; Rossing, MA; Schildkraut, J; Risch, H; Goodman, MT; Ovarian Cancer Association Consortium,
MLA Citation
Terry, KL, Karageorgi, S, Shvetsov, YB, Merritt, MA, Lurie, G, Thompson, PJ, Carney, ME, Weber, RP, Akushevich, L, Lo-Ciganic, W-H, Cushing-Haugen, K, Sieh, W, Moysich, K, Doherty, JA, Nagle, CM, Berchuck, A, Pearce, CL, Pike, M, Ness, RB, Webb, PM, Australian Cancer Study (Ovarian Cancer), , Australian Ovarian Cancer Study Group, , Rossing, MA, Schildkraut, J, Risch, H, Goodman, MT, and Ovarian Cancer Association Consortium, . "Genital powder use and risk of ovarian cancer: a pooled analysis of 8,525 cases and 9,859 controls." Cancer Prev Res (Phila) 6.8 (August 2013): 811-821.
PMID
23761272
Source
pubmed
Published In
Cancer Prevention Research
Volume
6
Issue
8
Publish Date
2013
Start Page
811
End Page
821
DOI
10.1158/1940-6207.CAPR-13-0037

Timing of end-of-life care discussion with performance on end-of-life quality indicators in ovarian cancer.

OBJECTIVES: (1) To describe the prevalence, timing and setting of documented end-of-life (EOL) discussions in patients with advanced ovarian cancer; and (2) to assess the impact of timing and setting of documented end-of-life discussions on EOL quality care measures. METHODS: A retrospective study of women who died of ovarian cancer diagnosed between 1999 and 2008 was conducted. The following are the EOL quality measures assessed: chemotherapy in the last 14 days of life, >1 hospitalization in the last 30 days, >1 ER visit in the last 30 days, intensive care unit (ICU) admission in the last 30 days, dying in an acute care setting, admitted to hospice ≤3 days. RESULTS: One hundred seventy-seven (80%) patients had documented end-of-life discussions. Median interval from EOL discussion until death was 29 days. Seventy-eight patients (44%) had EOL discussions as outpatient and 99 (56%) as inpatient. Sixty-four out of 220 (29%) patients' care did not conform to at least one EOL quality measure. An EOL discussion at least 30 days before death was associated with a lower incidence of: chemotherapy in the last 14 days of life (p=0.003), >1 hospitalization in the last 30 days (p<0.001), ICU admission in the last 30 days (p=0.005), dying in acute care setting (p=0.01), admitted to hospice ≤3 days (p=0.02). EOL discussion as outpatient was associated with fewer patients hospitalized >1 in the last 30days of life (p<0.001). CONCLUSIONS: End-of-life care discussions are occurring too late in the disease process. Conformance with EOL quality measures can be achieved with earlier end-of-life care discussions.

Authors
Lopez-Acevedo, M; Havrilesky, LJ; Broadwater, G; Kamal, AH; Abernethy, AP; Berchuck, A; Alvarez Secord, A; Tulsky, JA; Valea, F; Lee, PS
MLA Citation
Lopez-Acevedo, M, Havrilesky, LJ, Broadwater, G, Kamal, AH, Abernethy, AP, Berchuck, A, Alvarez Secord, A, Tulsky, JA, Valea, F, and Lee, PS. "Timing of end-of-life care discussion with performance on end-of-life quality indicators in ovarian cancer." Gynecol Oncol 130.1 (July 2013): 156-161.
PMID
23587882
Source
pubmed
Published In
Gynecologic Oncology
Volume
130
Issue
1
Publish Date
2013
Start Page
156
End Page
161
DOI
10.1016/j.ygyno.2013.04.010

Transcript expression in endometrial cancers from Black and White patients.

OBJECTIVE: Previous studies suggest that differences in molecular features of endometrial cancers between racial groups may contribute to the poorer survival in Blacks. The objective of this investigation was to determine whether gene expression among endometrial cancers is different between Blacks and Whites. METHODS: Fresh frozen tumors from 25 Black patients were matched by stage, grade, and histology to endometrial cancer specimens from 25 White patients. Each case was macrodissected to produce specimens possessing a minimum of 75% cancer cellularity. A subset of 10 matched pairs was also prepared using laser microdissection (LMD) to produce specimens possessing a minimum of 95% cancer cells. Total RNA isolated from each sample was analyzed using the Affymetrix Human Genome U133 Plus 2.0 arrays. Data were analyzed using principal component analysis and binary class comparison analyses. RESULTS: Unsupervised analysis of the 50 endometrial cancers failed to identify global gene expression profiles unique to Black or White patients. In a subset analysis of 10 matched pairs from Blacks and Whites prepared using LMD and macrodissection, unsupervised analysis did not reveal a unique gene expression profile associated with race in either set, but associations were identified that relate to sample preparation technique, histology and stage. CONCLUSIONS: Our microarray data revealed no global gene expression differences and identified few individual gene differences between endometrial cancers from Blacks and Whites. More comprehensive methods of transcriptome analysis could uncover RNAs that may underpin the disparity of outcome or prevalence of endometrial cancers in Blacks and Whites.

Authors
Maxwell, GL; Allard, J; Gadisetti, CVR; Litzi, T; Casablanca, Y; Chandran, U; Darcy, KM; Levine, DA; Berchuck, A; Hamilton, CA; Conrads, TP; Risinger, JI
MLA Citation
Maxwell, GL, Allard, J, Gadisetti, CVR, Litzi, T, Casablanca, Y, Chandran, U, Darcy, KM, Levine, DA, Berchuck, A, Hamilton, CA, Conrads, TP, and Risinger, JI. "Transcript expression in endometrial cancers from Black and White patients." Gynecol Oncol 130.1 (July 2013): 169-173.
PMID
23603370
Source
pubmed
Published In
Gynecologic Oncology
Volume
130
Issue
1
Publish Date
2013
Start Page
169
End Page
173
DOI
10.1016/j.ygyno.2013.04.017

Preface

Authors
Barakat, RR; Berchuck, A; Markman, M; Randall, ME
MLA Citation
Barakat, RR, Berchuck, A, Markman, M, and Randall, ME. "Preface." Principles and Practice of Gynecologic Oncology: Sixth Edition (May 8, 2013): xi-xii.
Source
scopus
Published In
Principles and Practice of Gynecologic Oncology: Sixth Edition
Publish Date
2013
Start Page
xi
End Page
xii

Principles and practice of gynecologic oncology: Sixth edition

© 2013, 2009, 2005, 2001, 1996, 1992 by Lippincott Williams & Wilkins, a Wolters Kluwer business. All rights reserved. Today, multidisciplinary approaches to treatment are at the heart of cancer care. They offer improved clinical outcomes, new possibilities in patient quality of life, and enable the development of true innovation in individualized treatment. To accurately reflect this modern day approach to cancer care, the content of the 6th edition of Principles and Practice of Gynecologic Oncology was written entirely by surgeons, medical oncologists, radiation oncologists, and pathologists. New to the editorial team, Dr. Andrew Berchuck has made significant contributions to the understanding of the molecular pathogenesis of ovarian and endometrial cancer in the book's content. Every chapter of this book has been either completely rewritten or extensively updated to ensure that everyone involved in treating women with gynecologic cancer will have the most comprehensive and up-to-date information on the subject. Traditionally available as a printed textbook, now it comes with a completely revamped digital experience, powered by Inkling!.

Authors
Barakat, RR; Berchuck, A; Markman, M; Randall, ME
MLA Citation
Barakat, RR, Berchuck, A, Markman, M, and Randall, ME. Principles and practice of gynecologic oncology: Sixth edition. May 8, 2013.
Source
scopus
Publish Date
2013
Start Page
1
End Page
1104

Molecular pathogenesis of gynecologic cancers

Authors
Berchuck, A; Levine, DA; Farley, JH; Birrer, MJ
MLA Citation
Berchuck, A, Levine, DA, Farley, JH, and Birrer, MJ. "Molecular pathogenesis of gynecologic cancers." Principles and Practice of Gynecologic Oncology: Sixth Edition. May 8, 2013. 30-59.
Source
scopus
Publish Date
2013
Start Page
30
End Page
59

Hereditary gynecologic cancers

Authors
Lu, KH; Berchuck, A; Kauff, ND
MLA Citation
Lu, KH, Berchuck, A, and Kauff, ND. "Hereditary gynecologic cancers." Principles and Practice of Gynecologic Oncology: Sixth Edition. May 8, 2013. 60-69.
Source
scopus
Publish Date
2013
Start Page
60
End Page
69

Integrated genomic characterization of endometrial carcinoma.

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.

Authors
Cancer Genome Atlas Research Network, ; Kandoth, C; Schultz, N; Cherniack, AD; Akbani, R; Liu, Y; Shen, H; Robertson, AG; Pashtan, I; Shen, R; Benz, CC; Yau, C; Laird, PW; Ding, L; Zhang, W; Mills, GB; Kucherlapati, R; Mardis, ER; Levine, DA
MLA Citation
Cancer Genome Atlas Research Network, , Kandoth, C, Schultz, N, Cherniack, AD, Akbani, R, Liu, Y, Shen, H, Robertson, AG, Pashtan, I, Shen, R, Benz, CC, Yau, C, Laird, PW, Ding, L, Zhang, W, Mills, GB, Kucherlapati, R, Mardis, ER, and Levine, DA. "Integrated genomic characterization of endometrial carcinoma." Nature 497.7447 (May 2, 2013): 67-73.
PMID
23636398
Source
pubmed
Published In
Nature
Volume
497
Issue
7447
Publish Date
2013
Start Page
67
End Page
73
DOI
10.1038/nature12113

Analysis of over 10,000 Cases finds no association between previously reported candidate polymorphisms and ovarian cancer outcome.

BACKGROUND: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. METHODS: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. RESULTS: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. CONCLUSIONS: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. IMPACT: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed.

Authors
White, KL; Vierkant, RA; Fogarty, ZC; Charbonneau, B; Block, MS; Pharoah, PDP; Chenevix-Trench, G; for AOCS/ACS group;, ; Rossing, MA; Cramer, DW; Pearce, CL; Schildkraut, JM; Menon, U; Kjaer, SK; Levine, DA; Gronwald, J; Culver, HA; Whittemore, AS; Karlan, BY; Lambrechts, D; Wentzensen, N; Kupryjanczyk, J; Chang-Claude, J; Bandera, EV; Hogdall, E; Heitz, F; Kaye, SB; Fasching, PA; Campbell, I; Goodman, MT; Pejovic, T; Bean, Y; Lurie, G; Eccles, D; Hein, A; Beckmann, MW; Ekici, AB; Paul, J et al.
MLA Citation
White, KL, Vierkant, RA, Fogarty, ZC, Charbonneau, B, Block, MS, Pharoah, PDP, Chenevix-Trench, G, for AOCS/ACS group, , Rossing, MA, Cramer, DW, Pearce, CL, Schildkraut, JM, Menon, U, Kjaer, SK, Levine, DA, Gronwald, J, Culver, HA, Whittemore, AS, Karlan, BY, Lambrechts, D, Wentzensen, N, Kupryjanczyk, J, Chang-Claude, J, Bandera, EV, Hogdall, E, Heitz, F, Kaye, SB, Fasching, PA, Campbell, I, Goodman, MT, Pejovic, T, Bean, Y, Lurie, G, Eccles, D, Hein, A, Beckmann, MW, Ekici, AB, and Paul, J et al. "Analysis of over 10,000 Cases finds no association between previously reported candidate polymorphisms and ovarian cancer outcome." Cancer Epidemiol Biomarkers Prev 22.5 (May 2013): 987-992.
PMID
23513043
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
22
Issue
5
Publish Date
2013
Start Page
987
End Page
992
DOI
10.1158/1055-9965.EPI-13-0028

Combined and interactive effects of environmental and GWAS-identified risk factors in ovarian cancer.

BACKGROUND: There are several well-established environmental risk factors for ovarian cancer, and recent genome-wide association studies have also identified six variants that influence disease risk. However, the interplay between such risk factors and susceptibility loci has not been studied. METHODS: Data from 14 ovarian cancer case-control studies were pooled, and stratified analyses by each environmental risk factor with tests for heterogeneity were conducted to determine the presence of interactions for all histologic subtypes. A genetic "risk score" was created to consider the effects of all six variants simultaneously. A multivariate model was fit to examine the association between all environmental risk factors and genetic risk score on ovarian cancer risk. RESULTS: Among 7,374 controls and 5,566 cases, there was no statistical evidence of interaction between the six SNPs or genetic risk score and the environmental risk factors on ovarian cancer risk. In a main effects model, women in the highest genetic risk score quartile had a 65% increased risk of ovarian cancer compared with women in the lowest [95% confidence interval (CI), 1.48-1.84]. Analyses by histologic subtype yielded risk differences across subtype for endometriosis (Phet < 0.001), parity (Phet < 0.01), and tubal ligation (Phet = 0.041). CONCLUSIONS: The lack of interactions suggests that a multiplicative model is the best fit for these data. Under such a model, we provide a robust estimate of the effect of each risk factor that sets the stage for absolute risk prediction modeling that considers both environmental and genetic risk factors. Further research into the observed differences in risk across histologic subtype is warranted.

Authors
Pearce, CL; Rossing, MA; Lee, AW; Ness, RB; Webb, PM; for Australian Cancer Study (Ovarian Cancer), ; Australian Ovarian Cancer Study Group, ; Chenevix-Trench, G; Jordan, SM; Stram, DA; Chang-Claude, J; Hein, R; Nickels, S; Lurie, G; Thompson, PJ; Carney, ME; Goodman, MT; Moysich, K; Hogdall, E; Jensen, A; Goode, EL; Fridley, BL; Cunningham, JM; Vierkant, RA; Weber, RP; Ziogas, A; Anton-Culver, H; Gayther, SA; Gentry-Maharaj, A; Menon, U; Ramus, SJ; Brinton, L; Wentzensen, N; Lissowska, J et al.
MLA Citation
Pearce, CL, Rossing, MA, Lee, AW, Ness, RB, Webb, PM, for Australian Cancer Study (Ovarian Cancer), , Australian Ovarian Cancer Study Group, , Chenevix-Trench, G, Jordan, SM, Stram, DA, Chang-Claude, J, Hein, R, Nickels, S, Lurie, G, Thompson, PJ, Carney, ME, Goodman, MT, Moysich, K, Hogdall, E, Jensen, A, Goode, EL, Fridley, BL, Cunningham, JM, Vierkant, RA, Weber, RP, Ziogas, A, Anton-Culver, H, Gayther, SA, Gentry-Maharaj, A, Menon, U, Ramus, SJ, Brinton, L, Wentzensen, N, and Lissowska, J et al. "Combined and interactive effects of environmental and GWAS-identified risk factors in ovarian cancer." Cancer Epidemiol Biomarkers Prev 22.5 (May 2013): 880-890.
PMID
23462924
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
22
Issue
5
Publish Date
2013
Start Page
880
End Page
890
DOI
10.1158/1055-9965.EPI-12-1030-T

Abstract 4850: Variation in circadian rhythm genes influence epithelial ovarian cancer risk and invasiveness.

Authors
Jim, H; Tyrer, J; Lin, H-Y; Han, G; Qu, X; Goode, EL; Chen, Z; Tsai, Y-Y; Cunningham, JM; Iversen, E; Ramus, S; Berchuck, A; Schildkraut, J; Monteiro, A; Gayther, S; Narod, SA; Sellers, TA; Pharoah, P; Phelan, CM
MLA Citation
Jim, H, Tyrer, J, Lin, H-Y, Han, G, Qu, X, Goode, EL, Chen, Z, Tsai, Y-Y, Cunningham, JM, Iversen, E, Ramus, S, Berchuck, A, Schildkraut, J, Monteiro, A, Gayther, S, Narod, SA, Sellers, TA, Pharoah, P, and Phelan, CM. "Abstract 4850: Variation in circadian rhythm genes influence epithelial ovarian cancer risk and invasiveness." April 15, 2013.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
8 Supplement
Publish Date
2013
Start Page
4850
End Page
4850
DOI
10.1158/1538-7445.AM2013-4850

Abstract 330A: Differential expression of angiogenic genes in invasive high grade serous ovarian carcinomas.

Authors
Siamakpour- Reihani, S; Jiang, C; Turner, T; Owzar, K; Berchuck, A; Dewhirst, M; Alvarez Secord, A
MLA Citation
Siamakpour- Reihani, S, Jiang, C, Turner, T, Owzar, K, Berchuck, A, Dewhirst, M, and Alvarez Secord, A. "Abstract 330A: Differential expression of angiogenic genes in invasive high grade serous ovarian carcinomas." April 15, 2013.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
8 Supplement
Publish Date
2013
Start Page
330A
End Page
330A
DOI
10.1158/1538-7445.AM2013-330A

Abstract 1352: Epithelial-mesenchymal transition (EMT) gene variants influence epithelial ovarian cancer risk in women of European, African and Asian ancestry.

Authors
Amankwah, EK; Tyrer, J; Lin, H-Y; Tsai, Y-Y; Chen, Z; Han, G; Qu, X; Goode, E; Cunninghan, J; Iverson, E; Ramus, S; Berchuck, A; Schildkraut, J; Monteiro, A; Gayther, S; Narod, S; Pharoah, P; Sellers, TA; Phelan, C
MLA Citation
Amankwah, EK, Tyrer, J, Lin, H-Y, Tsai, Y-Y, Chen, Z, Han, G, Qu, X, Goode, E, Cunninghan, J, Iverson, E, Ramus, S, Berchuck, A, Schildkraut, J, Monteiro, A, Gayther, S, Narod, S, Pharoah, P, Sellers, TA, and Phelan, C. "Abstract 1352: Epithelial-mesenchymal transition (EMT) gene variants influence epithelial ovarian cancer risk in women of European, African and Asian ancestry." April 15, 2013.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
8 Supplement
Publish Date
2013
Start Page
1352
End Page
1352
DOI
10.1158/1538-7445.AM2013-1352

Abstract 4767: Preclinical mouse model of recurrent epithelial ovarian cancer.

Authors
Park, J; Huang, Z; Berchuck, A; Murphy, S
MLA Citation
Park, J, Huang, Z, Berchuck, A, and Murphy, S. "Abstract 4767: Preclinical mouse model of recurrent epithelial ovarian cancer." April 15, 2013.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
8 Supplement
Publish Date
2013
Start Page
4767
End Page
4767
DOI
10.1158/1538-7445.AM2013-4767

Validation of ovarian cancer gene expression signatures for survival and subtype in formalin fixed paraffin embedded tissues.

INTRODUCTION: Gene expression signatures have been identified for epithelial ovarian cancer survival (TCGA) and intrinsic subtypes (Tothill et al.). One obstacle to clinical translation is that these signatures were developed using frozen tissue, whereas usually only formalin-fixed, paraffin embedded (FFPE) tissue is available. The aim of this study was to determine if gene expression signatures can be translated to fixed archival tissues. METHODS: RNA extracted from FFPE sections from 240 primary ovarian cancers was analyzed by DASL on Illumina BeadChip arrays. Concordance of expression at the individual gene level was assessed by comparing array data from the same cancers (30 frozen samples analyzed on Affymetrix arrays versus FFPE DASL). RESULTS: The correlation between FFPE and frozen survival signature estimates was 0.774. The TCGA signature using DASL was predictive of survival in 106 advanced stage high grade serous ovarian cancers (median survival 33 versus 60 months, estimated hazard ratio for death 2.30, P=0.0007). Similar to Tothill, we found using DASL that most high grade serous ovarian cancers (102/110, 93%) were assigned to subtypes 1, 2, 4 and 5, whereas most endometrioid, clear cell, mucinous and low grade serous cases (39/57, 68%) were assigned to subtypes 3 and 6 (P<10e-15). CONCLUSIONS: Although individual probe estimates of microarrays may be weakly correlated between FFPE and frozen samples, combinations of probes have robust ability to predict survival and subtype. This suggests that it may be possible to use these signatures for prognostic and predictive purposes as we seek to individualize the treatment of ovarian cancer.

Authors
Sfakianos, GP; Iversen, ES; Whitaker, R; Akushevich, L; Schildkraut, JM; Murphy, SK; Marks, JR; Berchuck, A
MLA Citation
Sfakianos, GP, Iversen, ES, Whitaker, R, Akushevich, L, Schildkraut, JM, Murphy, SK, Marks, JR, and Berchuck, A. "Validation of ovarian cancer gene expression signatures for survival and subtype in formalin fixed paraffin embedded tissues." Gynecol Oncol 129.1 (April 2013): 159-164.
PMID
23274563
Source
pubmed
Published In
Gynecologic Oncology
Volume
129
Issue
1
Publish Date
2013
Start Page
159
End Page
164
DOI
10.1016/j.ygyno.2012.12.030

Vitamin D receptor (VDR) polymorphisms and risk of ovarian cancer in Caucasian and African American women.

OBJECTIVE: Polymorphisms in the vitamin D receptor (VDR) gene have been shown in some studies to be associated with the risk of epithelial ovarian cancer (EOC) in Caucasian women. There are no published reports among African Americans. METHODS: Case-control data from the North Carolina Ovarian Cancer Study were analyzed using logistic regression to determine the association between seven VDR polymorphisms and EOC in both Caucasians (513 cases, 532 controls) and African Americans (74 cases, 79 controls). In a larger sample of African-Americans (125 cases, 155 controls), we assessed associations between six SNPs in proximity of rs7975232. RESULTS: African American women who carried at least one minor allele of rs7975232 were at higher risk for invasive EOC controlling for age and admixture with an odds ratio (OR) for association under the log-additive model of 2.08 (95% confidence interval (CI)=1.19, 3.63, p=0.010). No association was observed between any of the VDR variants and EOC among Caucasians. A larger sample of African Americans revealed a nearly two-fold increased risk of invasive EOC associated with rs7305032, a SNP in proximity to rs7975232 (R(2)=0.369) with a log-additive OR of 1.87 (95% CI=1.20, 2.93, p=0.006). CONCLUSIONS: This is the first report showing VDR variants associated with ovarian cancer risk in African American women. A larger study of African American women is needed to confirm these findings. These results imply that vitamin D exposure is a possible modifiable risk factor of ovarian cancer among African Americans.

Authors
Grant, DJ; Hoyo, C; Akushevich, L; Iversen, ES; Whitaker, R; Marks, J; Berchuck, A; Schildkraut, JM
MLA Citation
Grant, DJ, Hoyo, C, Akushevich, L, Iversen, ES, Whitaker, R, Marks, J, Berchuck, A, and Schildkraut, JM. "Vitamin D receptor (VDR) polymorphisms and risk of ovarian cancer in Caucasian and African American women." Gynecol Oncol 129.1 (April 2013): 173-178.
PMID
23262379
Source
pubmed
Published In
Gynecologic Oncology
Volume
129
Issue
1
Publish Date
2013
Start Page
173
End Page
178
DOI
10.1016/j.ygyno.2012.12.027

Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.

TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.

Authors
Bojesen, SE; Pooley, KA; Johnatty, SE; Beesley, J; Michailidou, K; Tyrer, JP; Edwards, SL; Pickett, HA; Shen, HC; Smart, CE; Hillman, KM; Mai, PL; Lawrenson, K; Stutz, MD; Lu, Y; Karevan, R; Woods, N; Johnston, RL; French, JD; Chen, X; Weischer, M; Nielsen, SF; Maranian, MJ; Ghoussaini, M; Ahmed, S; Baynes, C; Bolla, MK; Wang, Q; Dennis, J; McGuffog, L; Barrowdale, D; Lee, A; Healey, S; Lush, M; Tessier, DC; Vincent, D; Bacot, F; Australian Cancer Study, ; Australian Ovarian Cancer Study, et al.
MLA Citation
Bojesen, SE, Pooley, KA, Johnatty, SE, Beesley, J, Michailidou, K, Tyrer, JP, Edwards, SL, Pickett, HA, Shen, HC, Smart, CE, Hillman, KM, Mai, PL, Lawrenson, K, Stutz, MD, Lu, Y, Karevan, R, Woods, N, Johnston, RL, French, JD, Chen, X, Weischer, M, Nielsen, SF, Maranian, MJ, Ghoussaini, M, Ahmed, S, Baynes, C, Bolla, MK, Wang, Q, Dennis, J, McGuffog, L, Barrowdale, D, Lee, A, Healey, S, Lush, M, Tessier, DC, Vincent, D, Bacot, F, Australian Cancer Study, , and Australian Ovarian Cancer Study, et al. "Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer." Nat Genet 45.4 (April 2013): 371-384e2.
PMID
23535731
Source
pubmed
Published In
Nature Genetics
Volume
45
Issue
4
Publish Date
2013
Start Page
371
End Page
384e2
DOI
10.1038/ng.2566

GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer.

Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.

Authors
Pharoah, PDP; Tsai, Y-Y; Ramus, SJ; Phelan, CM; Goode, EL; Lawrenson, K; Buckley, M; Fridley, BL; Tyrer, JP; Shen, H; Weber, R; Karevan, R; Larson, MC; Song, H; Tessier, DC; Bacot, F; Vincent, D; Cunningham, JM; Dennis, J; Dicks, E; Australian Cancer Study, ; Australian Ovarian Cancer Study Group, ; Aben, KK; Anton-Culver, H; Antonenkova, N; Armasu, SM; Baglietto, L; Bandera, EV; Beckmann, MW; Birrer, MJ; Bloom, G; Bogdanova, N; Brenton, JD; Brinton, LA; Brooks-Wilson, A; Brown, R; Butzow, R et al.
MLA Citation
Pharoah, PDP, Tsai, Y-Y, Ramus, SJ, Phelan, CM, Goode, EL, Lawrenson, K, Buckley, M, Fridley, BL, Tyrer, JP, Shen, H, Weber, R, Karevan, R, Larson, MC, Song, H, Tessier, DC, Bacot, F, Vincent, D, Cunningham, JM, Dennis, J, Dicks, E, Australian Cancer Study, , Australian Ovarian Cancer Study Group, , Aben, KK, Anton-Culver, H, Antonenkova, N, Armasu, SM, Baglietto, L, Bandera, EV, Beckmann, MW, Birrer, MJ, Bloom, G, Bogdanova, N, Brenton, JD, Brinton, LA, Brooks-Wilson, A, Brown, R, and Butzow, R et al. "GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer." Nat Genet 45.4 (April 2013): 362-370e2.
PMID
23535730
Source
pubmed
Published In
Nature Genetics
Volume
45
Issue
4
Publish Date
2013
Start Page
362
End Page
370e2
DOI
10.1038/ng.2564

Tubal ligation and risk of ovarian cancer subtypes: a pooled analysis of case-control studies.

BACKGROUND: Tubal ligation is a protective factor for ovarian cancer, but it is unknown whether this protection extends to all invasive histological subtypes or borderline tumors. We undertook an international collaborative study to examine the association between tubal ligation and ovarian cancer subtypes. METHODS: We pooled primary data from 13 population-based case-control studies, including 10,157 patients with ovarian cancer (7942 invasive; 2215 borderline) and 13,904 control women. Invasive cases were analysed by histological type, grade and stage, and borderline cases were analysed by histological type. Pooled odds ratios were estimated using conditional logistic regression to match on site, race/ethnicity and age categories, and to adjust for age, oral contraceptive use duration and number of full-term births. RESULTS: Tubal ligation was associated with significantly reduced risks of invasive serous (OR, 0.81; 95% CI, 0.74-0.89; P < 0.001), endometrioid (OR, 0.48; 95% CI, 0.40-0.59; P < 0.001), clear cell (OR, 0.52; 95% CI, 0.40-0.67; P < 0.001) and mucinous (OR, 0.68; 95% CI, 0.52-0.89; P = 0.005) cancers. The magnitude of risk reduction was significantly greater for invasive endometrioid (P < 0.0001) and clear cell (P = 0.0018) than for serous cancer. No significant associations were found with borderline serous or mucinous tumours. CONCLUSIONS: We found that the protective effects of tubal ligation on ovarian cancer risk were subtype-specific. These findings provide insights into distinct aetiologies of ovarian cancer subtypes and mechanisms underlying the protective effects of tubal ligation.

Authors
Sieh, W; Salvador, S; McGuire, V; Weber, RP; Terry, KL; Rossing, MA; Risch, H; Wu, AH; Webb, PM; Moysich, K; Doherty, JA; Felberg, A; Miller, D; Jordan, SJ; Australian Cancer Study (Ovarian Cancer), ; Australian Ovarian Cancer Study Group, ; Goodman, MT; Lurie, G; Chang-Claude, J; Rudolph, A; Kjær, SK; Jensen, A; Høgdall, E; Bandera, EV; Olson, SH; King, MG; Rodriguez-Rodriguez, L; Kiemeney, LA; Marees, T; Massuger, LF; van Altena, AM; Ness, RB; Cramer, DW; Pike, MC; Pearce, CL; Berchuck, A et al.
MLA Citation
Sieh, W, Salvador, S, McGuire, V, Weber, RP, Terry, KL, Rossing, MA, Risch, H, Wu, AH, Webb, PM, Moysich, K, Doherty, JA, Felberg, A, Miller, D, Jordan, SJ, Australian Cancer Study (Ovarian Cancer), , Australian Ovarian Cancer Study Group, , Goodman, MT, Lurie, G, Chang-Claude, J, Rudolph, A, Kjær, SK, Jensen, A, Høgdall, E, Bandera, EV, Olson, SH, King, MG, Rodriguez-Rodriguez, L, Kiemeney, LA, Marees, T, Massuger, LF, van Altena, AM, Ness, RB, Cramer, DW, Pike, MC, Pearce, CL, and Berchuck, A et al. "Tubal ligation and risk of ovarian cancer subtypes: a pooled analysis of case-control studies." Int J Epidemiol 42.2 (April 2013): 579-589.
PMID
23569193
Source
pubmed
Published In
International Journal of Epidemiology
Volume
42
Issue
2
Publish Date
2013
Start Page
579
End Page
589
DOI
10.1093/ije/dyt042

BRCA1 immunohistochemistry in a molecularly characterized cohort of ovarian high-grade serous carcinomas.

BRCA1 and BRCA2 dysfunction, frequently seen in high-grade serous ovarian carcinomas, often results from germline mutations, somatic mutations, and promoter methylation. Identification of tumors with BRCA defects has therapeutic and prognostic implications. Identifying germline BRCA mutations is also important given the increased risk for hereditary breast and ovarian carcinoma. Our goal was to assess whether immunohistochemical analysis (IHC) for BRCA1 is an effective method for the detection of BRCA1 dysfunction in molecularly characterized high-grade ovarian serous carcinoma. We identified 43 high-grade ovarian serous carcinomas with known events in BRCA1 and BRCA2 included in The Cancer Genome Atlas Project. BRCA1 stain was first assessed without knowledge of the BRCA status, and a semiquantitative assessment for intensity and amount of staining was performed. The stains were reevaluated and divided into 3 categories (retained, loss, and equivocal) on the basis of correlation with genotyping data. Presence of retained BRCA staining was considered normal, whereas the other patterns, including equivocal staining or loss of staining, were considered abnormal. Two pathologists, blinded to the BRCA status, then scored 2 sets of validation cases selected on the basis of available molecular data-1 with only germline mutation status available (n=31) and 1 with comprehensive genomic data (n=39). The pathologists agreed 88% of the time in the training set and 91% in the validation sets. In the training set, abnormal BRCA staining was seen in 24 cases, of which 21 (87%) showed BRCA1 genetic abnormalities, 1 showed BRCA2 mutations, and 2 showed no BRCA abnormalities. Abnormal BRCA1 staining was noted in all 5 cases with BRCA1 germline mutations, in 3 (60%) of 5 with BRCA1 somatic mutations, and in 13 (93%) of 14 with BRCA1 promoter methylation. The 2 validation sets included 70 additional patients, and all cases with germline BRCA1 mutations (n=11) showed abnormal BRCA1 staining. Tumors with BRCA1 promoter methylation also showed abnormal staining in 6 (86%) of 7 cases. In the entire study, no cases with BRCA1 germline mutation showed intact immunostaining (negative predictive value=100%). This study shows that BRCA1 IHC is well correlated with molecular events in ovarian carcinoma. Considering the high negative predictive value for germline mutations, BRCA1 IHC appears to be an effective approach to stratify patients for germline genetic testing and to detect other mechanisms of BRCA1 dysfunction in high-grade serous ovarian carcinomas.

Authors
Garg, K; Levine, DA; Olvera, N; Dao, F; Bisogna, M; Secord, AA; Berchuck, A; Cerami, E; Schultz, N; Soslow, RA
MLA Citation
Garg, K, Levine, DA, Olvera, N, Dao, F, Bisogna, M, Secord, AA, Berchuck, A, Cerami, E, Schultz, N, and Soslow, RA. "BRCA1 immunohistochemistry in a molecularly characterized cohort of ovarian high-grade serous carcinomas." Am J Surg Pathol 37.1 (January 2013): 138-146.
PMID
23232854
Source
pubmed
Published In
American Journal of Surgical Pathology
Volume
37
Issue
1
Publish Date
2013
Start Page
138
End Page
146
DOI
10.1097/PAS.0b013e31826cabbd

ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and the Cancer Genome Atlas

Objective. ABCB1 encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance.We comprehensively evaluated this gene and flanking regions for an associationwith clinical outcome in epithelial ovarian cancer (EOC). Methods. The best candidates from fine-mapping analysis of 21 ABCB1 SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium(OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either 'standard' first-line paclitaxel-carboplatin chemotherapy (n = 1158) or any first-line chemotherapy regimen (n = 2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients. Result. Fine-mapping revealed that rs1128503, rs2032582, and rs1045642were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survivaloroverall survival inanalysis ofdata from14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77-1.01; p = 0.07). In contrast, ABCB1 expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours. Conclusion. Our study represents the largest analysis of ABCB1 SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival. © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Authors
Johnatty, SE; Beesley, J; Gao, B; Chen, X; Lu, Y; Law, MH; Henderson, MJ; Russell, AJ; Hedditch, EL; Emmanuel, C; al, E
MLA Citation
Johnatty, SE, Beesley, J, Gao, B, Chen, X, Lu, Y, Law, MH, Henderson, MJ, Russell, AJ, Hedditch, EL, Emmanuel, C, and al, E. "ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and the Cancer Genome Atlas." Gynecologic Oncology 131.1 (2013): 8-14.
Source
scival
Published In
Gynecologic Oncology
Volume
131
Issue
1
Publish Date
2013
Start Page
8
End Page
14
DOI
10.1016/j.ygyno.2013.07.107

Inherited variants in regulatory T cell genes and outcome of ovarian cancer.

Although ovarian cancer is the most lethal of gynecologic malignancies, wide variation in outcome following conventional therapy continues to exist. The presence of tumor-infiltrating regulatory T cells (Tregs) has a role in outcome of this disease, and a growing body of data supports the existence of inherited prognostic factors. However, the role of inherited variants in genes encoding Treg-related immune molecules has not been fully explored. We analyzed expression quantitative trait loci (eQTL) and sequence-based tagging single nucleotide polymorphisms (tagSNPs) for 54 genes associated with Tregs in 3,662 invasive ovarian cancer cases. With adjustment for known prognostic factors, suggestive results were observed among rarer histological subtypes; poorer survival was associated with minor alleles at SNPs in RGS1 (clear cell, rs10921202, p=2.7×10(-5)), LRRC32 and TNFRSF18/TNFRSF4 (mucinous, rs3781699, p=4.5×10(-4), and rs3753348, p=9.0×10(-4), respectively), and CD80 (endometrioid, rs13071247, p=8.0×10(-4)). Fo0r the latter, correlative data support a CD80 rs13071247 genotype association with CD80 tumor RNA expression (p=0.006). An additional eQTL SNP in CD80 was associated with shorter survival (rs7804190, p=8.1×10(-4)) among all cases combined. As the products of these genes are known to affect induction, trafficking, or immunosuppressive function of Tregs, these results suggest the need for follow-up phenotypic studies.

Authors
Goode, EL; DeRycke, M; Kalli, KR; Oberg, AL; Cunningham, JM; Maurer, MJ; Fridley, BL; Armasu, SM; Serie, DJ; Ramar, P; Goergen, K; Vierkant, RA; Rider, DN; Sicotte, H; Wang, C; Winterhoff, B; Phelan, CM; Schildkraut, JM; Weber, RP; Iversen, E; Berchuck, A; Sutphen, R; Birrer, MJ; Hampras, S; Preus, L; Gayther, SA; Ramus, SJ; Wentzensen, N; Yang, HP; Garcia-Closas, M; Song, H; Tyrer, J; Pharoah, PPD; Konecny, G; Sellers, TA; Ness, RB; Sucheston, LE; Odunsi, K; Hartmann, LC; Moysich, KB et al.
MLA Citation
Goode, EL, DeRycke, M, Kalli, KR, Oberg, AL, Cunningham, JM, Maurer, MJ, Fridley, BL, Armasu, SM, Serie, DJ, Ramar, P, Goergen, K, Vierkant, RA, Rider, DN, Sicotte, H, Wang, C, Winterhoff, B, Phelan, CM, Schildkraut, JM, Weber, RP, Iversen, E, Berchuck, A, Sutphen, R, Birrer, MJ, Hampras, S, Preus, L, Gayther, SA, Ramus, SJ, Wentzensen, N, Yang, HP, Garcia-Closas, M, Song, H, Tyrer, J, Pharoah, PPD, Konecny, G, Sellers, TA, Ness, RB, Sucheston, LE, Odunsi, K, Hartmann, LC, and Moysich, KB et al. "Inherited variants in regulatory T cell genes and outcome of ovarian cancer." PLoS One 8.1 (2013): e53903-.
PMID
23382860
Source
pubmed
Published In
PloS one
Volume
8
Issue
1
Publish Date
2013
Start Page
e53903
DOI
10.1371/journal.pone.0053903

Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer.

HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.

Authors
Shen, H; Fridley, BL; Song, H; Lawrenson, K; Cunningham, JM; Ramus, SJ; Cicek, MS; Tyrer, J; Stram, D; Larson, MC; Köbel, M; PRACTICAL Consortium, ; Ziogas, A; Zheng, W; Yang, HP; Wu, AH; Wozniak, EL; Woo, YL; Winterhoff, B; Wik, E; Whittemore, AS; Wentzensen, N; Weber, RP; Vitonis, AF; Vincent, D; Vierkant, RA; Vergote, I; Van Den Berg, D; Van Altena, AM; Tworoger, SS; Thompson, PJ; Tessier, DC; Terry, KL; Teo, S-H; Templeman, C; Stram, DO; Southey, MC; Sieh, W; Siddiqui, N; Shvetsov, YB et al.
MLA Citation
Shen, H, Fridley, BL, Song, H, Lawrenson, K, Cunningham, JM, Ramus, SJ, Cicek, MS, Tyrer, J, Stram, D, Larson, MC, Köbel, M, PRACTICAL Consortium, , Ziogas, A, Zheng, W, Yang, HP, Wu, AH, Wozniak, EL, Woo, YL, Winterhoff, B, Wik, E, Whittemore, AS, Wentzensen, N, Weber, RP, Vitonis, AF, Vincent, D, Vierkant, RA, Vergote, I, Van Den Berg, D, Van Altena, AM, Tworoger, SS, Thompson, PJ, Tessier, DC, Terry, KL, Teo, S-H, Templeman, C, Stram, DO, Southey, MC, Sieh, W, Siddiqui, N, and Shvetsov, YB et al. "Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer." Nat Commun 4 (2013): 1628-.
PMID
23535649
Source
pubmed
Published In
Nature Communications
Volume
4
Publish Date
2013
Start Page
1628
DOI
10.1038/ncomms2629

Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31.

Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.

Authors
Permuth-Wey, J; Lawrenson, K; Shen, HC; Velkova, A; Tyrer, JP; Chen, Z; Lin, H-Y; Chen, YA; Tsai, Y-Y; Qu, X; Ramus, SJ; Karevan, R; Lee, J; Lee, N; Larson, MC; Aben, KK; Anton-Culver, H; Antonenkova, N; Antoniou, AC; Armasu, SM; Australian Cancer Study, ; Australian Ovarian Cancer Study, ; Bacot, F; Baglietto, L; Bandera, EV; Barnholtz-Sloan, J; Beckmann, MW; Birrer, MJ; Bloom, G; Bogdanova, N; Brinton, LA; Brooks-Wilson, A; Brown, R; Butzow, R; Cai, Q; Campbell, I; Chang-Claude, J; Chanock, S et al.
MLA Citation
Permuth-Wey, J, Lawrenson, K, Shen, HC, Velkova, A, Tyrer, JP, Chen, Z, Lin, H-Y, Chen, YA, Tsai, Y-Y, Qu, X, Ramus, SJ, Karevan, R, Lee, J, Lee, N, Larson, MC, Aben, KK, Anton-Culver, H, Antonenkova, N, Antoniou, AC, Armasu, SM, Australian Cancer Study, , Australian Ovarian Cancer Study, , Bacot, F, Baglietto, L, Bandera, EV, Barnholtz-Sloan, J, Beckmann, MW, Birrer, MJ, Bloom, G, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Brown, R, Butzow, R, Cai, Q, Campbell, I, Chang-Claude, J, and Chanock, S et al. "Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31." Nat Commun 4 (2013): 1627-.
PMID
23535648
Source
pubmed
Published In
Nature Communications
Volume
4
Publish Date
2013
Start Page
1627
DOI
10.1038/ncomms2613

Gene expression analysis of early stage endometrial cancers reveals unique transcripts associated with grade and histology but not depth of invasion.

Endometrial cancer is the most common gynecologic malignancy in the United States but it remains poorly understood at the molecular level. This investigation was conducted to specifically assess whether gene expression changes underlie the clinical and pathologic factors traditionally used for determining treatment regimens in women with stage I endometrial cancer. These include the effect of tumor grade, depth of myometrial invasion and histotype. We utilized oligonucleotide microarrays to assess the transcript expression profile in epithelial glandular cells laser microdissected from 79 endometrioid and 12 serous stage I endometrial cancers with a heterogeneous distribution of grade and depth of myometrial invasion, along with 12 normal post-menopausal endometrial samples. Unsupervised multidimensional scaling analyses revealed that serous and endometrioid stage I cancers have similar transcript expression patterns when compared to normal controls where 900 transcripts were identified to be differentially expressed by at least fourfold (univariate t-test, p < 0.001) between the cancers and normal endometrium. This analysis also identified transcript expression differences between serous and endometrioid cancers and tumor grade, but no apparent differences were identified as a function of depth of myometrial invasion. Four genes were validated by quantitative PCR on an independent set of cancer and normal endometrium samples. These findings indicate that unique gene expression profiles are associated with histologic type and grade, but not myometrial invasion among early stage endometrial cancers. These data provide a comprehensive perspective on the molecular alterations associated with stage I endometrial cancer, particularly those subtypes that have the worst prognosis.

Authors
Risinger, JI; Allard, J; Chandran, U; Day, R; Chandramouli, GVR; Miller, C; Zahn, C; Oliver, J; Litzi, T; Marcus, C; Dubil, E; Byrd, K; Cassablanca, Y; Becich, M; Berchuck, A; Darcy, KM; Hamilton, CA; Conrads, TP; Maxwell, GL
MLA Citation
Risinger, JI, Allard, J, Chandran, U, Day, R, Chandramouli, GVR, Miller, C, Zahn, C, Oliver, J, Litzi, T, Marcus, C, Dubil, E, Byrd, K, Cassablanca, Y, Becich, M, Berchuck, A, Darcy, KM, Hamilton, CA, Conrads, TP, and Maxwell, GL. "Gene expression analysis of early stage endometrial cancers reveals unique transcripts associated with grade and histology but not depth of invasion. (Published online)" Front Oncol 3 (2013): 139-.
PMID
23785665
Source
pubmed
Published In
Frontiers in Oncology
Volume
3
Publish Date
2013
Start Page
139
DOI
10.3389/fonc.2013.00139

Timing of end-of-life care discussion with performance on end-of-life quality indicators in ovarian cancer

Objectives (1) To describe the prevalence, timing and setting of documented end-of-life (EOL) discussions in patients with advanced ovarian cancer; and (2) to assess the impact of timing and setting of documented end-of-life discussions on EOL quality care measures. Methods A retrospective study of women who died of ovarian cancer diagnosed between 1999 and 2008 was conducted. The following are the EOL quality measures assessed: chemotherapy in the last 14 days of life, > 1 hospitalization in the last 30 days, > 1 ER visit in the last 30 days, intensive care unit (ICU) admission in the last 30 days, dying in an acute care setting, admitted to hospice ≤ 3 days. Results One hundred seventy-seven (80%) patients had documented end-of-life discussions. Median interval from EOL discussion until death was 29 days. Seventy-eight patients (44%) had EOL discussions as outpatient and 99 (56%) as inpatient. Sixty-four out of 220 (29%) patients' care did not conform to at least one EOL quality measure. An EOL discussion at least 30 days before death was associated with a lower incidence of: chemotherapy in the last 14 days of life (p = 0.003), > 1 hospitalization in the last 30 days (p < 0.001), ICU admission in the last 30 days (p = 0.005), dying in acute care setting (p = 0.01), admitted to hospice ≤ 3 days (p = 0.02). EOL discussion as outpatient was associated with fewer patients hospitalized > 1 in the last 30 days of life (p < 0.001). Conclusions End-of-life care discussions are occurring too late in the disease process. Conformance with EOL quality measures can be achieved with earlier end-of-life care discussions. © 2013 Elsevier Inc.

Authors
Lopez-Acevedo, M; Havrilesky, LJ; Broadwater, G; Kamal, AH; Abernethy, AP; Berchuck, A; Secord, AA; Tulsky, JA; Valea, F; Lee, PS
MLA Citation
Lopez-Acevedo, M, Havrilesky, LJ, Broadwater, G, Kamal, AH, Abernethy, AP, Berchuck, A, Secord, AA, Tulsky, JA, Valea, F, and Lee, PS. "Timing of end-of-life care discussion with performance on end-of-life quality indicators in ovarian cancer." Gynecologic Oncology 130.1 (2013): 156-161.
Source
scival
Published In
Gynecologic Oncology
Volume
130
Issue
1
Publish Date
2013
Start Page
156
End Page
161
DOI
10.1016/j.ygyno.2013.04.010

Transcript expression in endometrial cancers from Black and White patients

Objective Previous studies suggest that differences in molecular features of endometrial cancers between racial groups may contribute to the poorer survival in Blacks. The objective of this investigation was to determine whether gene expression among endometrial cancers is different between Blacks and Whites. Methods Fresh frozen tumors from 25 Black patients were matched by stage, grade, and histology to endometrial cancer specimens from 25 White patients. Each case was macrodissected to produce specimens possessing a minimum of 75% cancer cellularity. A subset of 10 matched pairs was also prepared using laser microdissection (LMD) to produce specimens possessing a minimum of 95% cancer cells. Total RNA isolated from each sample was analyzed using the Affymetrix Human Genome U133 Plus 2.0 arrays. Data were analyzed using principal component analysis and binary class comparison analyses. Results Unsupervised analysis of the 50 endometrial cancers failed to identify global gene expression profiles unique to Black or White patients. In a subset analysis of 10 matched pairs from Blacks and Whites prepared using LMD and macrodissection, unsupervised analysis did not reveal a unique gene expression profile associated with race in either set, but associations were identified that relate to sample preparation technique, histology and stage. Conclusions Our microarray data revealed no global gene expression differences and identified few individual gene differences between endometrial cancers from Blacks and Whites. More comprehensive methods of transcriptome analysis could uncover RNAs that may underpin the disparity of outcome or prevalence of endometrial cancers in Blacks and Whites. © 2013 Elsevier Inc.

Authors
Maxwell, GL; Allard, J; Gadisetti, CVR; Litzi, T; Casablanca, Y; Chandran, U; Darcy, KM; Levine, DA; Berchuck, A; Hamilton, CA; Conrads, TP; Risinger, JI
MLA Citation
Maxwell, GL, Allard, J, Gadisetti, CVR, Litzi, T, Casablanca, Y, Chandran, U, Darcy, KM, Levine, DA, Berchuck, A, Hamilton, CA, Conrads, TP, and Risinger, JI. "Transcript expression in endometrial cancers from Black and White patients." Gynecologic Oncology 130.1 (2013): 169-173.
Source
scival
Published In
Gynecologic Oncology
Volume
130
Issue
1
Publish Date
2013
Start Page
169
End Page
173
DOI
10.1016/j.ygyno.2013.04.017

Validation of ovarian cancer gene expression signatures for survival and subtype in formalin fixed paraffin embedded tissues

Introduction Gene expression signatures have been identified for epithelial ovarian cancer survival (TCGA) and intrinsic subtypes (Tothill et al.). One obstacle to clinical translation is that these signatures were developed using frozen tissue, whereas usually only formalin-fixed, paraffin embedded (FFPE) tissue is available. The aim of this study was to determine if gene expression signatures can be translated to fixed archival tissues. Methods RNA extracted from FFPE sections from 240 primary ovarian cancers was analyzed by DASL on Illumina BeadChip arrays. Concordance of expression at the individual gene level was assessed by comparing array data from the same cancers (30 frozen samples analyzed on Affymetrix arrays versus FFPE DASL). Results The correlation between FFPE and frozen survival signature estimates was 0.774. The TCGA signature using DASL was predictive of survival in 106 advanced stage high grade serous ovarian cancers (median survival 33 versus 60 months, estimated hazard ratio for death 2.30, P = 0.0007). Similar to Tothill, we found using DASL that most high grade serous ovarian cancers (102/110, 93%) were assigned to subtypes 1, 2, 4 and 5, whereas most endometrioid, clear cell, mucinous and low grade serous cases (39/57, 68%) were assigned to subtypes 3 and 6 (P < 10e-15). Conclusions Although individual probe estimates of microarrays may be weakly correlated between FFPE and frozen samples, combinations of probes have robust ability to predict survival and subtype. This suggests that it may be possible to use these signatures for prognostic and predictive purposes as we seek to individualize the treatment of ovarian cancer. © 2012 Elsevier Inc.

Authors
Sfakianos, GP; Iversen, ES; Whitaker, R; Akushevich, L; Schildkraut, JM; Murphy, SK; Marks, JR; Berchuck, A
MLA Citation
Sfakianos, GP, Iversen, ES, Whitaker, R, Akushevich, L, Schildkraut, JM, Murphy, SK, Marks, JR, and Berchuck, A. "Validation of ovarian cancer gene expression signatures for survival and subtype in formalin fixed paraffin embedded tissues." Gynecologic Oncology 129.1 (2013): 159-164.
Source
scival
Published In
Gynecologic Oncology
Volume
129
Issue
1
Publish Date
2013
Start Page
159
End Page
164
DOI
10.1016/j.ygyno.2012.12.030

Predictors of failure to perform pelvic peritoneal cytology in endometrial cancer staging surgery

Authors
Lopez-Acevedo, M; Zhang, C; Secord, AA; Lee, PS; Havrilesky, LJ; Berchuck, A
MLA Citation
Lopez-Acevedo, M, Zhang, C, Secord, AA, Lee, PS, Havrilesky, LJ, and Berchuck, A. "Predictors of failure to perform pelvic peritoneal cytology in endometrial cancer staging surgery." JOURNAL OF CLINICAL ONCOLOGY 30.34 (December 1, 2012).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
34
Publish Date
2012

Predictors of failure to perform pelvic peritoneal cytology in endometrial cancer staging surgery.

201 Background: The Federation of Gynecology and Obstetrics (FIGO) staging system and the National Comprehensive Cancer Network (NCCN) guidelines for endometrial cancer recommend performing pelvic peritoneal cytology to look for the presence of cancer cells in the peritoneal cavity in patients who are undergoing surgical staging of apparent non-metastatic disease. About 10% of cases have positive cytology and this information is used in formulating plans for adjuvant therapy. However, adherence to the guidelines recommending that cytology be performed is not universal. In this study, we sought to identify factors associated with failure to perform pelvic peritoneal cytology at the time of endometrial cancer staging surgery.We performed a retrospective study of women with FIGO stage I/II endometrial adenocarcinoma who underwent endometrial cancer staging surgery at our institution from 1993-2007. Predictors of failure to perform cytology that were investigated included: surgeon, presence of adhesions, intraoperative blood loss and conversion from laparoscopy to laparotomy.Among 1,112 cases, peritoneal cytology was not performed in 76 (6.8%). In 30 cases cytology was not performed for valid reasons including 15 in which the surgery was performed vaginally, 10 in which the diagnosis of endometrial cancer was not known prior to surgery and 5 in which gross evidence of stage III/IV disease was found at surgery. Of the remaining 46 cases, 11 (23.9%) had surgery that was converted from laparoscopy to laparotomy, 16 (34.8%) had dense pelvic adhesions and 40 (87.0%) had an estimated blood loss greater than 100 ml. The frequency of these and other risk factors will be compared to that seen in a matched cohort of patients who did have pelvic peritoneal cytology performed.Our analysis will investigate predictors of failure to perform pelvic peritoneal cytology. Increased awareness of these factors has the potential to improve compliance with this accepted procedure that plays a role in planning adjuvant therapy for early stage endometrial cancer.

Authors
Zhang, C; Secord, AA; Lee, PS; Havrilesky, LJ; Berchuck, A
MLA Citation
Zhang, C, Secord, AA, Lee, PS, Havrilesky, LJ, and Berchuck, A. "Predictors of failure to perform pelvic peritoneal cytology in endometrial cancer staging surgery." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30.34_suppl (December 2012): 201-.
PMID
28147010
Source
epmc
Published In
Journal of Clinical Oncology
Volume
30
Issue
34_suppl
Publish Date
2012
Start Page
201

A phase I trial of dasatinib, an SRC-family kinase inhibitor, in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer.

PURPOSE: We conducted a phase I study of dasatinib, an oral SRC-family tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in the treatment of advanced and recurrent epithelial ovarian cancer. EXPERIMENTAL DESIGN: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included defining toxicity, response rate (RR), pharmacokinetics, and pharmacodynamics. Using a "3+3" design, cohorts of three to six patients received paclitaxel (175 mg/m(2)) and carboplatin (AUC 6) every 3 weeks with escalating doses of dasatinib (100, 120, and 150 mg daily), followed by an eight-patient expansion cohort. RESULTS: Twenty patients were enrolled between June 2007 and December 2009. The median age was 61 years (range: 42-82) with a median of 2 prior regimens (range: 0-6), and 71% had platinum-sensitive disease. There were three to six patients in each cohort, and eight in the expansion cohort. Pharmacokinetics were observed over the first two cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia). Other toxicities in all cycles included neutropenia (95% grade 3-4; 91% in the 150 mg dosing cohort), thrombocytopenia (35% grade 3-4), and fatigue (10% grade 3). The RR was 40% [three complete responses, (15%); five partial responses, (25%)],10 patients (50%) had stable disease, and two were not evaluable. The PFS(6-month) actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively. CONCLUSIONS: Due to the high incidence of myelosuppression with subsequent cycles, the recommended phase II dose of dasatinib is 150 mg daily in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity.

Authors
Secord, AA; Teoh, DK; Barry, WT; Yu, M; Broadwater, G; Havrilesky, LJ; Lee, PS; Berchuck, A; Lancaster, J; Wenham, RM
MLA Citation
Secord, AA, Teoh, DK, Barry, WT, Yu, M, Broadwater, G, Havrilesky, LJ, Lee, PS, Berchuck, A, Lancaster, J, and Wenham, RM. "A phase I trial of dasatinib, an SRC-family kinase inhibitor, in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer." Clin Cancer Res 18.19 (October 1, 2012): 5489-5498.
PMID
22837181
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
18
Issue
19
Publish Date
2012
Start Page
5489
End Page
5498
DOI
10.1158/1078-0432.CCR-12-0507

Genetic testing in ovarian cancer: getting better, and maybe not just for disease susceptibility anymore.

Authors
Berchuck, A
MLA Citation
Berchuck, A. "Genetic testing in ovarian cancer: getting better, and maybe not just for disease susceptibility anymore." Obstet Gynecol 120.2 Pt 1 (August 2012): 221-222.
PMID
22825078
Source
pubmed
Published In
Obstetrics and Gynecology
Volume
120
Issue
2 Pt 1
Publish Date
2012
Start Page
221
End Page
222
DOI
10.1097/AOG.0b013e3182602599

A multicenter, randomized, phase 2 clinical trial to evaluate the efficacy and safety of combination docetaxel and carboplatin and sequential therapy with docetaxel then carboplatin in patients with recurrent platinum-sensitive ovarian cancer.

BACKGROUND: The aim of this randomized clinical trial was to evaluate the efficacy and safety of combination (cDC) and sequential (sDC) weekly docetaxel and carboplatin in women with recurrent platinum-sensitive epithelial ovarian cancer (EOC). METHODS: Participants were randomized to either weekly docetaxel 30 mg/m(2) on days 1 and 8 and carboplatin area under the curve (AUC) = 6 on day 1, every 3 weeks or docetaxel 30 mg/m(2) on days 1 and 8, every 3 weeks for 6 cycles followed by carboplatin AUC = 6 on day 1, every 3 weeks for 6 cycles or until disease progression. The primary endpoint was measurable progression-free survival (PFS). RESULTS: Between January 2004 and March 2007, 150 participants were enrolled. The response rate was 55.4% and 43.2% for those treated with cDC and sDC, respectively. The median PFS was 13.7 months (95% confidence interval [CI], 9.9-16.8) for cDC and 8.4 months (95% CI, 7.1-11.0) for sDC. On the basis of an exploratory analysis, patients treated with sDC were at a 62% increased risk of disease progression compared to those treated with cDC (hazard ratio = 1.62; 95% CI, 1.08-2.45; P = .02). The median overall survival time was similar in both groups (33.2 and 30.1 months, P = .2). The incidence of grade 2 or 3 neurotoxicity and grade 3 or 4 neutropenia was higher with cDC than with sDC (11.7% vs 8.5%; 36.8% vs 11.3%). The sDC group demonstrated significant improvements in the Functional Assessment for Cancer Therapy-Ovarian, Quality of Life Trial Outcome Index scores compared with the combination cohort (P = .013). CONCLUSIONS: Both cDC and sDC regimens have activity in recurrent platinum-sensitive EOC with acceptable toxicity profiles. The cDC regimen may provide a PFS advantage over sDC.

Authors
Alvarez Secord, A; Berchuck, A; Higgins, RV; Nycum, LR; Kohler, MF; Puls, LE; Holloway, RW; Lewandowski, GS; Valea, FA; Havrilesky, LJ
MLA Citation
Alvarez Secord, A, Berchuck, A, Higgins, RV, Nycum, LR, Kohler, MF, Puls, LE, Holloway, RW, Lewandowski, GS, Valea, FA, and Havrilesky, LJ. "A multicenter, randomized, phase 2 clinical trial to evaluate the efficacy and safety of combination docetaxel and carboplatin and sequential therapy with docetaxel then carboplatin in patients with recurrent platinum-sensitive ovarian cancer." Cancer 118.13 (July 1, 2012): 3283-3293.
PMID
22072307
Source
pubmed
Published In
Cancer
Volume
118
Issue
13
Publish Date
2012
Start Page
3283
End Page
3293
DOI
10.1002/cncr.26610

Abstract LB-87: Methylated-mediated repression of ZNF154 in ovarian cancer is associated with poor overall survival

Authors
Okamoto, T; Yamaguchi, K; Huang, Z; Whitaker, R; Konishi, I; Berchuck, A; Murphy, SK
MLA Citation
Okamoto, T, Yamaguchi, K, Huang, Z, Whitaker, R, Konishi, I, Berchuck, A, and Murphy, SK. "Abstract LB-87: Methylated-mediated repression of ZNF154 in ovarian cancer is associated with poor overall survival." Cancer Research 72.8 Supplement (April 15, 2012): LB-87-LB-87.
Source
crossref
Published In
Cancer Research
Volume
72
Issue
8 Supplement
Publish Date
2012
Start Page
LB-87
End Page
LB-87
DOI
10.1158/1538-7445.AM2012-LB-87

Abstract 5363: Aggregation rather than monoclonal expansion explains ovarian cancer spheroid formation

Authors
Huang, Z; Lowery, WJ; Berchuck, A; Murphy, SK
MLA Citation
Huang, Z, Lowery, WJ, Berchuck, A, and Murphy, SK. "Abstract 5363: Aggregation rather than monoclonal expansion explains ovarian cancer spheroid formation." Cancer Research 72.8 Supplement (April 15, 2012): 5363-5363.
Source
crossref
Published In
Cancer Research
Volume
72
Issue
8 Supplement
Publish Date
2012
Start Page
5363
End Page
5363
DOI
10.1158/1538-7445.AM2012-5363

Abstract 2603: Subtype-specific ovarian cancer risk associated with SNPs in IL1A :

Authors
Charbonneau, B; White, KL; Schildkraut, JM; Palmieri, RT; Iversen, E; Berchuck, A; Vierkant, RA; Rider, DN; Cicek, MS; Sutphen, R; Birrer, MJ; Pharoah, PPD; Song, H; Tyrer, J; Gayther, SA; Ramus, SJ; Wentzensen, N; Yang, HP; Garcia-Closas, M; Phelan, CM; Cunningham, JM; Fridley, BL; Sellers, TA; Goode, EL
MLA Citation
Charbonneau, B, White, KL, Schildkraut, JM, Palmieri, RT, Iversen, E, Berchuck, A, Vierkant, RA, Rider, DN, Cicek, MS, Sutphen, R, Birrer, MJ, Pharoah, PPD, Song, H, Tyrer, J, Gayther, SA, Ramus, SJ, Wentzensen, N, Yang, HP, Garcia-Closas, M, Phelan, CM, Cunningham, JM, Fridley, BL, Sellers, TA, and Goode, EL. "Abstract 2603: Subtype-specific ovarian cancer risk associated with SNPs in IL1A :." Cancer Research 72.8 Supplement (April 15, 2012): 2603-2603.
Source
crossref
Published In
Cancer Research
Volume
72
Issue
8 Supplement
Publish Date
2012
Start Page
2603
End Page
2603
DOI
10.1158/1538-7445.AM2012-2603

The influence of radiation modality and lymph node dissection on survival in early-stage endometrial cancer.

BACKGROUND: The appropriate uses of lymph node dissection (LND) and adjuvant radiation therapy (RT) for Stage I endometrial cancer are controversial. We explored the impact of specific RT modalities (whole pelvic RT [WPRT], vaginal brachytherapy [VB]) and LND status on survival. MATERIALS AND METHODS: The Surveillance Epidemiology and End Results dataset was queried for all surgically treated International Federation of Gynecology and Obstetrics (FIGO) Stage I endometrial cancers; subjects were stratified into low, intermediate and high risk cohorts using modifications of Gynecologic Oncology Group (GOG) protocol 99 and PORTEC (Postoperative Radiation Therapy in Endometrial Cancer) trial criteria. Five-year overall survival was estimated, and comparisons were performed via the log-rank test. RESULTS: A total of 56,360 patients were identified: 70.4% low, 26.2% intermediate, and 3.4% high risk. A total of 41.6% underwent LND and 17.6% adjuvant RT. In low-risk disease, LND was associated with higher survival (93.7 LND vs. 92.7% no LND, p < 0.001), whereas RT was not (91.6% RT vs. 92.9% no RT, p = 0.23). In intermediate-risk disease, LND (82.1% LND vs. 76.5% no LND, p < 0.001) and RT (80.6% RT vs. 74.9% no RT, p < 0.001) were associated with higher survival without differences between RT modalities. In high-risk disease, LND (68.8% LND vs. 54.1% no LND, p < 0.001) and RT (66.9% RT vs. 57.2% no RT, p < 0.001) were associated with increased survival; if LND was not performed, VB alone was inferior to WPRT (p = 0.01). CONCLUSION: Both WPRT and VB alone are associated with increased survival in the intermediate-risk group. In the high-risk group, in the absence of LND, only WPRT is associated with increased survival. LND was also associated with increased survival.

Authors
Chino, JP; Jones, E; Berchuck, A; Secord, AA; Havrilesky, LJ
MLA Citation
Chino, JP, Jones, E, Berchuck, A, Secord, AA, and Havrilesky, LJ. "The influence of radiation modality and lymph node dissection on survival in early-stage endometrial cancer." Int J Radiat Oncol Biol Phys 82.5 (April 1, 2012): 1872-1879.
PMID
21640502
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
82
Issue
5
Publish Date
2012
Start Page
1872
End Page
1879
DOI
10.1016/j.ijrobp.2011.03.054

Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies.

BACKGROUND: Endometriosis is a risk factor for epithelial ovarian cancer; however, whether this risk extends to all invasive histological subtypes or borderline tumours is not clear. We undertook an international collaborative study to assess the association between endometriosis and histological subtypes of ovarian cancer. METHODS: Data from 13 ovarian cancer case-control studies, which were part of the Ovarian Cancer Association Consortium, were pooled and logistic regression analyses were undertaken to assess the association between self-reported endometriosis and risk of ovarian cancer. Analyses of invasive cases were done with respect to histological subtypes, grade, and stage, and analyses of borderline tumours by histological subtype. Age, ethnic origin, study site, parity, and duration of oral contraceptive use were included in all analytical models. FINDINGS: 13 226 controls and 7911 women with invasive ovarian cancer were included in this analysis. 818 and 738, respectively, reported a history of endometriosis. 1907 women with borderline ovarian cancer were also included in the analysis, and 168 of these reported a history of endometriosis. Self-reported endometriosis was associated with a significantly increased risk of clear-cell (136 [20·2%] of 674 cases vs 818 [6·2%] of 13 226 controls, odds ratio 3·05, 95% CI 2·43-3·84, p<0·0001), low-grade serous (31 [9·2%] of 336 cases, 2·11, 1·39-3·20, p<0·0001), and endometrioid invasive ovarian cancers (169 [13·9%] of 1220 cases, 2·04, 1·67-2·48, p<0·0001). No association was noted between endometriosis and risk of mucinous (31 [6·0%] of 516 cases, 1·02, 0·69-1·50, p=0·93) or high-grade serous invasive ovarian cancer (261 [7·1%] of 3659 cases, 1·13, 0·97-1·32, p=0·13), or borderline tumours of either subtype (serous 103 [9·0%] of 1140 cases, 1·20, 0·95-1·52, p=0·12, and mucinous 65 [8·5%] of 767 cases, 1·12, 0·84-1·48, p=0·45). INTERPRETATION: Clinicians should be aware of the increased risk of specific subtypes of ovarian cancer in women with endometriosis. Future efforts should focus on understanding the mechanisms that might lead to malignant transformation of endometriosis so as to help identify subsets of women at increased risk of ovarian cancer. FUNDING: Ovarian Cancer Research Fund, National Institutes of Health, California Cancer Research Program, California Department of Health Services, Lon V Smith Foundation, European Community's Seventh Framework Programme, German Federal Ministry of Education and Research of Germany, Programme of Clinical Biomedical Research, German Cancer Research Centre, Eve Appeal, Oak Foundation, UK National Institute of Health Research, National Health and Medical Research Council of Australia, US Army Medical Research and Materiel Command, Cancer Council Tasmania, Cancer Foundation of Western Australia, Mermaid 1, Danish Cancer Society, and Roswell Park Alliance Foundation.

Authors
Pearce, CL; Templeman, C; Rossing, MA; Lee, A; Near, AM; Webb, PM; Nagle, CM; Doherty, JA; Cushing-Haugen, KL; Wicklund, KG; Chang-Claude, J; Hein, R; Lurie, G; Wilkens, LR; Carney, ME; Goodman, MT; Moysich, K; Kjaer, SK; Hogdall, E; Jensen, A; Goode, EL; Fridley, BL; Larson, MC; Schildkraut, JM; Palmieri, RT; Cramer, DW; Terry, KL; Vitonis, AF; Titus, LJ; Ziogas, A; Brewster, W; Anton-Culver, H; Gentry-Maharaj, A; Ramus, SJ; Anderson, AR; Brueggmann, D; Fasching, PA; Gayther, SA; Huntsman, DG et al.
MLA Citation
Pearce, CL, Templeman, C, Rossing, MA, Lee, A, Near, AM, Webb, PM, Nagle, CM, Doherty, JA, Cushing-Haugen, KL, Wicklund, KG, Chang-Claude, J, Hein, R, Lurie, G, Wilkens, LR, Carney, ME, Goodman, MT, Moysich, K, Kjaer, SK, Hogdall, E, Jensen, A, Goode, EL, Fridley, BL, Larson, MC, Schildkraut, JM, Palmieri, RT, Cramer, DW, Terry, KL, Vitonis, AF, Titus, LJ, Ziogas, A, Brewster, W, Anton-Culver, H, Gentry-Maharaj, A, Ramus, SJ, Anderson, AR, Brueggmann, D, Fasching, PA, Gayther, SA, and Huntsman, DG et al. "Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies." Lancet Oncol 13.4 (April 2012): 385-394.
PMID
22361336
Source
pubmed
Published In
The Lancet Oncology
Volume
13
Issue
4
Publish Date
2012
Start Page
385
End Page
394
DOI
10.1016/S1470-2045(11)70404-1

Role of common genetic variants in ovarian cancer susceptibility and outcome: progress to date from the Ovarian Cancer Association Consortium (OCAC).

In this article, we review the current knowledge of the inherited genetics of epithelial ovarian cancer (EOC) susceptibility and clinical outcome. We focus on recent developments in identifying low-penetrance susceptibility genes and the role of the Ovarian Cancer Association Consortium (OCAC) in these discoveries. The OCAC was established to facilitate large-scale replication analyses for reported genetic associations for EOC. Since its inception, the OCAC has conducted both candidate gene and genome-wide association studies (GWAS); the latter has identified six established loci for EOC susceptibility, most of which showed stronger association with the serous histological subtype. Future GWAS and sequencing studies are likely to result in the discovery of additional susceptibility loci and may result in established associations with clinical outcome. Additional rare and uncommon ovarian cancer loci will likely be uncovered from high-throughput next-generation sequencing studies. Applying these novel findings to establish improved preventative and clinical intervention strategies will be one of the major challenges of future work.

Authors
Bolton, KL; Ganda, C; Berchuck, A; Pharaoh, PDP; Gayther, SA
MLA Citation
Bolton, KL, Ganda, C, Berchuck, A, Pharaoh, PDP, and Gayther, SA. "Role of common genetic variants in ovarian cancer susceptibility and outcome: progress to date from the Ovarian Cancer Association Consortium (OCAC)." J Intern Med 271.4 (April 2012): 366-378. (Review)
PMID
22443200
Source
pubmed
Published In
Journal of Internal Medicine
Volume
271
Issue
4
Publish Date
2012
Start Page
366
End Page
378
DOI
10.1111/j.1365-2796.2011.02509.x

Ovarian cancer risk associated with inherited inflammation-related variants.

The importance of inflammation pathways to the development of many human cancers prompted us to examine the associations between single-nucleotide polymorphisms (SNP) in inflammation-related genes and risk of ovarian cancer. In a multisite case-control study, we genotyped SNPs in a large panel of inflammatory genes in 930 epithelial ovarian cancer cases and 1,037 controls using a custom array and analyzed by logistic regression. SNPs with P < 0.10 were evaluated among 3,143 cases and 2,102 controls from the Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI) post-GWAS collaboration. Combined analysis revealed association with SNPs rs17561 and rs4848300 in the interleukin gene IL1A which varied by histologic subtype (P(heterogeneity) = 0.03). For example, IL1A rs17561, which correlates with numerous inflammatory phenotypes, was associated with decreased risk of clear cell, mucinous, and endometrioid subtype, but not with the most common serous subtype. Genotype at rs1864414 in the arachidonate 5-lipoxygenase ALOX5 was also associated with decreased risk. Thus, inherited variation in IL1A and ALOX5 seems to affect ovarian cancer risk which, for IL1A, is limited to rarer subtypes. Given the importance of inflammation in tumorigenesis and growing evidence of subtype-specific features in ovarian cancer, functional investigations will be important to help clarify the importance of inherited variation related to inflammation in ovarian carcinogenesis.

Authors
White, KL; Schildkraut, JM; Palmieri, RT; Iversen, ES; Berchuck, A; Vierkant, RA; Rider, DN; Charbonneau, B; Cicek, MS; Sutphen, R; Birrer, MJ; Pharoah, PPD; Song, H; Tyrer, J; Gayther, SA; Ramus, SJ; Wentzensen, N; Yang, HP; Garcia-Closas, M; Phelan, CM; Cunningham, JM; Fridley, BL; Sellers, TA; Goode, EL; Ovarian Cancer Association Consortium,
MLA Citation
White, KL, Schildkraut, JM, Palmieri, RT, Iversen, ES, Berchuck, A, Vierkant, RA, Rider, DN, Charbonneau, B, Cicek, MS, Sutphen, R, Birrer, MJ, Pharoah, PPD, Song, H, Tyrer, J, Gayther, SA, Ramus, SJ, Wentzensen, N, Yang, HP, Garcia-Closas, M, Phelan, CM, Cunningham, JM, Fridley, BL, Sellers, TA, Goode, EL, and Ovarian Cancer Association Consortium, . "Ovarian cancer risk associated with inherited inflammation-related variants." Cancer Res 72.5 (March 1, 2012): 1064-1069.
PMID
22282663
Source
pubmed
Published In
Cancer Research
Volume
72
Issue
5
Publish Date
2012
Start Page
1064
End Page
1069
DOI
10.1158/0008-5472.CAN-11-3512

Minimally invasive surgery for endometrial cancer: the horse is already out of the barn.

Authors
Berchuck, A; Secord, AA; Havrilesky, LJ
MLA Citation
Berchuck, A, Secord, AA, and Havrilesky, LJ. "Minimally invasive surgery for endometrial cancer: the horse is already out of the barn." J Clin Oncol 30.7 (March 1, 2012): 681-682.
PMID
22291090
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
30
Issue
7
Publish Date
2012
Start Page
681
End Page
682
DOI
10.1200/JCO.2011.40.5506

Common variation in Nemo-like kinase is associated with risk of ovarian cancer.

BACKGROUND: Overexpression of mitotic kinases has been associated with prognosis, histologic grade, and clinical stage in ovarian cancer, but the relationship between inherited variation in these genes and ovarian cancer risk has not been well defined. METHODS: We measured associations between 397 single nucleotide polymorphisms (SNPs) from 67 mitotic kinases and invasive epithelial ovarian cancer risk in two case-control studies (n = 671 cases; n = 939 controls). Thirty-six candidate SNPs (P < 0.05) were assessed in a replication analysis consisting of three additional studies (n = 1,094 cases; n = 829 controls). RESULTS: In initial analysis, thirty-six SNPs were suggestive of association with risk of serous ovarian cancer, all subtypes of ovarian cancer, or both (P < 0.05). Replication analyses suggested an association between rs2125846 in the Nemo-like kinase (NLK) gene and ovarian cancer (serous OR = 1.36, 95% CI: 1.11-1.67, P = 1.77 × 10(-3); all subtypes OR = 1.30, 95% CI: 1.08-1.56, P = 2.97 × 10(-3)). Furthermore, rs2125846 was associated with risk in the combined discovery and replication sets (serous OR = 1.33, 95% CI: 1.15-1.54; all subtypes OR = 1.27, 95% CI: 1.12-1.45). CONCLUSIONS: Variation in NLK may be associated with risk of invasive epithelial ovarian cancer. Further studies are needed to confirm and understand the biologic relationship between this mitotic kinase and ovarian cancer risk. IMPACT: An association between SNPs in NLK and ovarian cancer may provide biologic insight into the development of this disease.

Authors
Stevens, KN; Kelemen, LE; Wang, X; Fridley, BL; Vierkant, RA; Fredericksen, Z; Armasu, SM; Tsai, Y-Y; Berchuck, A; Narod, SA; Phelan, CM; Sutphen, R; Birrer, MJ; Schildkraut, JM; Sellers, TA; Goode, EL; Ovarian Cancer Association Consortium, ; Couch, FJ
MLA Citation
Stevens, KN, Kelemen, LE, Wang, X, Fridley, BL, Vierkant, RA, Fredericksen, Z, Armasu, SM, Tsai, Y-Y, Berchuck, A, Narod, SA, Phelan, CM, Sutphen, R, Birrer, MJ, Schildkraut, JM, Sellers, TA, Goode, EL, Ovarian Cancer Association Consortium, , and Couch, FJ. "Common variation in Nemo-like kinase is associated with risk of ovarian cancer." Cancer Epidemiol Biomarkers Prev 21.3 (March 2012): 523-528.
PMID
22253297
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
21
Issue
3
Publish Date
2012
Start Page
523
End Page
528
DOI
10.1158/1055-9965.EPI-11-0797

Nonsteroidal antiinflammatory drugs and progestins synergistically enhance cell death in ovarian epithelial cells.

OBJECTIVE: There is growing evidence that progestins and nonsteroidal antiinflammatory drugs (NSAIDs) may prevent ovarian cancer. Because both induce apoptosis, we investigated the potential for synergistic impact of combined drug treatment on cell death. STUDY DESIGN: Using normal and malignant human ovarian epithelial cells and an NSAID-sensitive human colon cancer cell line, we evaluated the effects of progestins and NSAIDs alone and in combination on apoptosis. RESULTS: Both progestins and NSAIDs dose dependently inhibited cell growth (P < .0001). Doses of NSAIDs or progestins that independently reduced cell viability by less than 30% synergistically reduced cell viability by 70-95% when combined. Similarly, the NSAID/progestin combination conferred 4- to 18-fold (P < .05) increased apoptosis over either treatment alone. CONCLUSION: Our results suggest it may be possible to combine progestins and NSAIDs to achieve ovarian cancer prevention at lower doses of each than are required for single administration, thereby lessening the risk of side effects posed by these agents.

Authors
Rodriguez, GC; Turbov, JM; Berchuck, A; Stack, MS; Hurteau, JA; Thaete, LG; Barry, CP
MLA Citation
Rodriguez, GC, Turbov, JM, Berchuck, A, Stack, MS, Hurteau, JA, Thaete, LG, and Barry, CP. "Nonsteroidal antiinflammatory drugs and progestins synergistically enhance cell death in ovarian epithelial cells." Am J Obstet Gynecol 206.3 (March 2012): 253.e1-253.e9.
PMID
22206747
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
206
Issue
3
Publish Date
2012
Start Page
253.e1
End Page
253.e9
DOI
10.1016/j.ajog.2011.11.012

DNA methylation profiles distinguish serous, mucinous and clear cell but not endometrioid epithelial ovarian cancers

Authors
Murphy, S; Yang, H; Yamaguchi, K; Huang, Z; Konishi, I; Berchuck, A
MLA Citation
Murphy, S, Yang, H, Yamaguchi, K, Huang, Z, Konishi, I, and Berchuck, A. "DNA methylation profiles distinguish serous, mucinous and clear cell but not endometrioid epithelial ovarian cancers." GYNECOLOGIC ONCOLOGY 125 (March 2012): S99-S99.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
125
Publish Date
2012
Start Page
S99
End Page
S99
DOI
10.1016/j.ygyno.2011.12.237

Frequency of the cancer genome atlas expression subtypes differs between early and advanced stage high grade serous ovarian cancers

Authors
Berchuck, A; Sfakianos, G; Whitaker, R; Levine, D; Murphy, S; Marks, J; Iversen, E
MLA Citation
Berchuck, A, Sfakianos, G, Whitaker, R, Levine, D, Murphy, S, Marks, J, and Iversen, E. "Frequency of the cancer genome atlas expression subtypes differs between early and advanced stage high grade serous ovarian cancers." GYNECOLOGIC ONCOLOGY 125 (March 2012): S133-S133.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
125
Publish Date
2012
Start Page
S133
End Page
S133
DOI
10.1016/j.ygyno.2011.12.325

Clinical translation of the cancer genome atlas signature for ovarian cancer survival

Authors
Sfakianos, G; Iversen, E; Lowery, W; Whitaker, R; Akushevich, L; Schildkraut, J; Marks, J; Berchuck, A
MLA Citation
Sfakianos, G, Iversen, E, Lowery, W, Whitaker, R, Akushevich, L, Schildkraut, J, Marks, J, and Berchuck, A. "Clinical translation of the cancer genome atlas signature for ovarian cancer survival." GYNECOLOGIC ONCOLOGY 125 (March 2012): S42-S42.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
125
Publish Date
2012
Start Page
S42
End Page
S42
DOI
10.1016/j.ygyno.2011.12.101

Loss of p16 in advanced stage epithelial ovarian cancer is associated with chemoresistant disease, suboptimal debulking and poor progression-free survival: A Gynecologic Oncology Group study

Authors
Wallace, A; Darcy, K; Alvarez-Secord, A; Hutson, A; Tritchler, D; Kirchgraber, L; Grace, L; Whitaker, R; Berchuck, A; Havrilesky, L
MLA Citation
Wallace, A, Darcy, K, Alvarez-Secord, A, Hutson, A, Tritchler, D, Kirchgraber, L, Grace, L, Whitaker, R, Berchuck, A, and Havrilesky, L. "Loss of p16 in advanced stage epithelial ovarian cancer is associated with chemoresistant disease, suboptimal debulking and poor progression-free survival: A Gynecologic Oncology Group study." GYNECOLOGIC ONCOLOGY 125 (March 2012): S37-S37.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
125
Publish Date
2012
Start Page
S37
End Page
S37
DOI
10.1016/j.ygyno.2011.12.084

Cost-effectiveness of combination versus sequential docetaxel and carboplatin for the treatment of platinum-sensitive, recurrent ovarian cancer.

BACKGROUND: In a randomized controlled trial (RCT) of patients with recurrent, platinum-sensitive ovarian cancer, the combination weekly docetaxel and carboplatin was associated a with progression-free survival (PFS) of 13.7 months compared with 8.4 months for sequential, single-agent docetaxel followed by carboplatin. The objective of the current study was to construct a cost-utility model to compare these 2 regimens with the incorporation of prospectively collected quality-of-life (QoL) data. METHODS: An RCT of concurrent docetaxel and carboplatin (cDC) versus docetaxel followed by carboplatin (sequential docetaxel and carboplatin [sDC]) was the basis for a Markov decision model, and the primary effectiveness outcome was PFS. Costs were estimated using US dollars based on Medicare reimbursements for chemotherapy regimens, bone marrow support, and management of adverse events. QoL data obtained using the Functional Assessment of Cancer Therapy-General questionnaire were converted to utilities. Costs and incremental cost-effectiveness ratios (ICERs) were reported in US dollars per quality-adjusted life year (QALY). Extensive 1-way sensitivity analyses and a Monte Carlo probabilistic sensitivity analysis were performed. RESULTS: The least expensive strategy was sDC, which cost an average of $20,381, compared with cDC, which cost an average of $25,122. cDC had an ICER of $25,239 per QALY compared with sDC. cDC remained cost-effective, with an ICER <$50,000 per QALY, over a range of costs and estimates. In Monte Carlo sensitivity analysis using a $50,000 per QALY willingness-to-pay threshold, cDC was either dominant or cost-effective with an ICER <$50,000 per QALY in 83% of simulations. CONCLUSIONS: Combined weekly cDC appeared to be cost-effective compared with sDC as treatment strategy for patients with platinum-sensitive ovarian cancer, even when accounting for slightly lower QoL during treatment.

Authors
Havrilesky, LJ; Pokrzywinski, R; Revicki, D; Higgins, RV; Nycum, LR; Kohler, MF; Berchuck, A; Myers, ER; Secord, AA
MLA Citation
Havrilesky, LJ, Pokrzywinski, R, Revicki, D, Higgins, RV, Nycum, LR, Kohler, MF, Berchuck, A, Myers, ER, and Secord, AA. "Cost-effectiveness of combination versus sequential docetaxel and carboplatin for the treatment of platinum-sensitive, recurrent ovarian cancer." Cancer 118.2 (January 15, 2012): 386-391.
PMID
21598242
Source
pubmed
Published In
Cancer
Volume
118
Issue
2
Publish Date
2012
Start Page
386
End Page
391
DOI
10.1002/cncr.26199

Loss of ARID1A-associated protein expression is a frequent event in clear cell and endometrioid ovarian cancers.

BACKGROUND: Inactivating somatic mutations in the ARID1A gene are described in a significant fraction of clear cell and endometrioid ovarian cancers leading to loss of the corresponding protein (BAF250a). Expression of BAF250a was examined in clear cell and endometrioid cancers accrued as part of the North Carolina Ovarian Cancer Study, a population-based case-control study, to determine whether loss of expression is associated with clinical and epidemiological features. METHODS: Immunostaining for BAF250a was performed using 212 clear cell and endometrioid ovarian cancers. Associations between loss of BAF250a and clinical and epidemiological features were examined. Variables were analyzed by logistic regression. RESULTS: Loss of BAF250a expression was noted in 96 (45%) of 212 cancers: 34 (41%) of 82 clear cell cases and 62 (48%) of 130 endometrioid cases. There was no relationship between the loss of BAF250a and stage, grade, survival, or epidemiological variables. CONCLUSIONS: These data confirm that loss of the ARID1A-encoded protein BAF250a is a frequent event in the genesis of clear cell and endometrioid ovarian cancers. Loss of BAF250a was not associated with clinical or epidemiologic characteristics. One explanation for these findings is that inactivation of the chromatin remodeling pathway may be a requisite event in the development of these cancers.

Authors
Lowery, WJ; Schildkraut, JM; Akushevich, L; Bentley, R; Marks, JR; Huntsman, D; Berchuck, A
MLA Citation
Lowery, WJ, Schildkraut, JM, Akushevich, L, Bentley, R, Marks, JR, Huntsman, D, and Berchuck, A. "Loss of ARID1A-associated protein expression is a frequent event in clear cell and endometrioid ovarian cancers." Int J Gynecol Cancer 22.1 (January 2012): 9-14.
PMID
22193641
Source
pubmed
Published In
International Journal of Gynecological Cancer
Volume
22
Issue
1
Publish Date
2012
Start Page
9
End Page
14
DOI
10.1097/IGC.0b013e318231f140

Endometriosis and ovarian cancer - Authors' reply

Authors
Pearce, CL; Berchuck, A
MLA Citation
Pearce, CL, and Berchuck, A. "Endometriosis and ovarian cancer - Authors' reply." The Lancet Oncology 13.5 (2012): e190-.
Source
scival
Published In
The Lancet Oncology
Volume
13
Issue
5
Publish Date
2012
Start Page
e190
DOI
10.1016/S1470-2045(12)70103-1

An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer (Journal of Clinical Oncology (2007) 25 (517-525))

Authors
Dressman, HK; Berchuck, A; Chan, G; Zhai, J; Bild, A; Sayer, R; Cragun, J; Clarke, J; Whitaker, RS; Li, L; Gray, J; Marks, J; Ginsburg, GS; Potti, A; West, M; Nevins, JR; Lancaster, JM
MLA Citation
Dressman, HK, Berchuck, A, Chan, G, Zhai, J, Bild, A, Sayer, R, Cragun, J, Clarke, J, Whitaker, RS, Li, L, Gray, J, Marks, J, Ginsburg, GS, Potti, A, West, M, Nevins, JR, and Lancaster, JM. "An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer (Journal of Clinical Oncology (2007) 25 (517-525))." Journal of Clinical Oncology 30.6 (2012): 678--.
Source
scival
Published In
Journal of Clinical Oncology
Volume
30
Issue
6
Publish Date
2012
Start Page
678-
DOI
10.1200/JCO.2012.42.0331

Analysis of PSPHL as a Candidate Gene Influencing the Racial Disparity in Endometrial Cancer.

Endometrial cancer is the most commonly diagnosed gynecologic malignancy in the United States. A well recognized disparity by race in both incidence and survival outcome exists for this cancer. Specifically Caucasians are about two times more likely to develop endometrial cancer than are African-Americans. However, African-American women are more likely to die from this disease than are Caucasians. The basis for this disparity remains unknown. Previous studies have identified differences in the types and frequencies of gene mutations among endometrial cancers from Caucasians and African-Americans suggesting that the tumors from these two groups might have differing underlying genetic defects. We performed a gene expression microarray study in an effort to identify differentially expressed transcripts between African-American and Caucasian women's endometrial cancers. Our gene expression screen identified a list of potential biomarkers that are differentially expressed between these two groups of cancers. Of these we identified a poorly characterized transcript with a region of homology to phospho serine phosphatase (PSPH) and designated phospho serine phosphatase like (PSPHL) as the most differentially over-expressed gene in cancers from African-Americans. We further clarified the nature of expressed transcripts. Northern blot analysis confirmed the message was limited to a transcript of under 1 kB. Sequence analysis of transcripts confirmed two alternate open reading frame (ORF) isoforms due to alternative splicing events. Splice specific primer sets confirmed both isoforms were differentially expressed in tissues from Caucasians and African-Americans. We further examined the expression in other tissues from women to include normal endometrium, normal and malignant ovary. In all cases PSPHL expression was more often present in tissues from African-Americans than Caucasians. Our data confirm the African-American based expression of the PSPHL transcript in endometrial cancer and also identify its expression in other tissues from African-Americans including ovary and ovarian cancer. PSPHL represents a candidate gene that might influence the observed racial disparity in endometrial and other cancers.

Authors
Allard, JE; Chandramouli, GVR; Stagliano, K; Hood, BL; Litzi, T; Shoji, Y; Boyd, J; Berchuck, A; Conrads, TP; Maxwell, GL; Risinger, JI
MLA Citation
Allard, JE, Chandramouli, GVR, Stagliano, K, Hood, BL, Litzi, T, Shoji, Y, Boyd, J, Berchuck, A, Conrads, TP, Maxwell, GL, and Risinger, JI. "Analysis of PSPHL as a Candidate Gene Influencing the Racial Disparity in Endometrial Cancer. (Published online)" Front Oncol 2 (2012): 65-.
PMID
22783543
Source
pubmed
Published In
Frontiers in Oncology
Volume
2
Publish Date
2012
Start Page
65
DOI
10.3389/fonc.2012.00065

Regular Multivitamin Supplement Use, Single Nucleotide Polymorphisms in ATIC, SHMT2, and SLC46A1, and Risk of Ovarian Carcinoma.

ATIC, SHMT2, and SLC46A1 have essential roles in one-carbon (1-C) transfer. The authors examined whether associations between ovarian carcinoma and 15 variants in these genes are modified by regular multivitamin use, a source of 1-C donors, among Caucasian participants from two US case-control studies. Using a phased study design, variant-by-multivitamin interactions were tested, and associations between variants and ovarian carcinoma were reported stratified by multivitamin supplement use. Per-allele risk associations were modified by multivitamin use at six variants among 655 cases and 920 controls (Phase 1). In a larger sample of 968 cases and 1,265 controls (Phases 1 and 2), interactions were significant (P ≤ 0.03) for two variants, particularly among regular multivitamin users: ATIC rs7586969 [odds ratio (OR) = 0.7, 95% confidence interval (CI) = 0.6-0.9] and ATIC rs16853834 (OR = 1.5, 95% CI = 1.1-2.0). The two ATIC single nucleotide polymorphisms (SNPs) did not share the same haplotype; however, the haplotypes they comprised mirrored their SNP risk associations among regular multivitamin supplement users. A multi-variant analysis was also performed by comparing the observed likelihood ratio test statistic from adjusted models with and without the two ATIC variant-by-multivitamin interaction terms with a null distribution of test statistics generated by permuting case status 10,000 times. The corresponding observed P value of 0.001 was more extreme than the permutation-derived P value of 0.009, suggesting rejection of the null hypothesis of no association. In summary, there is little statistical evidence that the 15 variants are independently associated with risk of ovarian carcinoma. However, the statistical interaction of ATIC variants with regular multivitamin intake, when evaluated at both the SNP and gene level, may support these findings as relevant to ovarian health and disease processes.

Authors
Kelemen, LE; Wang, Q; Dinu, I; Vierkant, RA; Tsai, Y-Y; Cunningham, JM; Phelan, CM; Fridley, BL; Amankwah, EK; Iversen, ES; Berchuck, A; Schildkraut, JM; Goode, EL; Sellers, TA
MLA Citation
Kelemen, LE, Wang, Q, Dinu, I, Vierkant, RA, Tsai, Y-Y, Cunningham, JM, Phelan, CM, Fridley, BL, Amankwah, EK, Iversen, ES, Berchuck, A, Schildkraut, JM, Goode, EL, and Sellers, TA. "Regular Multivitamin Supplement Use, Single Nucleotide Polymorphisms in ATIC, SHMT2, and SLC46A1, and Risk of Ovarian Carcinoma. (Published online)" Front Genet 3 (2012): 33-.
PMID
22461784
Source
pubmed
Published In
Frontiers in Genetics
Volume
3
Publish Date
2012
Start Page
33
DOI
10.3389/fgene.2012.00033

Ovarian cancer progenitor/stem cells: Therapeutic potential

A number of studies provide evidence for the existence of ovarian cancer stem cells, defined by functional attributes, foremost the ability to reconstruct the heterogeneity of the original tumor in immunocompromised mice through asymmetric cell division. As satisfying as the concept of an ovarian cancer stem cell is to explain the origins of ovarian cancer, can this concept be applied universally to explain the diversity in the histologic types of epithelial ovarian cancer? Can the unique features of an ovarian cancer stem cell population be exploited to therapeutically disarm these cells? Herein we explore these questions, beginning with a brief description of cancer stem cells in general and then turning more specifically to what is known about ovarian cancer stem cells. We then explore the potential for therapeutic targeting of these cells, and what the future holds for implementation of such approaches toward improving survival of women with ovarian cancer. © 2011 Springer Science+Business Media, LLC.

Authors
Murphy, SK; Berchuck, A
MLA Citation
Murphy, SK, and Berchuck, A. "Ovarian cancer progenitor/stem cells: Therapeutic potential." (December 1, 2011): 223-244. (Chapter)
Source
scopus
Publish Date
2011
Start Page
223
End Page
244
DOI
10.1007/978-1-4419-7216-3_11

Quantitative detection of RASSF1A DNA promoter methylation in tumors and serum of patients with serous epithelial ovarian cancer.

OBJECTIVE: Detection of cell free tumor-specific DNA methylation has been proposed as a potentially useful noninvasive mechanism to detect malignancies, including ovarian cancer, and to monitor response to treatment. However, there are few easily implemented quantitative approaches available for DNA methylation analysis. Our objectives were to develop an absolute quantitative method for detection of DNA methylation using RASSF1A, a known target of promoter methylation in ovarian cancer, and test the ability to detect RASSF1A methylation in tumors and serum specimens of women with ovarian cancer. METHODS: Bisulfite modified DNAs were subjected to real time PCR using nondiscriminatory PCR primers and a probe with sequence containing a single CpG site, theoretically able to capture the methylation status of that CpG for every allele within a given specimen. Input DNA was normalized to ACTB levels detected simultaneously by assay multiplexing. Methylation levels were established by comparison to results obtained from universally methylated DNA. RESULTS: The assay was able to detect one methylated RASSF1A allele in 100,000 unmethylated alleles. RASSF1A was methylated in 54 of 106 (51%) invasive serous ovarian cancers analyzed and methylation status was concordant in 20/20 matched preoperative serum-tumor pairs. Serial serum specimens taken over the course of treatment for 8 of 9 patients showed fluctuations in RASSF1A methylation concomitant with disease status. CONCLUSIONS: This novel assay provides a real-time PCR-based method for absolute quantitation of DNA methylation. Our results support feasibility of monitoring RASSF1A methylation from serum samples taken over the course of treatment from women with ovarian cancer.

Authors
Bondurant, AE; Huang, Z; Whitaker, RS; Simel, LR; Berchuck, A; Murphy, SK
MLA Citation
Bondurant, AE, Huang, Z, Whitaker, RS, Simel, LR, Berchuck, A, and Murphy, SK. "Quantitative detection of RASSF1A DNA promoter methylation in tumors and serum of patients with serous epithelial ovarian cancer." Gynecol Oncol 123.3 (December 2011): 581-587.
PMID
21955482
Source
pubmed
Published In
Gynecologic Oncology
Volume
123
Issue
3
Publish Date
2011
Start Page
581
End Page
587
DOI
10.1016/j.ygyno.2011.08.029

BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival.

PURPOSE: Despite initial sensitivity to chemotherapy, ovarian cancers (OVCA) often develop drug resistance, which limits patient survival. Using specimens and/or genomic data from 289 patients and a panel of cancer cell lines, we explored genome-wide expression changes that underlie the evolution of OVCA chemoresistance and characterized the BCL2 antagonist of cell death (BAD) apoptosis pathway as a determinant of chemosensitivity and patient survival. EXPERIMENTAL DESIGN: Serial OVCA cell cisplatin treatments were performed in parallel with measurements of genome-wide expression changes. Pathway analysis was carried out on genes associated with increasing cisplatin resistance (EC(50)). BAD-pathway expression and BAD protein phosphorylation were evaluated in patient samples and cell lines as determinants of chemosensitivity and/or clinical outcome and as therapeutic targets. RESULTS: Induced in vitro OVCA cisplatin resistance was associated with BAD-pathway expression (P < 0.001). In OVCA cell lines and primary specimens, BAD protein phosphorylation was associated with platinum resistance (n = 147, P < 0.0001) and also with overall patient survival (n = 134, P = 0.0007). Targeted modulation of BAD-phosphorylation levels influenced cisplatin sensitivity. A 47-gene BAD-pathway score was associated with in vitro phosphorylated BAD levels and with survival in 142 patients with advanced-stage (III/IV) serous OVCA. Integration of BAD-phosphorylation or BAD-pathway score with OVCA surgical cytoreductive status was significantly associated with overall survival by log-rank test (P = 0.004 and P < 0.0001, respectively). CONCLUSION: The BAD apoptosis pathway influences OVCA chemosensitivity and overall survival, likely via modulation of BAD phosphorylation. The pathway has clinical relevance as a biomarker of therapeutic response, patient survival, and as a promising therapeutic target.

Authors
Marchion, DC; Cottrill, HM; Xiong, Y; Chen, N; Bicaku, E; Fulp, WJ; Bansal, N; Chon, HS; Stickles, XB; Kamath, SG; Hakam, A; Li, L; Su, D; Moreno, C; Judson, PL; Berchuck, A; Wenham, RM; Apte, SM; Gonzalez-Bosquet, J; Bloom, GC; Eschrich, SA; Sebti, S; Chen, D-T; Lancaster, JM
MLA Citation
Marchion, DC, Cottrill, HM, Xiong, Y, Chen, N, Bicaku, E, Fulp, WJ, Bansal, N, Chon, HS, Stickles, XB, Kamath, SG, Hakam, A, Li, L, Su, D, Moreno, C, Judson, PL, Berchuck, A, Wenham, RM, Apte, SM, Gonzalez-Bosquet, J, Bloom, GC, Eschrich, SA, Sebti, S, Chen, D-T, and Lancaster, JM. "BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival." Clin Cancer Res 17.19 (October 1, 2011): 6356-6366.
PMID
21849418
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
19
Publish Date
2011
Start Page
6356
End Page
6366
DOI
10.1158/1078-0432.CCR-11-0735

A genomic-based signature of response to chemotherapy in ovarian cancer fails to predict clinical outcome in two independent cohorts.

Authors
Barry, W; Chen, W; Sfakianos, G; Isner, P; Datto, M; Kuderer, N; Lyman, G; Abernethy, A; Ginsburg, G; Berchuck, A
MLA Citation
Barry, W, Chen, W, Sfakianos, G, Isner, P, Datto, M, Kuderer, N, Lyman, G, Abernethy, A, Ginsburg, G, and Berchuck, A. "A genomic-based signature of response to chemotherapy in ovarian cancer fails to predict clinical outcome in two independent cohorts." October 2011.
Source
wos-lite
Published In
European Journal of Cancer
Volume
47
Publish Date
2011
Start Page
S8
End Page
S8

Rethinking ovarian cancer: recommendations for improving outcomes.

There have been major advances in our understanding of the cellular and molecular biology of the human malignancies that are collectively referred to as ovarian cancer. At a recent Helene Harris Memorial Trust meeting, an international group of researchers considered actions that should be taken to improve the outcome for women with ovarian cancer. Nine major recommendations are outlined in this Opinion article.

Authors
Vaughan, S; Coward, JI; Bast, RC; Berchuck, A; Berek, JS; Brenton, JD; Coukos, G; Crum, CC; Drapkin, R; Etemadmoghadam, D; Friedlander, M; Gabra, H; Kaye, SB; Lord, CJ; Lengyel, E; Levine, DA; McNeish, IA; Menon, U; Mills, GB; Nephew, KP; Oza, AM; Sood, AK; Stronach, EA; Walczak, H; Bowtell, DD; Balkwill, FR
MLA Citation
Vaughan, S, Coward, JI, Bast, RC, Berchuck, A, Berek, JS, Brenton, JD, Coukos, G, Crum, CC, Drapkin, R, Etemadmoghadam, D, Friedlander, M, Gabra, H, Kaye, SB, Lord, CJ, Lengyel, E, Levine, DA, McNeish, IA, Menon, U, Mills, GB, Nephew, KP, Oza, AM, Sood, AK, Stronach, EA, Walczak, H, Bowtell, DD, and Balkwill, FR. "Rethinking ovarian cancer: recommendations for improving outcomes. (Published online)" Nat Rev Cancer 11.10 (September 23, 2011): 719-725.
PMID
21941283
Source
pubmed
Published In
Nature Reviews Cancer
Volume
11
Issue
10
Publish Date
2011
Start Page
719
End Page
725
DOI
10.1038/nrc3144

Large prospective study of ovarian cancer screening in high-risk women: CA125 cut-point defined by menopausal status.

Previous screening trials for early detection of ovarian cancer in postmenopausal women have used the standard CA125 cut-point of 35 U/mL, the 98th percentile in this population yielding a 2% false positive rate, whereas the same cut-point in trials of premenopausal women results in substantially higher false positive rates. We investigated demographic and clinical factors predicting CA125 distributions, including 98th percentiles, in a large population of high-risk women participating in two ovarian cancer screening studies with common eligibility criteria and screening protocols. Baseline CA125 values and clinical and demographic data from 3,692 women participating in screening studies conducted by the National Cancer Institute-sponsored Cancer Genetics Network and Gynecologic Oncology Group were combined for this preplanned analysis. Because of the large effect of menopausal status on CA125 levels, statistical analyses were conducted separately in pre- and postmenopausal subjects to determine the impact of other baseline factors on predicted CA125 cut-points on the basis of 98th percentile. The primary clinical factor affecting CA125 cut-points was menopausal status, with premenopausal women having a significantly higher cut-point of 50 U/mL, while in postmenopausal subjects the standard cut-point of 35 U/mL was recapitulated. In premenopausal women, current oral contraceptive (OC) users had a cut-point of 40 U/mL. To achieve a 2% false positive rate in ovarian cancer screening trials and in high-risk women choosing to be screened, the cut-point for initial CA125 testing should be personalized primarily for menopausal status (50 for premenopausal women, 40 for premenopausal on OC, and 35 for postmenopausal women).

Authors
Skates, SJ; Mai, P; Horick, NK; Piedmonte, M; Drescher, CW; Isaacs, C; Armstrong, DK; Buys, SS; Rodriguez, GC; Horowitz, IR; Berchuck, A; Daly, MB; Domchek, S; Cohn, DE; Van Le, L; Schorge, JO; Newland, W; Davidson, SA; Barnes, M; Brewster, W; Azodi, M; Nerenstone, S; Kauff, ND; Fabian, CJ; Sluss, PM; Nayfield, SG; Kasten, CH; Finkelstein, DM; Greene, MH; Lu, K
MLA Citation
Skates, SJ, Mai, P, Horick, NK, Piedmonte, M, Drescher, CW, Isaacs, C, Armstrong, DK, Buys, SS, Rodriguez, GC, Horowitz, IR, Berchuck, A, Daly, MB, Domchek, S, Cohn, DE, Van Le, L, Schorge, JO, Newland, W, Davidson, SA, Barnes, M, Brewster, W, Azodi, M, Nerenstone, S, Kauff, ND, Fabian, CJ, Sluss, PM, Nayfield, SG, Kasten, CH, Finkelstein, DM, Greene, MH, and Lu, K. "Large prospective study of ovarian cancer screening in high-risk women: CA125 cut-point defined by menopausal status." Cancer Prev Res (Phila) 4.9 (September 2011): 1401-1408.
PMID
21893500
Source
pubmed
Published In
Cancer Prevention Research
Volume
4
Issue
9
Publish Date
2011
Start Page
1401
End Page
1408
DOI
10.1158/1940-6207.CAPR-10-0402

Cost comparison of strategies for the management of venous thromboembolic event risk following laparotomy for ovarian cancer.

OBJECTIVE: To evaluate the costs and effectiveness of thromboprophylaxis strategies following laparotomy for ovarian cancer. METHODS: We constructed a decision model to evaluate six strategies for management of postoperative venous thromboembolism (VTE) risk: (1) no thromboprophylaxis; (2) inpatient sequential compression device (SCD); (3) inpatient unfractionated heparin (UFH) 5000 units TID; (4) inpatient low molecular weight heparin (LMWH) 40 mg daily; (5) UFH 5000 units TID×1 month; (6) LMWH 40 mg daily×1 month. Rates of VTE, heparin-induced thrombocytopenia, and significant bleeding for each strategy were obtained from published literature. Costs were based on institutional charges or obtained from the Agency for Healthcare Research and Quality Nationwide Inpatient Sample database for 2008 and average wholesale pricing. Sensitivity analyses were performed to account for uncertainty in estimates. RESULTS: In the base case, UFH×1 month was the least expensive (mean cost $1611) and most effective (VTE risk 1.9%) strategy. LMWH×1 month was equally effective but more expensive ($2197). Inpatient UFH, inpatient LMWH, and SCDs were less effective and more expensive than UFH×1 month. In the sensitivity analysis, cost rankings remained unchanged unless the baseline probability of VTE was assumed <6.5%, the cost of VTE treatment was <$20,000, or the cost of bleeding was >$4500. LMWH×1 month became least expensive when cost was decreased 38%. CONCLUSION: Based on current evidence, extended prophylaxis with UFH is the least expensive and most effective strategy to prevent postoperative VTE following laparotomy for ovarian cancer.

Authors
Teoh, D; Berchuck, A; Alvarez Secord, A; Lee, PS; Lowery, WJ; Sfakianos, GP; Valea, FA; Myers, ER; Havrilesky, LJ
MLA Citation
Teoh, D, Berchuck, A, Alvarez Secord, A, Lee, PS, Lowery, WJ, Sfakianos, GP, Valea, FA, Myers, ER, and Havrilesky, LJ. "Cost comparison of strategies for the management of venous thromboembolic event risk following laparotomy for ovarian cancer." Gynecol Oncol 122.3 (September 2011): 467-472.
PMID
21752434
Source
pubmed
Published In
Gynecologic Oncology
Volume
122
Issue
3
Publish Date
2011
Start Page
467
End Page
472
DOI
10.1016/j.ygyno.2011.06.014

Mechanical stiffness grades metastatic potential in patient tumor cells and in cancer cell lines.

Cancer cells are defined by their ability to invade through the basement membrane, a critical step during metastasis. While increased secretion of proteases, which facilitates degradation of the basement membrane, and alterations in the cytoskeletal architecture of cancer cells have been previously studied, the contribution of the mechanical properties of cells in invasion is unclear. Here, we applied a magnetic tweezer system to establish that stiffness of patient tumor cells and cancer cell lines inversely correlates with migration and invasion through three-dimensional basement membranes, a correlation known as a power law. We found that cancer cells with the highest migratory and invasive potential are five times less stiff than cells with the lowest migration and invasion potential. Moreover, decreasing cell stiffness by pharmacologic inhibition of myosin II increases invasiveness, whereas increasing cell stiffness by restoring expression of the metastasis suppressor TβRIII/betaglycan decreases invasiveness. These findings are the first demonstration of the power-law relation between the stiffness and the invasiveness of cancer cells and show that mechanical phenotypes can be used to grade the metastatic potential of cell populations with the potential for single cell grading. The measurement of a mechanical phenotype, taking minutes rather than hours needed for invasion assays, is promising as a quantitative diagnostic method and as a discovery tool for therapeutics. By showing that altering stiffness predictably alters invasiveness, our results indicate that pathways regulating these mechanical phenotypes are novel targets for molecular therapy of cancer.

Authors
Swaminathan, V; Mythreye, K; O'Brien, ET; Berchuck, A; Blobe, GC; Superfine, R
MLA Citation
Swaminathan, V, Mythreye, K, O'Brien, ET, Berchuck, A, Blobe, GC, and Superfine, R. "Mechanical stiffness grades metastatic potential in patient tumor cells and in cancer cell lines." Cancer Res 71.15 (August 1, 2011): 5075-5080.
PMID
21642375
Source
pubmed
Published In
Cancer Research
Volume
71
Issue
15
Publish Date
2011
Start Page
5075
End Page
5080
DOI
10.1158/0008-5472.CAN-11-0247

MicroRNA processing and binding site polymorphisms are not replicated in the Ovarian Cancer Association Consortium.

BACKGROUND: Single nucleotide polymorphisms (SNP) in microRNA-related genes have been associated with epithelial ovarian cancer (EOC) risk in two reports, yet associated alleles may be inconsistent across studies. METHODS: We conducted a pooled analysis of previously identified SNPs by combining genotype data from 3,973 invasive EOC cases and 3,276 controls from the Ovarian Cancer Association Consortium. We also conducted imputation to obtain dense coverage of genes and comparable genotype data for all studies. In total, 226 SNPs within 15 kb of 4 miRNA biogenesis genes (DDX20, DROSHA, GEMIN4, and XPO5) and 23 SNPs located within putative miRNA binding sites of 6 genes (CAV1, COL18A1, E2F2, IL1R1, KRAS, and UGT2A3) were genotyped or imputed and analyzed in the entire dataset. RESULTS: After adjustment for European ancestry, no overall association was observed between any of the analyzed SNPs and EOC risk. CONCLUSIONS: Common variants in these evaluated genes do not seem to be strongly associated with EOC risk. IMPACT: This analysis suggests earlier associations between EOC risk and SNPs in these genes may have been chance findings, possibly confounded by population admixture. To more adequately evaluate the relationship between genetic variants and cancer risk, large sample sizes are needed, adjustment for population stratification should be carried out, and use of imputed SNP data should be considered.

Authors
Permuth-Wey, J; Chen, Z; Tsai, Y-Y; Lin, H-Y; Chen, YA; Barnholtz-Sloan, J; Birrer, MJ; Chanock, SJ; Cramer, DW; Cunningham, JM; Fenstermacher, D; Fridley, BL; Garcia-Closas, M; Gayther, SA; Gentry-Maharaj, A; Gonzalez-Bosquet, J; Iversen, E; Jim, H; McLaughlin, J; Menon, U; Narod, SA; Phelan, CM; Ramus, SJ; Risch, H; Song, H; Sutphen, R; Terry, KL; Tyrer, J; Vierkant, RA; Wentzensen, N; Lancaster, JM; Cheng, JQ; Berchuck, A; Pharoah, PDP; Schildkraut, JM; Goode, EL; Sellers, TA et al.
MLA Citation
Permuth-Wey, J, Chen, Z, Tsai, Y-Y, Lin, H-Y, Chen, YA, Barnholtz-Sloan, J, Birrer, MJ, Chanock, SJ, Cramer, DW, Cunningham, JM, Fenstermacher, D, Fridley, BL, Garcia-Closas, M, Gayther, SA, Gentry-Maharaj, A, Gonzalez-Bosquet, J, Iversen, E, Jim, H, McLaughlin, J, Menon, U, Narod, SA, Phelan, CM, Ramus, SJ, Risch, H, Song, H, Sutphen, R, Terry, KL, Tyrer, J, Vierkant, RA, Wentzensen, N, Lancaster, JM, Cheng, JQ, Berchuck, A, Pharoah, PDP, Schildkraut, JM, Goode, EL, and Sellers, TA et al. "MicroRNA processing and binding site polymorphisms are not replicated in the Ovarian Cancer Association Consortium." Cancer Epidemiol Biomarkers Prev 20.8 (August 2011): 1793-1797.
PMID
21636674
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
20
Issue
8
Publish Date
2011
Start Page
1793
End Page
1797
DOI
10.1158/1055-9965.EPI-11-0397

Adverse events associated with laparoscopy vs laparotomy in the treatment of endometrial cancer.

OBJECTIVE: The objective of the study was to compare adverse event rates between laparoscopic vs open surgery for endometrial cancer. STUDY DESIGN: This was a retrospective cohort study comparing 107 women who underwent laparoscopy with 269 age- and body mass index-matched women who underwent laparotomy for treatment of endometrial cancer. RESULTS: Adverse event rates were similar between cohorts (37% laparoscopy vs 43% laparotomy, P=.248). Laparotomies had higher rates of cellulitis (16% vs 7%, P=.018) and open wound infection (9% vs 2%, P=.02), whereas laparoscopy had higher rates of sensory peripheral nerve deficit (5% vs 0%, P=.008) and lymphedema (7% vs 1%, P=.003). Laparoscopy was associated with longer mean operating room times but with shorter hospital stays and lower mean blood loss. CONCLUSION: Laparoscopy was associated with decreased rates of surgical site infections but had an increased risk of peripheral sensory nerve deficits and lymphedema when compared with laparotomy.

Authors
Barnett, JC; Havrilesky, LJ; Bondurant, AE; Fleming, ND; Lee, PS; Secord, AA; Berchuck, A; Valea, FA
MLA Citation
Barnett, JC, Havrilesky, LJ, Bondurant, AE, Fleming, ND, Lee, PS, Secord, AA, Berchuck, A, and Valea, FA. "Adverse events associated with laparoscopy vs laparotomy in the treatment of endometrial cancer." Am J Obstet Gynecol 205.2 (August 2011): 143.e1-143.e6.
PMID
21514921
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
205
Issue
2
Publish Date
2011
Start Page
143.e1
End Page
143.e6
DOI
10.1016/j.ajog.2011.03.012

Association between KRAS rs61764370 and triple-negative breast cancer--a false positive?

Authors
Pharoah, P; Antoniou, A; Berchuck, A; Chenevix-Trench, G; Gayther, S; Goode, E; Milne, R; Sellers, T; Tyrer, J
MLA Citation
Pharoah, P, Antoniou, A, Berchuck, A, Chenevix-Trench, G, Gayther, S, Goode, E, Milne, R, Sellers, T, and Tyrer, J. "Association between KRAS rs61764370 and triple-negative breast cancer--a false positive?." Lancet Oncol 12.8 (August 2011): 723-724. (Letter)
PMID
21807336
Source
pubmed
Published In
The Lancet Oncology
Volume
12
Issue
8
Publish Date
2011
Start Page
723
End Page
724
DOI
10.1016/S1470-2045(11)70156-5

Genetic variation in insulin-like growth factor 2 may play a role in ovarian cancer risk.

The insulin-like growth factor (IGF) signaling axis plays an important role in cancer biology. We hypothesized that genetic variation in this pathway may influence risk of ovarian cancer. A three-center study of non-Hispanic whites including 1880 control women, 1135 women with invasive epithelial ovarian cancer and 321 women with borderline epithelial ovarian tumors was carried out to test the association between tag single-nucleotide polymorphisms (tSNPs) (n=58) in this pathway and risk of ovarian cancer. We found no association between variation in IGF1, IGFBP1 or IGFBP3 and risk of invasive disease, whereas five tSNPs in IGF2 were associated with risk of invasive epithelial ovarian cancer at P<0.05 and followed-up one of the associated SNPs. We conducted genotyping in 3216 additional non-Hispanic white cases and 5382 additional controls and were able to independently replicate our initial findings. In the combined set of studies, rs4320932 was associated with a 13% decreased risk of ovarian cancer per copy of the minor allele carried (95% confidence interval 0.81-0.93, P-trend=7.4 × 10(-5)). No heterogeneity of effect across study centers was observed (p(het)=0.25). IGF2 is emerging as an important gene for ovarian cancer; additional genotyping is warranted to further confirm these associations with IGF2 and to narrow down the region harboring the causal SNP.

Authors
Pearce, CL; Doherty, JA; Van Den Berg, DJ; Moysich, K; Hsu, C; Cushing-Haugen, KL; Conti, DV; Ramus, SJ; Gentry-Maharaj, A; Menon, U; Gayther, SA; Pharoah, PDP; Song, H; Kjaer, SK; Hogdall, E; Hogdall, C; Whittemore, AS; McGuire, V; Sieh, W; Gronwald, J; Medrek, K; Jakubowska, A; Lubinski, J; Chenevix-Trench, G; AOCS/ACS Study Group, ; Beesley, J; Webb, PM; Berchuck, A; Schildkraut, JM; Iversen, ES; Moorman, PG; Edlund, CK; Stram, DO; Pike, MC; Ness, RB; Rossing, MA; Wu, AH
MLA Citation
Pearce, CL, Doherty, JA, Van Den Berg, DJ, Moysich, K, Hsu, C, Cushing-Haugen, KL, Conti, DV, Ramus, SJ, Gentry-Maharaj, A, Menon, U, Gayther, SA, Pharoah, PDP, Song, H, Kjaer, SK, Hogdall, E, Hogdall, C, Whittemore, AS, McGuire, V, Sieh, W, Gronwald, J, Medrek, K, Jakubowska, A, Lubinski, J, Chenevix-Trench, G, AOCS/ACS Study Group, , Beesley, J, Webb, PM, Berchuck, A, Schildkraut, JM, Iversen, ES, Moorman, PG, Edlund, CK, Stram, DO, Pike, MC, Ness, RB, Rossing, MA, and Wu, AH. "Genetic variation in insulin-like growth factor 2 may play a role in ovarian cancer risk." Hum Mol Genet 20.11 (June 1, 2011): 2263-2272.
PMID
21422097
Source
pubmed
Published In
Human Molecular Genetics
Volume
20
Issue
11
Publish Date
2011
Start Page
2263
End Page
2272
DOI
10.1093/hmg/ddr087

The role of KRAS rs61764370 in invasive epithelial ovarian cancer: implications for clinical testing.

PURPOSE: An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3'-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published article, analyzing fewer than 1,000 subjects in total, has examined this association. EXPERIMENTAL DESIGN: Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from 19 studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival (PFS) data and 18 studies with all-cause mortality data. RESULTS: No evidence of association was observed between genotype and risk of unselected EOC (OR = 1.02, 95% CI: 0.95-1.10), serous EOC (OR = 1.08, 95% CI: 0.98-1.18), familial EOC (OR = 1.09, 95% CI: 0.78-1.54), or among women carrying deleterious mutations in BRCA1 (OR = 1.09, 95% CI: 0.88-1.36). There was little evidence for association with survival time among unselected cases (HR = 1.10, 95% CI: 0.99-1.22), among serous cases (HR = 1.12, 95% CI = 0.99-1.28), or with PFS in 540 cases treated with carboplatin and paclitaxel (HR = 1.18, 95% CI: 0.93-1.52). CONCLUSIONS: These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction, therefore, seems unwarranted.

Authors
Pharoah, PDP; Palmieri, RT; Ramus, SJ; Gayther, SA; Andrulis, IL; Anton-Culver, H; Antonenkova, N; Antoniou, AC; Goldgar, D; BCFR Investigators, ; Beattie, MS; Beckmann, MW; Birrer, MJ; Bogdanova, N; Bolton, KL; Brewster, W; Brooks-Wilson, A; Brown, R; Butzow, R; Caldes, T; Caligo, MA; Campbell, I; Chang-Claude, J; Chen, YA; Cook, LS; Couch, FJ; Cramer, DW; Cunningham, JM; Despierre, E; Doherty, JA; Dörk, T; Dürst, M; Eccles, DM; Ekici, AB; Easton, D; EMBRACE Investigators, ; Fasching, PA et al.
MLA Citation
Pharoah, PDP, Palmieri, RT, Ramus, SJ, Gayther, SA, Andrulis, IL, Anton-Culver, H, Antonenkova, N, Antoniou, AC, Goldgar, D, BCFR Investigators, , Beattie, MS, Beckmann, MW, Birrer, MJ, Bogdanova, N, Bolton, KL, Brewster, W, Brooks-Wilson, A, Brown, R, Butzow, R, Caldes, T, Caligo, MA, Campbell, I, Chang-Claude, J, Chen, YA, Cook, LS, Couch, FJ, Cramer, DW, Cunningham, JM, Despierre, E, Doherty, JA, Dörk, T, Dürst, M, Eccles, DM, Ekici, AB, Easton, D, EMBRACE Investigators, , and Fasching, PA et al. "The role of KRAS rs61764370 in invasive epithelial ovarian cancer: implications for clinical testing." Clin Cancer Res 17.11 (June 1, 2011): 3742-3750.
PMID
21385923
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
11
Publish Date
2011
Start Page
3742
End Page
3750
DOI
10.1158/1078-0432.CCR-10-3405

Proteomic analysis of stage I endometrial cancer tissue: identification of proteins associated with oxidative processes and inflammation.

OBJECTIVE: The present study aimed to identify differentially expressed proteins employing a high resolution mass spectrometry (MS)-based proteomic analysis of endometrial cancer cells harvested using laser microdissection. METHODS: A differential MS-based proteomic analysis was conducted from discrete epithelial cell populations gathered by laser microdissection from 91 pathologically reviewed stage I endometrial cancer tissue samples (79 endometrioid and 12 serous) and 10 samples of normal endometrium from postmenopausal women. Hierarchical cluster analysis of protein abundance levels derived from a spectral count analysis revealed a number of proteins whose expression levels were common as well as unique to both histologic types. An independent set of endometrial cancer specimens from 394 patients were used to externally validate the differential expression of select proteins. RESULTS: 209 differentially expressed proteins were identified in a comparison of stage I endometrial cancers and normal post-menopausal endometrium controls (Q<0.005). A number of differentially abundant proteins in stage I endometrial cancer were identified and independently validated by western blot and tissue microarray analyses. Multiple proteins identified with elevated abundance in stage I endometrial cancer are functionally associated with inflammation (annexins) and oxidative processes (peroxiredoxins). PRDX1 and ANXA2 were both confirmed as being overexpressed in stage I cancer compared to normal endometrium by independent TMA (Q=0.008 and Q=0.00002 respectively). CONCLUSIONS: These data provide the basis for further investigation of previously unrecognized novel pathways involved in early stage endometrial carcinogenesis and provide possible targets for prevention strategies that are inclusive of both endometrioid and serous histologic subtypes.

Authors
Maxwell, GL; Hood, BL; Day, R; Chandran, U; Kirchner, D; Kolli, VSK; Bateman, NW; Allard, J; Miller, C; Sun, M; Flint, MS; Zahn, C; Oliver, J; Banerjee, S; Litzi, T; Parwani, A; Sandburg, G; Rose, S; Becich, MJ; Berchuck, A; Kohn, E; Risinger, JI; Conrads, TP
MLA Citation
Maxwell, GL, Hood, BL, Day, R, Chandran, U, Kirchner, D, Kolli, VSK, Bateman, NW, Allard, J, Miller, C, Sun, M, Flint, MS, Zahn, C, Oliver, J, Banerjee, S, Litzi, T, Parwani, A, Sandburg, G, Rose, S, Becich, MJ, Berchuck, A, Kohn, E, Risinger, JI, and Conrads, TP. "Proteomic analysis of stage I endometrial cancer tissue: identification of proteins associated with oxidative processes and inflammation." Gynecol Oncol 121.3 (June 1, 2011): 586-594.
PMID
21458040
Source
pubmed
Published In
Gynecologic Oncology
Volume
121
Issue
3
Publish Date
2011
Start Page
586
End Page
594
DOI
10.1016/j.ygyno.2011.02.031

Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer.

Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell-mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines; AIFM2, AKTIP, AXIN2, CASP5, FILIP1L, RBBP8, RGC32, RUVBL1 and STAG3. Sixty-three tagging single nucleotide polymorphisms (tSNPs) in these genes were genotyped in 1,799 invasive ovarian cancer cases and 3,045 controls to look for associations with disease risk. Two SNPs in RUVBL1, rs13063604 and rs7650365, were associated with increased risk of serous ovarian cancer [HetOR = 1.42 (1.15-1.74) and the HomOR = 1.63 (1.10-1.42), p-trend = 0.0002] and [HetOR = 0.97 (0.80-1.17), HomOR = 0.74 (0.58-0.93), p-trend = 0.009], respectively. We genotyped rs13063604 and rs7650365 in an additional 4,590 cases and 6,031 controls from ten sites from the United States, Europe and Australia; however, neither SNP was significant in Stage 2. We also evaluated the potential role of tSNPs in these nine genes in ovarian cancer development by testing for allele-specific loss of heterozygosity (LOH) in 286 primary ovarian tumours. We found frequent LOH for tSNPs in AXIN2, AKTIP and RGC32 (64, 46 and 34%, respectively) and one SNP, rs1637001, in STAG3 showed significant allele-specific LOH with loss of the common allele in 94% of informative tumours (p = 0.015). Array comparative genomic hybridisation indicated that this nonrandom allelic imbalance was due to amplification of the rare allele. In conclusion, we show evidence for the involvement of a common allele of STAG3 in the development of epithelial ovarian cancer.

Authors
Notaridou, M; Quaye, L; Dafou, D; Jones, C; Song, H; Høgdall, E; Kjaer, SK; Christensen, L; Høgdall, C; Blaakaer, J; McGuire, V; Wu, AH; Van Den Berg, DJ; Pike, MC; Gentry-Maharaj, A; Wozniak, E; Sher, T; Jacobs, IJ; Tyrer, J; Schildkraut, JM; Moorman, PG; Iversen, ES; Jakubowska, A; Mędrek, K; Lubiński, J; Ness, RB; Moysich, KB; Lurie, G; Wilkens, LR; Carney, ME; Wang-Gohrke, S; Doherty, JA; Rossing, MA; Beckmann, MW; Thiel, FC; Ekici, AB; Chen, X; Beesley, J et al.
MLA Citation
Notaridou, M, Quaye, L, Dafou, D, Jones, C, Song, H, Høgdall, E, Kjaer, SK, Christensen, L, Høgdall, C, Blaakaer, J, McGuire, V, Wu, AH, Van Den Berg, DJ, Pike, MC, Gentry-Maharaj, A, Wozniak, E, Sher, T, Jacobs, IJ, Tyrer, J, Schildkraut, JM, Moorman, PG, Iversen, ES, Jakubowska, A, Mędrek, K, Lubiński, J, Ness, RB, Moysich, KB, Lurie, G, Wilkens, LR, Carney, ME, Wang-Gohrke, S, Doherty, JA, Rossing, MA, Beckmann, MW, Thiel, FC, Ekici, AB, Chen, X, and Beesley, J et al. "Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer." Int J Cancer 128.9 (May 1, 2011): 2063-2074.
PMID
20635389
Source
pubmed
Published In
International Journal of Cancer
Volume
128
Issue
9
Publish Date
2011
Start Page
2063
End Page
2074
DOI
10.1002/ijc.25554

Association of KRAS SNP rs61764370 with risk of invasive epithelial ovarian cancer: Implications for clinical testing

Authors
Berchuck, A; Pharoah, P; Ramus, S; Gayther, S; Palmieri, R; Pearce, C; Couch, F; Antonio, A; Goode, E; Schildkraut, J; Chenevix-Trench, G; Sellers, T; Risch, H; Modifiers, CI; Consortium, OCA
MLA Citation
Berchuck, A, Pharoah, P, Ramus, S, Gayther, S, Palmieri, R, Pearce, C, Couch, F, Antonio, A, Goode, E, Schildkraut, J, Chenevix-Trench, G, Sellers, T, Risch, H, Modifiers, CI, and Consortium, OCA. "Association of KRAS SNP rs61764370 with risk of invasive epithelial ovarian cancer: Implications for clinical testing." GYNECOLOGIC ONCOLOGY 121.2 (May 1, 2011): S2-S3.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
121
Issue
2
Publish Date
2011
Start Page
S2
End Page
S3
DOI
10.1016/j.ygyno.2011.02.028

Xenobiotic-Metabolizing gene polymorphisms and ovarian cancer risk.

Because selected xenobiotic-metabolizing enzymes process pro-carcinogens that could initiate ovarian carcinogenesis, we hypothesized that single nucleotide polymorphisms (SNPs) in the genes encoding xenobiotic-metabolizing enzymes are associated with risk of ovarian cancer. Cases with invasive epithelial ovarian cancer (N = 1571 including 956 of serous sub-type) and controls (N = 2046) from three studies were genotyped at 11 SNPs in EPHX1, ADH4, ADH1A, NQO2, NAT2, GSTP1, CYP1A1, and NQO1, following an initial SNP screen in a subset of participants. Logistic regression analysis of genotypes obtained via Illumina GoldenGate and Sequenom iPlex technologies revealed the following age- and study-adjusted associations: EPHX1 rs1051740 with increased serous ovarian cancer risk [per-allele odds ratio (OR) 1.17, 95% confidence interval (95% CI) 1.04-1.32, P = 0.01), ADH4 r1042364 with decreased ovarian cancer risk (OR 0.90, 95% CI: 0.81-1.00, P = 0.05), and NQO1 rs291766 with increased ovarian cancer risk (OR 1.11, 95% CI: 1.00-1.23, P = 0.04). These findings are consistent with prior studies implicating these genes in carcinogenesis and suggest that this collection of variants is worthy of follow-up in additional studies.

Authors
Goode, EL; White, KL; Vierkant, RA; Phelan, CM; Cunningham, JM; Schildkraut, JM; Berchuck, A; Larson, MC; Fridley, BL; Olson, JE; Webb, PM; Chen, X; Beesley, J; Chenevix-Trench, G; Sellers, TA; Ovarian Cancer Association Consortium, ; Australian Ovarian Cancer Study Group,
MLA Citation
Goode, EL, White, KL, Vierkant, RA, Phelan, CM, Cunningham, JM, Schildkraut, JM, Berchuck, A, Larson, MC, Fridley, BL, Olson, JE, Webb, PM, Chen, X, Beesley, J, Chenevix-Trench, G, Sellers, TA, Ovarian Cancer Association Consortium, , and Australian Ovarian Cancer Study Group, . "Xenobiotic-Metabolizing gene polymorphisms and ovarian cancer risk." Mol Carcinog 50.5 (May 2011): 397-402.
PMID
21480392
Source
pubmed
Published In
Molecular Carcinogenesis
Volume
50
Issue
5
Publish Date
2011
Start Page
397
End Page
402
DOI
10.1002/mc.20714

Prostate cancer susceptibility polymorphism rs2660753 is not associated with invasive ovarian cancer.

BACKGROUND: We previously reported an association between rs2660753, a prostate cancer susceptibility polymorphism, and invasive epithelial ovarian cancer (EOC; OR = 1.2, 95% CI=1.0-1.4, P(trend) = 0.01) that showed a stronger association with the serous histological subtype (OR = 1.3, 95% CI = 1.1-1.5, P(trend) = 0.003). METHODS: We sought to replicate this association in 12 other studies comprising 4,482 cases and 6,894 controls of white non-Hispanic ancestry in the Ovarian Cancer Association Consortium. RESULTS: No evidence for an association with all cancers or serous cancers was observed in a combined analysis of data from the replication studies (all: OR = 1.0, 95% CI = 0.9-1.1, P(trend) = 0.61; serous: OR = 1.0, 95% CI = 0.9-1.1, P(trend) = 0.85) or from the combined analysis of discovery and replication studies (all: OR = 1.0, 95% CI = 1.0-1.1, P(trend) = 0.28; serous: OR = 1.1, 95% CI = 1.0-1.2, P(trend) = 0.11). There was no evidence for statistical heterogeneity in ORs across the studies. CONCLUSIONS: Although rs2660753 is a strong prostate cancer susceptibility polymorphism, the association with another hormonally related cancer, invasive EOC, is not supported by this replication study. IMPACT: Our findings, based on a larger sample size, emphasize the importance of replicating potentially promising genetic risk associations.

Authors
Amankwah, EK; Kelemen, LE; Wang, Q; Song, H; Chenevix-Trench, G; Australian Ovarian Cancer Study Group, ; Beesley, J; Webb, PM; Australian Cancer Study (Ovarian Cancer), ; Pearce, CL; Wu, AH; Pike, MC; Stram, DO; Chang-Claude, J; Wang-Gohrke, S; Ness, RB; Goode, EL; Cunningham, JM; Fridley, BL; Vierkant, RA; Tworoger, SS; Whittemore, AS; McGuire, V; Sieh, W; Gayther, SA; Gentry-Maharaj, A; Menon, U; Ramus, SJ; Rossing, MA; Doherty, JA; Goodman, MT; Carney, ME; Lurie, G; Wilkens, LR; Kjær, SK et al.
MLA Citation
Amankwah, EK, Kelemen, LE, Wang, Q, Song, H, Chenevix-Trench, G, Australian Ovarian Cancer Study Group, , Beesley, J, Webb, PM, Australian Cancer Study (Ovarian Cancer), , Pearce, CL, Wu, AH, Pike, MC, Stram, DO, Chang-Claude, J, Wang-Gohrke, S, Ness, RB, Goode, EL, Cunningham, JM, Fridley, BL, Vierkant, RA, Tworoger, SS, Whittemore, AS, McGuire, V, Sieh, W, Gayther, SA, Gentry-Maharaj, A, Menon, U, Ramus, SJ, Rossing, MA, Doherty, JA, Goodman, MT, Carney, ME, Lurie, G, Wilkens, LR, and Kjær, SK et al. "Prostate cancer susceptibility polymorphism rs2660753 is not associated with invasive ovarian cancer." Cancer Epidemiol Biomarkers Prev 20.5 (May 2011): 1028-1031.
PMID
21415361
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
20
Issue
5
Publish Date
2011
Start Page
1028
End Page
1031
DOI
10.1158/1055-9965.EPI-11-0053

Abstract 3014: Quantitative accuracy of Illumina HumanMethylation27 Infinium BeadChip data assessed by pyrosequencing

Authors
Huang, Z; Yamaguchi, K; Berchuck, A; Murphy, SK
MLA Citation
Huang, Z, Yamaguchi, K, Berchuck, A, and Murphy, SK. "Abstract 3014: Quantitative accuracy of Illumina HumanMethylation27 Infinium BeadChip data assessed by pyrosequencing." Cancer Research 71.8 Supplement (April 15, 2011): 3014-3014.
Source
crossref
Published In
Cancer Research
Volume
71
Issue
8 Supplement
Publish Date
2011
Start Page
3014
End Page
3014
DOI
10.1158/1538-7445.AM2011-3014

Dasatinib (BMS-35482) has synergistic activity with paclitaxel and carboplatin in ovarian cancer cells.

PURPOSE: To explore the activity of dasatinib alone and in combination with paclitaxel and carboplatin in ovarian cancer cells and to determine if dasatinib activity can be predicted based on evaluation of the SRC pathway. EXPERIMENTAL DESIGN: Microarray analysis was performed for IGROV1, OVCAR3, A2780 and SKOV3 ovarian cancer cells and the status of the genomic SRC signature pathway was determined. Cells were treated with carboplatin, paclitaxel and dasatinib individually and in combination. Pre- and post-treatment phospho-SRC (pSRC) and SRC protein expression was determined. Dose-response curves were constructed, and drug interaction was assessed by the Combination Index (CI) method. RESULTS: SRC protein expression levels reflected the SRC pathway genomic signature in the cell lines with the lowest (SKOV3) and highest (IGROV1) pathway expression, but not in those with intermediate expression (OVCAR3, A2780). Dasatinib treatment caused loss of pSRC in all cell lines, with 50% growth inhibition for IGROV1 at 70 nM, OVCAR3 at 34 nM, A2780 at 4.1 μM and SKOV3 at 530 nM. Dasatinib combined with cytotoxics yielded a synergistic effect (CI=0.46 to 0.79) in all cell lines except SKOV3. CONCLUSION: Dasatinib in combination with standard chemotherapeutic agents appears to interact in a synergistic manner in some ovarian cancer cell lines. Further research is needed to evaluate tumor cell characteristics which predict response to dasatinib.

Authors
Teoh, D; Ayeni, TA; Rubatt, JM; Adams, DJ; Grace, L; Starr, MD; Barry, WT; Berchuck, A; Murphy, SK; Secord, AA
MLA Citation
Teoh, D, Ayeni, TA, Rubatt, JM, Adams, DJ, Grace, L, Starr, MD, Barry, WT, Berchuck, A, Murphy, SK, and Secord, AA. "Dasatinib (BMS-35482) has synergistic activity with paclitaxel and carboplatin in ovarian cancer cells." Gynecol Oncol 121.1 (April 2011): 187-192.
PMID
21208651
Source
pubmed
Published In
Gynecologic Oncology
Volume
121
Issue
1
Publish Date
2011
Start Page
187
End Page
192
DOI
10.1016/j.ygyno.2010.11.017

Prevention and early detection of cancer.

Authors
Berchuck, A; Einstein, MH
MLA Citation
Berchuck, A, and Einstein, MH. "Prevention and early detection of cancer." Gynecol Oncol 121.1 (April 2011): 1-.
PMID
21419284
Source
pubmed
Published In
Gynecologic Oncology
Volume
121
Issue
1
Publish Date
2011
Start Page
1
DOI
10.1016/j.ygyno.2011.02.009

Reduction of ovarian and oviductal cancers in calorie-restricted laying chickens.

Epithelial ovarian cancer (OVAC) remains a highly lethal malignancy. It is a leading cause of cancer deaths among women in the United States causing more deaths than all other gynecologic malignancies combined. The pathogenesis of OVAC is not completely understood, but the process of repeated ovulation is believed to lead to genetic damage in the ovarian epithelium. As part of a prospective trial designed to evaluate OVAC chemopreventive strategies using the chicken model, caloric restriction (55% less energy) was used to inhibit ovulation in groups of hens receiving chemopreventives, thereby minimizing the impact of ovulation on the incidence of reproductive tract cancer. A separate group of chickens was maintained concurrently in the same environment, and managed similarly, except that caloric intake was not restricted. Among birds not receiving chemopreventive agents, we compared caloric versus noncaloric restricted birds to determine the relations between calorie restriction and risk of developing adenocarcinoma of the reproductive tract. Mortality in the calorie-restricted group was almost half that of those on full feed. Calorie-restricted chickens maintained body weights averaging 1.423 kg compared with the full-fed birds at 1.892 kg. Ovulation rate varied with the full-fed group producing 64% more eggs than the calorie-restricted group. Total reproductive cancers occurred in 57 (33.3%) birds for the full-fed group and 26 (10.3%) birds for the calorie-restricted group. On the basis of histopathology, 45 (26.3%) birds in the full-fed group had ovarian adenocarcinoma compared with 16 (6.3%) birds in the calorie-restricted group. Calorie restriction in laying hens resulted in a near five-fold reduction in OVAC.

Authors
Carver, DK; Barnes, HJ; Anderson, KE; Petitte, JN; Whitaker, R; Berchuck, A; Rodriguez, GC
MLA Citation
Carver, DK, Barnes, HJ, Anderson, KE, Petitte, JN, Whitaker, R, Berchuck, A, and Rodriguez, GC. "Reduction of ovarian and oviductal cancers in calorie-restricted laying chickens." Cancer Prev Res (Phila) 4.4 (April 2011): 562-567.
PMID
21325563
Source
pubmed
Published In
Cancer Prevention Research
Volume
4
Issue
4
Publish Date
2011
Start Page
562
End Page
567
DOI
10.1158/1940-6207.CAPR-10-0294

Loss of ARID1A is a frequent event in clear cell and endometrioid ovarian cancers

Authors
Lowery, W; Schildkraut, J; Akushevich, L; Bentley, R; Huntsman, D; Marks, J; Berchuck, A
MLA Citation
Lowery, W, Schildkraut, J, Akushevich, L, Bentley, R, Huntsman, D, Marks, J, and Berchuck, A. "Loss of ARID1A is a frequent event in clear cell and endometrioid ovarian cancers." GYNECOLOGIC ONCOLOGY 121.1 (March 2011): S21-S21.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
121
Issue
1
Publish Date
2011
Start Page
S21
End Page
S21
DOI
10.1016/j.ygyno.2010.12.054

DNA methylation markers associated with serous ovarian cancer subtypes

Authors
Chandavarkar, U; Campan, M; Houshdaran, S; Pearce, C; Shen, H; Widschwendter, M; Berchuck, A; Roman, L; Laird, P
MLA Citation
Chandavarkar, U, Campan, M, Houshdaran, S, Pearce, C, Shen, H, Widschwendter, M, Berchuck, A, Roman, L, and Laird, P. "DNA methylation markers associated with serous ovarian cancer subtypes." GYNECOLOGIC ONCOLOGY 121.1 (March 2011): S48-S48.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
121
Issue
1
Publish Date
2011
Start Page
S48
End Page
S48
DOI
10.1016/j.ygyno.2010.12.117

Common single-nucleotide polymorphisms in the BNC2, HOXD1 and MERIT40 regions contribute significantly to racial differences in ovarian cancer incidence

Authors
Berchuck, A; Pike, M; Schildkraut, J; Pearce, C
MLA Citation
Berchuck, A, Pike, M, Schildkraut, J, and Pearce, C. "Common single-nucleotide polymorphisms in the BNC2, HOXD1 and MERIT40 regions contribute significantly to racial differences in ovarian cancer incidence." GYNECOLOGIC ONCOLOGY 121.1 (March 2011): S7-S7.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
121
Issue
1
Publish Date
2011
Start Page
S7
End Page
S7
DOI
10.1016/j.ygyno.2010.12.019

Concordant gene expression profiles in matched primary and recurrent serous ovarian cancers predict platinum response

Authors
Sfakianos, G; Yan, J; Whitaker, R; Murphy, S; Berchuck, A
MLA Citation
Sfakianos, G, Yan, J, Whitaker, R, Murphy, S, and Berchuck, A. "Concordant gene expression profiles in matched primary and recurrent serous ovarian cancers predict platinum response." GYNECOLOGIC ONCOLOGY 121.1 (March 2011): S46-S46.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
121
Issue
1
Publish Date
2011
Start Page
S46
End Page
S46
DOI
10.1016/j.ygyno.2010.12.112

Genes functionally regulated by methylation in ovarian cancer are involved in cell proliferation, development and morphogenesis

Authors
Yamaguchi, K; Baba, T; Konishi, I; Matsumura, N; Murphy, S; Huang, Z; Berchuck, A
MLA Citation
Yamaguchi, K, Baba, T, Konishi, I, Matsumura, N, Murphy, S, Huang, Z, and Berchuck, A. "Genes functionally regulated by methylation in ovarian cancer are involved in cell proliferation, development and morphogenesis." GYNECOLOGIC ONCOLOGY 121.1 (March 2011): S69-S69.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
121
Issue
1
Publish Date
2011
Start Page
S69
End Page
S69
DOI
10.1016/j.ygyno.2010.12.165

Cost comparison of strategies for the management of venous thromboembolic event risk following laparotomy for ovarian cancer

Authors
Teoh, D; Myers, E; Berchuck, A; Alvarez-Secord, A; Lee, P; Lowery, W; Sfakiancs, G; Havrilesky, L
MLA Citation
Teoh, D, Myers, E, Berchuck, A, Alvarez-Secord, A, Lee, P, Lowery, W, Sfakiancs, G, and Havrilesky, L. "Cost comparison of strategies for the management of venous thromboembolic event risk following laparotomy for ovarian cancer." GYNECOLOGIC ONCOLOGY 121.1 (March 2011): S11-S11.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
121
Issue
1
Publish Date
2011
Start Page
S11
End Page
S11
DOI
10.1016/j.ygyno.2010.12.031

Genomewide methylation analyses reveal a prominent role of HINF1 network genes, via hypomethylation, in ovarian clear cell carcinoma

Authors
Yamaguchi, K; Baba, T; Matsumura, N; Mandai, M; Konishi, I; Berchuck, A; Murphy, S
MLA Citation
Yamaguchi, K, Baba, T, Matsumura, N, Mandai, M, Konishi, I, Berchuck, A, and Murphy, S. "Genomewide methylation analyses reveal a prominent role of HINF1 network genes, via hypomethylation, in ovarian clear cell carcinoma." GYNECOLOGIC ONCOLOGY 121.1 (March 2011): S8-S8.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
121
Issue
1
Publish Date
2011
Start Page
S8
End Page
S8
DOI
10.1016/j.ygyno.2010.12.021

BAD apoptosis pathway expression and survival from cancer

Authors
Lancaster, J; Chen, D; Marchion, D; Xiong, Y; Berchuck, A; Judson, P; Bosquet, JG; Wenham, R; Apte, S; Fulp, W
MLA Citation
Lancaster, J, Chen, D, Marchion, D, Xiong, Y, Berchuck, A, Judson, P, Bosquet, JG, Wenham, R, Apte, S, and Fulp, W. "BAD apoptosis pathway expression and survival from cancer." GYNECOLOGIC ONCOLOGY 121.1 (March 2011): S24-S24.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
121
Issue
1
Publish Date
2011
Start Page
S24
End Page
S24
DOI
10.1016/j.ygyno.2010.12.060

Development of an ovarian cancer screening decision model that incorporates disease heterogeneity: implications for potential mortality reduction.

BACKGROUND: Pathologic and genetic data suggest that epithelial ovarian cancer may consist of indolent and aggressive phenotypes. The objective of the current study was to estimate the impact of a 2-phenotype paradigm of epithelial ovarian cancer on the mortality reduction achievable using available screening technologies. METHODS: The authors modified a Markov model of ovarian cancer natural history (the 1-phenotype model) to incorporate aggressive and indolent phenotypes (the 2-phenotype model) based on histopathologic criteria. Stage distribution, incidence, and mortality were calibrated to data from the Surveillance, Epidemiology, and End Results Program of the US National Cancer Institute. For validation, a Monte Carlo microsimulation (1000,000 events) of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) multimodality prevalence screen was performed. Mortality reduction and positive predictive value (PPV) were estimated for annual screening. RESULTS: In validation against UKCTOCS data, the model-predicted percentage of screen-detected cancers diagnosed at stage I and II was 41% compared with 47% (UKCTOCS data), and the model-predicted PPV of screening was 27% compared with 35% (UKCTOCS data). The model-estimated PPV of a strategy of annual population-based screening in the United States at ages 50 to 85 years was 14%. The mortality reduction using annual postmenopausal screening was 14.7% (1-phenotype model) and 10.9% (2-phenotype model). Mortality reduction was lower with the 2-phenotype model than with the 1-phenotype model regardless of screening frequency or test sensitivity; 68% of cancer deaths are accounted for by the aggressive phenotype. CONCLUSIONS: The current analysis suggested that reductions in ovarian cancer mortality using available screening technologies on an annual basis are likely to be modest. A model that incorporated 2 clinical phenotypes of ovarian carcinoma into its natural history predicted an even smaller potential reduction in mortality because of the more frequent diagnosis of indolent cancers at early stages.

Authors
Havrilesky, LJ; Sanders, GD; Kulasingam, S; Chino, JP; Berchuck, A; Marks, JR; Myers, ER
MLA Citation
Havrilesky, LJ, Sanders, GD, Kulasingam, S, Chino, JP, Berchuck, A, Marks, JR, and Myers, ER. "Development of an ovarian cancer screening decision model that incorporates disease heterogeneity: implications for potential mortality reduction." Cancer 117.3 (February 1, 2011): 545-553.
PMID
21254049
Source
pubmed
Published In
Cancer
Volume
117
Issue
3
Publish Date
2011
Start Page
545
End Page
553
DOI
10.1002/cncr.25624

Epigenetic suppression of the TGF-beta pathway revealed by transcriptome profiling in ovarian cancer.

Epithelial ovarian cancer is the leading cause of death among gynecologic malignancies. Diagnosis usually occurs after metastatic spread, largely reflecting vague symptoms of early disease combined with lack of an effective screening strategy. Epigenetic mechanisms of gene regulation, including DNA methylation, are fundamental to normal cellular function and also play a major role in carcinogenesis. To elucidate the biological and clinical relevance of DNA methylation in ovarian cancer, we conducted expression microarray analysis of 39 cell lines and 17 primary culture specimens grown in the presence or absence of DNA methyltransferase (DNMT) inhibitors. Two parameters, induction of expression and standard deviation among untreated samples, identified 378 candidate methylated genes, many relevant to TGF-beta signaling. We analyzed 43 of these genes and they all exhibited methylation. Treatment with DNMT inhibitors increased TGF-beta pathway activity. Hierarchical clustering of ovarian cancers using the 378 genes reproducibly generated a distinct gene cluster strongly correlated with TGF-beta pathway activity that discriminates patients based on age. These data suggest that accumulation of age-related epigenetic modifications leads to suppression of TGF-beta signaling and contributes to ovarian carcinogenesis.

Authors
Matsumura, N; Huang, Z; Mori, S; Baba, T; Fujii, S; Konishi, I; Iversen, ES; Berchuck, A; Murphy, SK
MLA Citation
Matsumura, N, Huang, Z, Mori, S, Baba, T, Fujii, S, Konishi, I, Iversen, ES, Berchuck, A, and Murphy, SK. "Epigenetic suppression of the TGF-beta pathway revealed by transcriptome profiling in ovarian cancer." Genome Res 21.1 (January 2011): 74-82.
PMID
21156726
Source
pubmed
Published In
Genome research
Volume
21
Issue
1
Publish Date
2011
Start Page
74
End Page
82
DOI
10.1101/gr.108803.110

Progesterone receptor gene polymorphisms and risk of endometriosis: results from an international collaborative effort.

OBJECTIVE: To investigate the association between self-reported endometriosis and the putative functional promoter +331C/T single nucleotide polymorphism and the PROGINS allele. DESIGN: Control subjects from ovarian cancer case-control studies participating in the international Ovarian Cancer Association Consortium. The majority of controls are drawn from population-based studies. SETTING: An international ovarian cancer consortium including studies from Australia, Europe, and the United States. PATIENT(S): Five thousand eight hundred twelve white female controls, of whom 348 had endometriosis, from eight ovarian cancer case-control studies. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genotypes for the +331C/T single nucleotide polymorphism and PROGINS allele and a history of endometriosis. RESULT(S): The occurrence of endometriosis was reduced in women carrying one or more copies of the +331 T allele (odds ratio=0.65; 95% confidence interval: 0.43-0.98), whereas there was no association between the PROGINS allele and endometriosis (odds ratio=0.94, 95% confidence interval 0.76-1.16). CONCLUSION(S): Additional studies of the +331C/T variant are warranted given the current finding and the equivocal results of previous studies. The +331 T allele has been shown to result in a reduced progesterone (P) receptor A to P receptor B ratio, and if the observed association with endometriosis is confirmed it would suggest that this ratio is important for this disease.

Authors
Near, AM; Wu, AH; Templeman, C; Van Den Berg, DJ; Doherty, JA; Rossing, MA; Goode, EL; Cunningham, JM; Vierkant, RA; Fridley, BL; Chenevix-Trench, G; Webb, PM; Kjær, SK; Hogdall, E; Gayther, SA; Ramus, SJ; Menon, U; Gentry-Maharaj, A; Schildkraut, JM; Moorman, PG; Palmieri, RT; Ness, RB; Moysich, K; Cramer, DW; Terry, KL; Vitonis, AF; Pike, MC; Berchuck, A; Pearce, CL; Ovarian Cancer Association Consortium, ; Australian Cancer Study (Ovarian Cancer) (ACS), et al.
MLA Citation
Near, AM, Wu, AH, Templeman, C, Van Den Berg, DJ, Doherty, JA, Rossing, MA, Goode, EL, Cunningham, JM, Vierkant, RA, Fridley, BL, Chenevix-Trench, G, Webb, PM, Kjær, SK, Hogdall, E, Gayther, SA, Ramus, SJ, Menon, U, Gentry-Maharaj, A, Schildkraut, JM, Moorman, PG, Palmieri, RT, Ness, RB, Moysich, K, Cramer, DW, Terry, KL, Vitonis, AF, Pike, MC, Berchuck, A, Pearce, CL, Ovarian Cancer Association Consortium, , and Australian Cancer Study (Ovarian Cancer) (ACS), et al. "Progesterone receptor gene polymorphisms and risk of endometriosis: results from an international collaborative effort." Fertil Steril 95.1 (January 2011): 40-45.
PMID
20719308
Source
pubmed
Published In
Fertility and Sterility
Volume
95
Issue
1
Publish Date
2011
Start Page
40
End Page
45
DOI
10.1016/j.fertnstert.2010.06.059

Retraction: Genomic signatures to guide the use of chemotherapeutics.

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Retraction: Genomic signatures to guide the use of chemotherapeutics." Nat Med 17.1 (January 2011): 135-.
PMID
21217686
Source
pubmed
Published In
Nature Medicine
Volume
17
Issue
1
Publish Date
2011
Start Page
135
DOI
10.1038/nm0111-135

Polymorphisms in stromal genes and susceptibility to serous epithelial ovarian cancer: a report from the Ovarian Cancer Association Consortium.

Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among Caucasians were estimated with odds ratios (OR) among 397 cases and 920 controls in two U.S.-based studies (discovery set), 436 cases and 1,098 controls in Australia (replication set 1) and a consortium of 15 studies comprising 1,668 cases and 4,249 controls (replication set 2). The discovery set and replication set 1 (833 cases and 2,013 controls) showed statistically homogeneous (P(heterogeneity)≥0.48) decreased risks of sEOC at four variants: DCN rs3138165, rs13312816 and rs516115, and LUM rs17018765 (OR = 0.6 to 0.9; P(trend) = 0.001 to 0.03). Results from replication set 2 were statistically homogeneous (P(heterogeneity)≥0.13) and associated with increased risks at DCN rs3138165 and rs13312816, and LUM rs17018765: all ORs = 1.2; P(trend)≤0.02. The ORs at the four variants were statistically heterogeneous across all 18 studies (P(heterogeneity)≤0.03), which precluded combining. In post-hoc analyses, interactions were observed between each variant and recruitment period (P(interaction)≤0.003), age at diagnosis (P(interaction) = 0.04), and year of diagnosis (P(interaction) = 0.05) in the five studies with available information (1,044 cases, 2,469 controls). We conclude that variants in DCN and LUM are not directly associated with sEOC, and that confirmation of possible effect modification of the variants by non-genetic factors is required.

Authors
Amankwah, EK; Wang, Q; Schildkraut, JM; Tsai, Y-Y; Ramus, SJ; Fridley, BL; Beesley, J; Johnatty, SE; Webb, PM; Chenevix-Trench, G; Australian Ovarian Cancer Study Group, ; Dale, LC; Lambrechts, D; Amant, F; Despierre, E; Vergote, I; Gayther, SA; Gentry-Maharaj, A; Menon, U; Chang-Claude, J; Wang-Gohrke, S; Anton-Culver, H; Ziogas, A; Dörk, T; Dürst, M; Antonenkova, N; Bogdanova, N; Brown, R; Flanagan, JM; Kaye, SB; Paul, J; Bützow, R; Nevanlinna, H; Campbell, I; Eccles, DM; Karlan, BY; Gross, J et al.
MLA Citation
Amankwah, EK, Wang, Q, Schildkraut, JM, Tsai, Y-Y, Ramus, SJ, Fridley, BL, Beesley, J, Johnatty, SE, Webb, PM, Chenevix-Trench, G, Australian Ovarian Cancer Study Group, , Dale, LC, Lambrechts, D, Amant, F, Despierre, E, Vergote, I, Gayther, SA, Gentry-Maharaj, A, Menon, U, Chang-Claude, J, Wang-Gohrke, S, Anton-Culver, H, Ziogas, A, Dörk, T, Dürst, M, Antonenkova, N, Bogdanova, N, Brown, R, Flanagan, JM, Kaye, SB, Paul, J, Bützow, R, Nevanlinna, H, Campbell, I, Eccles, DM, Karlan, BY, and Gross, J et al. "Polymorphisms in stromal genes and susceptibility to serous epithelial ovarian cancer: a report from the Ovarian Cancer Association Consortium." PLoS One 6.5 (2011): e19642-.
PMID
21637745
Source
pubmed
Published In
PloS one
Volume
6
Issue
5
Publish Date
2011
Start Page
e19642
DOI
10.1371/journal.pone.0019642

Estrogen receptor beta rs1271572 polymorphism and invasive ovarian carcinoma risk: pooled analysis within the Ovarian Cancer Association Consortium.

The association of ovarian carcinoma risk with the polymorphism rs1271572 in the estrogen receptor beta (ESR2) gene was examined in 4946 women with primary invasive ovarian carcinoma and 6582 controls in a pooled analysis of ten case-control studies within the Ovarian Cancer Association Consortium (OCAC). All participants were non-Hispanic white women. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression adjusted for site and age. Women with the TT genotype were at increased risk of ovarian carcinoma compared to carriers of the G allele (OR = 1.10; 95%; CI: 1.01-1.21; p = 0.04); the OR was 1.09 (CI: 0.99-1.20; p = 0.07) after excluding data from the center (Hawaii) that nominated this SNP for OCAC genotyping A stronger association of rs1271572 TT versus GT/GG with risk was observed among women aged ≤50 years versus older women (OR = 1.35; CI: 1.12-1.62; p = 0.002; p for interaction = 0.02) that remained statistically significant after excluding Hawaii data (OR = 1.34; CI: 1.11-1.61; p = 0.009). No heterogeneity of the association was observed by study, menopausal status, gravidity, parity, use of contraceptive or menopausal hormones, tumor histological type, or stage at diagnosis. This pooled analysis suggests that rs1271572 might influence the risk of ovarian cancer, in particular among younger women.

Authors
Lurie, G; Wilkens, LR; Thompson, PJ; Shvetsov, YB; Matsuno, RK; Carney, ME; Palmieri, RT; Wu, AH; Pike, MC; Pearce, CL; Menon, U; Gentry-Maharaj, A; Gayther, SA; Ramus, SJ; Whittemore, AS; McGuire, V; Sieh, W; Pharoah, PDP; Song, H; Gronwald, J; Jakubowska, A; Cybulski, C; Lubinski, J; Schildkraut, JM; Berchuck, A; Krüger Kjær, S; Høgdall, E; Fasching, PA; Beckmann, MW; Ekici, AB; Hein, A; Chenevix-Trench, G; Webb, PM; Beesley, J; Australian Ovarian Cancer Study Group, et al.
MLA Citation
Lurie, G, Wilkens, LR, Thompson, PJ, Shvetsov, YB, Matsuno, RK, Carney, ME, Palmieri, RT, Wu, AH, Pike, MC, Pearce, CL, Menon, U, Gentry-Maharaj, A, Gayther, SA, Ramus, SJ, Whittemore, AS, McGuire, V, Sieh, W, Pharoah, PDP, Song, H, Gronwald, J, Jakubowska, A, Cybulski, C, Lubinski, J, Schildkraut, JM, Berchuck, A, Krüger Kjær, S, Høgdall, E, Fasching, PA, Beckmann, MW, Ekici, AB, Hein, A, Chenevix-Trench, G, Webb, PM, Beesley, J, and Australian Ovarian Cancer Study Group, et al. "Estrogen receptor beta rs1271572 polymorphism and invasive ovarian carcinoma risk: pooled analysis within the Ovarian Cancer Association Consortium." PLoS One 6.6 (2011): e20703-.
PMID
21673961
Source
pubmed
Published In
PloS one
Volume
6
Issue
6
Publish Date
2011
Start Page
e20703
DOI
10.1371/journal.pone.0020703

Genome-scale screen for DNA methylation-based detection markers for ovarian cancer.

BACKGROUND: The identification of sensitive biomarkers for the detection of ovarian cancer is of high clinical relevance for early detection and/or monitoring of disease recurrence. We developed a systematic multi-step biomarker discovery and verification strategy to identify candidate DNA methylation markers for the blood-based detection of ovarian cancer. METHODOLOGY/PRINCIPAL FINDINGS: We used the Illumina Infinium platform to analyze the DNA methylation status of 27,578 CpG sites in 41 ovarian tumors. We employed a marker selection strategy that emphasized sensitivity by requiring consistency of methylation across tumors, while achieving specificity by excluding markers with methylation in control leukocyte or serum DNA. Our verification strategy involved testing the ability of identified markers to monitor disease burden in serially collected serum samples from ovarian cancer patients who had undergone surgical tumor resection compared to CA-125 levels. We identified one marker, IFFO1 promoter methylation (IFFO1-M), that is frequently methylated in ovarian tumors and that is rarely detected in the blood of normal controls. When tested in 127 serially collected sera from ovarian cancer patients, IFFO1-M showed post-resection kinetics significantly correlated with serum CA-125 measurements in six out of 16 patients. CONCLUSIONS/SIGNIFICANCE: We implemented an effective marker screening and verification strategy, leading to the identification of IFFO1-M as a blood-based candidate marker for sensitive detection of ovarian cancer. Serum levels of IFFO1-M displayed post-resection kinetics consistent with a reflection of disease burden. We anticipate that IFFO1-M and other candidate markers emerging from this marker development pipeline may provide disease detection capabilities that complement existing biomarkers.

Authors
Campan, M; Moffitt, M; Houshdaran, S; Shen, H; Widschwendter, M; Daxenbichler, G; Long, T; Marth, C; Laird-Offringa, IA; Press, MF; Dubeau, L; Siegmund, KD; Wu, AH; Groshen, S; Chandavarkar, U; Roman, LD; Berchuck, A; Pearce, CL; Laird, PW
MLA Citation
Campan, M, Moffitt, M, Houshdaran, S, Shen, H, Widschwendter, M, Daxenbichler, G, Long, T, Marth, C, Laird-Offringa, IA, Press, MF, Dubeau, L, Siegmund, KD, Wu, AH, Groshen, S, Chandavarkar, U, Roman, LD, Berchuck, A, Pearce, CL, and Laird, PW. "Genome-scale screen for DNA methylation-based detection markers for ovarian cancer." PLoS One 6.12 (2011): e28141-.
PMID
22163280
Source
pubmed
Published In
PloS one
Volume
6
Issue
12
Publish Date
2011
Start Page
e28141
DOI
10.1371/journal.pone.0028141

KRAS rs61764370 in epithelial ovarian cancer-response

Authors
Risch, HA; Berchuck, A; Pharoah, PDP
MLA Citation
Risch, HA, Berchuck, A, and Pharoah, PDP. "KRAS rs61764370 in epithelial ovarian cancer-response." Clinical Cancer Research 17.20 (2011): 6610--.
PMID
24353399
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
20
Publish Date
2011
Start Page
6610-
DOI
10.1158/1078-0432.CCR-11-1504

Integrated genomic analyses of ovarian carcinoma

A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology. © 2011 Macmillan Publishers Limited. All rights reserved.

Authors
Bell, D; Berchuck, A; Birrer, M; Chien, J; Cramer, DW; Dao, F; Dhir, R; Disaia, P; Gabra, H; Glenn, P; Godwin, AK; Gross, J; Hartmann, L; Huang, M; Huntsman, DG; Iacocca, M; Imielinski, M; Kalloger, S; Karlan, BY; Levine, DA; Mills, GB; Morrison, C; Mutch, D; Olvera, N; Orsulic, S; Park, K; Petrelli, N; Rabeno, B; Rader, JS; Sikic, BI; Smith-Mccune, K; Sood, AK; Bowtell, D; Penny, R; Testa, JR; Chang, K; Dinh, HH; Drummond, JA; Fowler, G; Gunaratne, P; Hawes, AC; Kovar, CL; Lewis, LR et al.
MLA Citation
Bell, D, Berchuck, A, Birrer, M, Chien, J, Cramer, DW, Dao, F, Dhir, R, Disaia, P, Gabra, H, Glenn, P, Godwin, AK, Gross, J, Hartmann, L, Huang, M, Huntsman, DG, Iacocca, M, Imielinski, M, Kalloger, S, Karlan, BY, Levine, DA, Mills, GB, Morrison, C, Mutch, D, Olvera, N, Orsulic, S, Park, K, Petrelli, N, Rabeno, B, Rader, JS, Sikic, BI, Smith-Mccune, K, Sood, AK, Bowtell, D, Penny, R, Testa, JR, Chang, K, Dinh, HH, Drummond, JA, Fowler, G, Gunaratne, P, Hawes, AC, Kovar, CL, and Lewis, LR et al. "Integrated genomic analyses of ovarian carcinoma." Nature 474.7353 (2011): 609-615.
PMID
21720365
Source
scival
Published In
Nature
Volume
474
Issue
7353
Publish Date
2011
Start Page
609
End Page
615
DOI
10.1038/nature10166

Gynecologic Oncology: Editorial

Authors
Berchuck, A; Einstein, MH
MLA Citation
Berchuck, A, and Einstein, MH. "Gynecologic Oncology: Editorial." Gynecologic Oncology 121.1 (2011): 1--.
Source
scival
Published In
Gynecologic Oncology
Volume
121
Issue
1
Publish Date
2011
Start Page
1-
DOI
10.1016/j.ygyno.2011.02.009

Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12 (1294-1300))

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12 (1294-1300))." Nature Medicine 17.1 (2011): 135--.
Source
scival
Published In
Nature Medicine
Volume
17
Issue
1
Publish Date
2011
Start Page
135-
DOI
10.1038/nm0111-135

What Are The Causes Of Death For Women With Early-stage Endometrial Cancer?

Authors
Chino, JP; Berchuck, A; Havrilesky, L
MLA Citation
Chino, JP, Berchuck, A, and Havrilesky, L. "What Are The Causes Of Death For Women With Early-stage Endometrial Cancer?." INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS 81.2 (2011): S470-S470.
Source
wos-lite
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
81
Issue
2
Publish Date
2011
Start Page
S470
End Page
S470

Projecting the need for gynecologic oncologists for the next 40 years.

OBJECTIVE: To estimate the ratio of gynecologic cancer cases to practicing gynecologic oncologists in the United States over the next 40 years. METHODS: Using population projections from the U.S. Census Bureau and incidence and mortality rates from Surveillance, Epidemiology and End Results surveys, we estimated the annual number of new gynecologic cancer cases through 2050; the effects of human papillomavirus (HPV) vaccination was included in cervical cancer estimates. The number of practicing gynecologic oncologists was projected through 2050 using data from the 2005 Society of Gynecologic Oncologists Practice Survey, current Society of Gynecologic Oncologists membership information, American Board of Obstetrics and Gynecology and Gynecologic Oncology oral examination results, and mortality estimates from U.S. life tables. Projected time in practice was sex-dependent based on Society of Gynecologic Oncologists Practice Survey. For sensitivity analyses, we varied annual number and sex distribution of fellowship graduates, HPV vaccination coverage rates, and future incidence of overweight and obesity. RESULTS: At constant training rates, the annual number of new cancer cases per practicing gynecologic oncologist will rise from 112 in 2010 to 133 in 2050, a 19% increase. If the annual number of fellowship graduates increases by 25%, the ratio of cancer cases per gynecologic oncologist will decrease to 106, a 5% decrease. Projections are more sensitive to changes in physician demographics than to changes in HPV vaccination coverage rates. CONCLUSION: The gynecologic cancer caseload of practicing gynecologic oncologists will increase by almost 20% over the next 40 years at constant training rates. Changes in the projected sex distribution of fellowship graduates and their time in practice affect these projections.

Authors
Wallace, AH; Havrilesky, LJ; Valea, FA; Barnett, JC; Berchuck, A; Myers, ER
MLA Citation
Wallace, AH, Havrilesky, LJ, Valea, FA, Barnett, JC, Berchuck, A, and Myers, ER. "Projecting the need for gynecologic oncologists for the next 40 years." Obstet Gynecol 116.6 (December 2010): 1366-1372.
PMID
21099604
Source
pubmed
Published In
Obstetrics and Gynecology
Volume
116
Issue
6
Publish Date
2010
Start Page
1366
End Page
1372
DOI
10.1097/AOG.0b013e3181fc3a22

A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24.

Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (in BNC2). Here, we report on nine additional candidate loci (defined as having P ≤ 10⁻⁴) identified after stratifying cases by histology, which we genotyped in an additional 4,353 cases and 6,021 controls. We confirmed two new susceptibility loci with P ≤ 5 × 10⁻⁸ (8q24, P = 8.0 × 10⁻¹⁵ and 2q31, P = 3.8 × 10⁻¹⁴) and identified two additional loci that approached genome-wide significance (3q25, P = 7.1 × 10⁻⁸ and 17q21, P = 1.4 × 10⁻⁷). The associations of these loci with serous ovarian cancer were generally stronger than with other cancer subtypes. Analysis of HOXD1, MYC, TIPARP and SKAP1 at these loci and of BNC2 at 9p22 supports a functional role for these genes in ovarian cancer development.

Authors
Goode, EL; Chenevix-Trench, G; Song, H; Ramus, SJ; Notaridou, M; Lawrenson, K; Widschwendter, M; Vierkant, RA; Larson, MC; Kjaer, SK; Birrer, MJ; Berchuck, A; Schildkraut, J; Tomlinson, I; Kiemeney, LA; Cook, LS; Gronwald, J; Garcia-Closas, M; Gore, ME; Campbell, I; Whittemore, AS; Sutphen, R; Phelan, C; Anton-Culver, H; Pearce, CL; Lambrechts, D; Rossing, MA; Chang-Claude, J; Moysich, KB; Goodman, MT; Dörk, T; Nevanlinna, H; Ness, RB; Rafnar, T; Hogdall, C; Hogdall, E; Fridley, BL et al.
MLA Citation
Goode, EL, Chenevix-Trench, G, Song, H, Ramus, SJ, Notaridou, M, Lawrenson, K, Widschwendter, M, Vierkant, RA, Larson, MC, Kjaer, SK, Birrer, MJ, Berchuck, A, Schildkraut, J, Tomlinson, I, Kiemeney, LA, Cook, LS, Gronwald, J, Garcia-Closas, M, Gore, ME, Campbell, I, Whittemore, AS, Sutphen, R, Phelan, C, Anton-Culver, H, Pearce, CL, Lambrechts, D, Rossing, MA, Chang-Claude, J, Moysich, KB, Goodman, MT, Dörk, T, Nevanlinna, H, Ness, RB, Rafnar, T, Hogdall, C, Hogdall, E, and Fridley, BL et al. "A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24." Nat Genet 42.10 (October 2010): 874-879.
PMID
20852632
Source
pubmed
Published In
Nature Genetics
Volume
42
Issue
10
Publish Date
2010
Start Page
874
End Page
879
DOI
10.1038/ng.668

Common variants at 19p13 are associated with susceptibility to ovarian cancer.

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10⁻⁴ and P = 6 × 10⁻⁴, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10⁻⁹ and P = 4 × 10⁻¹¹, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.

Authors
Bolton, KL; Tyrer, J; Song, H; Ramus, SJ; Notaridou, M; Jones, C; Sher, T; Gentry-Maharaj, A; Wozniak, E; Tsai, Y-Y; Weidhaas, J; Paik, D; Van Den Berg, DJ; Stram, DO; Pearce, CL; Wu, AH; Brewster, W; Anton-Culver, H; Ziogas, A; Narod, SA; Levine, DA; Kaye, SB; Brown, R; Paul, J; Flanagan, J; Sieh, W; McGuire, V; Whittemore, AS; Campbell, I; Gore, ME; Lissowska, J; Yang, HP; Medrek, K; Gronwald, J; Lubinski, J; Jakubowska, A; Le, ND; Cook, LS; Kelemen, LE; Brooks-Wilson, A; Massuger, LFAG et al.
MLA Citation
Bolton, KL, Tyrer, J, Song, H, Ramus, SJ, Notaridou, M, Jones, C, Sher, T, Gentry-Maharaj, A, Wozniak, E, Tsai, Y-Y, Weidhaas, J, Paik, D, Van Den Berg, DJ, Stram, DO, Pearce, CL, Wu, AH, Brewster, W, Anton-Culver, H, Ziogas, A, Narod, SA, Levine, DA, Kaye, SB, Brown, R, Paul, J, Flanagan, J, Sieh, W, McGuire, V, Whittemore, AS, Campbell, I, Gore, ME, Lissowska, J, Yang, HP, Medrek, K, Gronwald, J, Lubinski, J, Jakubowska, A, Le, ND, Cook, LS, Kelemen, LE, Brooks-Wilson, A, and Massuger, LFAG et al. "Common variants at 19p13 are associated with susceptibility to ovarian cancer." Nat Genet 42.10 (October 2010): 880-884.
PMID
20852633
Source
pubmed
Published In
Nature Genetics
Volume
42
Issue
10
Publish Date
2010
Start Page
880
End Page
884
DOI
10.1038/ng.666

Prophylactic and risk-reducing bilateral salpingo-oophorectomy: recommendations based on risk of ovarian cancer.

Women who do not have a documented germline mutation or who do not have a strong family history suspicious for a germline mutation are considered to be at average risk of ovarian cancer. Women who have confirmed deleterious BRCA1 and BRCA2 germline mutations are high risk of ovarian cancer. In addition, women who have a strong family history of either ovarian or breast cancer may carry a deleterious mutation and must be presumed to be at higher-than-average risk, even if they have not been tested, because there could be other mutations that are either untested or yet undiscovered that confirm higher-than-average risk of these diseases. We reviewed studies pertaining to prophylactic bilateral salpingo-oophorectomy in women at average risk of ovarian cancer who are undergoing hysterectomy for benign disease. We also reviewed the role of prophylactic bilateral salpingo-oophorectomy in preventing ovarian cancer based on the level of risk of the patient. For women at average risk of ovarian cancer who are undergoing a hysterectomy for benign conditions, the decision to perform prophylactic bilateral salpingo-oophorectomy should be individualized after appropriate informed consent, including a careful analysis of personal risk factors. Several studies suggest an overall negative health effect when prophylactic bilateral salpingo-oophorectomy is performed before the age of menopause. Ovarian conservation before menopause may be especially important in patients with a personal or strong family history of cardiovascular or neurological disease. Conversely, women at high risk of ovarian cancer should undergo risk-reducing bilateral salpingo-oophorectomy.

Authors
Berek, JS; Chalas, E; Edelson, M; Moore, DH; Burke, WM; Cliby, WA; Berchuck, A; Society of Gynecologic Oncologists Clinical Practice Committee,
MLA Citation
Berek, JS, Chalas, E, Edelson, M, Moore, DH, Burke, WM, Cliby, WA, Berchuck, A, and Society of Gynecologic Oncologists Clinical Practice Committee, . "Prophylactic and risk-reducing bilateral salpingo-oophorectomy: recommendations based on risk of ovarian cancer." Obstet Gynecol 116.3 (September 2010): 733-743. (Review)
PMID
20733460
Source
pubmed
Published In
Obstetrics and Gynecology
Volume
116
Issue
3
Publish Date
2010
Start Page
733
End Page
743
DOI
10.1097/AOG.0b013e3181ec5fc1

Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot".

We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n=675) and controls (n=1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n=1,233 serous invasive cases; n=3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. Pper-allele>or=0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele=0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p=0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.

Authors
Johnatty, SE; Beesley, J; Chen, X; Macgregor, S; Duffy, DL; Spurdle, AB; deFazio, A; Gava, N; Webb, PM; Rossing, MA; Doherty, JA; Goodman, MT; Lurie, G; Thompson, PJ; Wilkens, LR; Ness, RB; Moysich, KB; Chang-Claude, J; Wang-Gohrke, S; Cramer, DW; Terry, KL; Hankinson, SE; Tworoger, SS; Garcia-Closas, M; Yang, H; Lissowska, J; Chanock, SJ; Pharoah, PD; Song, H; Whitemore, AS; Pearce, CL; Stram, DO; Wu, AH; Pike, MC; Gayther, SA; Ramus, SJ; Menon, U; Gentry-Maharaj, A; Anton-Culver, H; Ziogas, A et al.
MLA Citation
Johnatty, SE, Beesley, J, Chen, X, Macgregor, S, Duffy, DL, Spurdle, AB, deFazio, A, Gava, N, Webb, PM, Rossing, MA, Doherty, JA, Goodman, MT, Lurie, G, Thompson, PJ, Wilkens, LR, Ness, RB, Moysich, KB, Chang-Claude, J, Wang-Gohrke, S, Cramer, DW, Terry, KL, Hankinson, SE, Tworoger, SS, Garcia-Closas, M, Yang, H, Lissowska, J, Chanock, SJ, Pharoah, PD, Song, H, Whitemore, AS, Pearce, CL, Stram, DO, Wu, AH, Pike, MC, Gayther, SA, Ramus, SJ, Menon, U, Gentry-Maharaj, A, Anton-Culver, H, and Ziogas, A et al. "Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot". (Published online)" PLoS Genet 6.7 (July 8, 2010): e1001016-.
PMID
20628624
Source
pubmed
Published In
PLoS genetics
Volume
6
Issue
7
Publish Date
2010
Start Page
e1001016
DOI
10.1371/journal.pgen.1001016

Genetic variation in TYMS in the one-carbon transfer pathway is associated with ovarian carcinoma types in the Ovarian Cancer Association Consortium.

BACKGROUND: We previously reported the risks of ovarian carcinoma for common polymorphisms in one-carbon transfer genes. We sought to replicate associations for DPYD rs1801265, DNMT3A rs13420827, MTHFD1 rs1950902, MTHFS rs17284990, and TYMS rs495139 with risk of ovarian carcinoma overall and to use the large sample of assembled cases to investigate associations by histologic type. METHODS: Associations were evaluated in the Ovarian Cancer Association Consortium, including 16 studies of 5,593 epithelial ovarian carcinoma cases and 9,962 controls of white non-Hispanic origin. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age and study site. RESULTS: The five polymorphisms were not associated with ovarian carcinoma overall (P(trend) > 0.13); however, associations for the minor allele at TYMS rs495139 were observed for carcinomas of mucinous type (OR, 1.19; 95% CI, 1.03-1.39; P = 0.02), clear cell type (OR, 0.86; 95% CI, 0.75-0.99; P = 0.04), and endometrioid type (OR, 0.90; 95% CI, 0.81-0.99; P = 0.04; P(heterogeneity) = 0.001). Restriction to low-grade mucinous carcinomas further strengthened the association for the mucinous type (OR, 1.32; 95% CI, 1.07-1.62; P = 0.01). TYMS rs495139 was not associated with serous type (OR, 1.06; 95% CI, 1.00-1.13; P = 0.05). CONCLUSIONS: TYMS rs495139 may be associated with a differential risk of ovarian carcinoma types, indicating the importance of accurate histopathologic classification. IMPACT: Biomarkers that distinguish ovarian carcinoma types are few, and TYMS rs495139 may provide a novel clue to type etiology.

Authors
Kelemen, LE; Goodman, MT; McGuire, V; Rossing, MA; Webb, PM; Australian Cancer Study (Ovarian Cancer) Study Group, ; Köbel, M; Anton-Culver, H; Beesley, J; Berchuck, A; Brar, S; Carney, ME; Chang-Claude, J; Chenevix-Trench, G; Australian Ovarian Cancer Study Group, ; Cramer, DW; Cunningham, JM; Dicioccio, RA; Doherty, JA; Easton, DF; Fredericksen, ZS; Fridley, BL; Gates, MA; Gayther, SA; Gentry-Maharaj, A; Høgdall, E; Kjaer, SK; Lurie, G; Menon, U; Moorman, PG; Moysich, K; Ness, RB et al.
MLA Citation
Kelemen, LE, Goodman, MT, McGuire, V, Rossing, MA, Webb, PM, Australian Cancer Study (Ovarian Cancer) Study Group, , Köbel, M, Anton-Culver, H, Beesley, J, Berchuck, A, Brar, S, Carney, ME, Chang-Claude, J, Chenevix-Trench, G, Australian Ovarian Cancer Study Group, , Cramer, DW, Cunningham, JM, Dicioccio, RA, Doherty, JA, Easton, DF, Fredericksen, ZS, Fridley, BL, Gates, MA, Gayther, SA, Gentry-Maharaj, A, Høgdall, E, Kjaer, SK, Lurie, G, Menon, U, Moorman, PG, Moysich, K, and Ness, RB et al. "Genetic variation in TYMS in the one-carbon transfer pathway is associated with ovarian carcinoma types in the Ovarian Cancer Association Consortium." Cancer Epidemiol Biomarkers Prev 19.7 (July 2010): 1822-1830.
PMID
20570913
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
19
Issue
7
Publish Date
2010
Start Page
1822
End Page
1830
DOI
10.1158/1055-9965.EPI-09-1317

Microcell-mediated chromosome transfer identifies EPB41L3 as a functional suppressor of epithelial ovarian cancers.

We used a functional complementation approach to identify tumor-suppressor genes and putative therapeutic targets for ovarian cancer. Microcell-mediated transfer of chromosome 18 in the ovarian cancer cell line TOV21G induced in vitro and in vivo neoplastic suppression. Gene expression microarray profiling in TOV21G(+18) hybrids identified 14 candidate genes on chromosome 18 that were significantly overexpressed and therefore associated with neoplastic suppression. Further analysis of messenger RNA and protein expression for these genes in additional ovarian cancer cell lines indicated that EPB41L3 (erythrocyte membrane protein band 4.1-like 3, alternative names DAL-1 and 4.1B) was a candidate ovarian cancer-suppressor gene. Immunoblot analysis showed that EPB41L3 was activated in TOV21G(+18) hybrids, expressed in normal ovarian epithelial cell lines, but was absent in 15 (78%) of 19 ovarian cancer cell lines. Using immunohistochemistry, 66% of 794 invasive ovarian tumors showed no EPB41L3 expression compared with only 24% of benign ovarian tumors and 0% of normal ovarian epithelial tissues. EPB41L3 was extensively methylated in ovarian cancer cell lines and primary ovarian tumors compared with normal tissues (P = .00004), suggesting this may be the mechanism of gene inactivation in ovarian cancers. Constitutive reexpression of EPB41L3 in a three-dimensional multicellular spheroid model of ovarian cancer caused significant growth suppression and induced apoptosis. Transmission and scanning electron microscopy demonstrated many similarities between EPB41L3-expressing cells and chromosome 18 donor-recipient hybrids, suggesting that EPB41L3 is the gene responsible for neoplastic suppression after chromosome 18 transfer. Finally, an inducible model of EPB41L3 expression in three-dimensional spheroids confirmed that reexpression of EPB41L3 induces extensive apoptotic cell death in ovarian cancers.

Authors
Dafou, D; Grun, B; Sinclair, J; Lawrenson, K; Benjamin, EC; Hogdall, E; Kruger-Kjaer, S; Christensen, L; Sowter, HM; Al-Attar, A; Edmondson, R; Darby, S; Berchuck, A; Laird, PW; Pearce, CL; Ramus, SJ; Jacobs, IJ; Gayther, SA
MLA Citation
Dafou, D, Grun, B, Sinclair, J, Lawrenson, K, Benjamin, EC, Hogdall, E, Kruger-Kjaer, S, Christensen, L, Sowter, HM, Al-Attar, A, Edmondson, R, Darby, S, Berchuck, A, Laird, PW, Pearce, CL, Ramus, SJ, Jacobs, IJ, and Gayther, SA. "Microcell-mediated chromosome transfer identifies EPB41L3 as a functional suppressor of epithelial ovarian cancers." Neoplasia 12.7 (July 2010): 579-589.
PMID
20651987
Source
pubmed
Published In
Neoplasia (New York, N.Y.)
Volume
12
Issue
7
Publish Date
2010
Start Page
579
End Page
589

Expression signatures of TP53 mutations in serous ovarian cancers.

BACKGROUND: Mutations in the TP53 gene are extremely common and occur very early in the progression of serous ovarian cancers. Gene expression patterns that relate to mutational status may provide insight into the etiology and biology of the disease. METHODS: The TP53 coding region was sequenced in 89 frozen serous ovarian cancers, 40 early stage (I/II) and 49 advanced stage (III/IV). Affymetrix U133A expression data was used to define gene expression patterns by mutation, type of mutation, and cancer stage. RESULTS: Missense or chain terminating (null) mutations in TP53 were found in 59/89 (66%) ovarian cancers. Early stage cancers had a significantly higher rate of null mutations than late stage disease (38% vs. 8%, p < 0.03). In advanced stage cases, mutations were more prevalent in short term survivors than long term survivors (81% vs. 30%, p = 0.0004). Gene expression patterns had a robust ability to predict TP53 status within training data. By using early versus late stage disease for out of sample predictions, the signature derived from early stage cancers could accurately (86%) predict mutation status of late stage cancers. CONCLUSIONS: This represents the first attempt to define a genomic signature of TP53 mutation in ovarian cancer. Patterns of gene expression characteristic of TP53 mutation could be discerned and included several genes that are known p53 targets or have been described in the context of expression signatures of TP53 mutation in breast cancer.

Authors
Bernardini, MQ; Baba, T; Lee, PS; Barnett, JC; Sfakianos, GP; Secord, AA; Murphy, SK; Iversen, E; Marks, JR; Berchuck, A
MLA Citation
Bernardini, MQ, Baba, T, Lee, PS, Barnett, JC, Sfakianos, GP, Secord, AA, Murphy, SK, Iversen, E, Marks, JR, and Berchuck, A. "Expression signatures of TP53 mutations in serous ovarian cancers. (Published online)" BMC Cancer 10 (May 26, 2010): 237-.
Website
http://hdl.handle.net/10161/4356
PMID
20504346
Source
pubmed
Published In
BMC Cancer
Volume
10
Publish Date
2010
Start Page
237
DOI
10.1186/1471-2407-10-237

Influence of radiation modality and nodal dissection on survival in high-risk early-stage endometrial cancer

Authors
Chino, JP; Jones, E; Berchuck, A; Havrilesky, L
MLA Citation
Chino, JP, Jones, E, Berchuck, A, and Havrilesky, L. "Influence of radiation modality and nodal dissection on survival in high-risk early-stage endometrial cancer." JOURNAL OF CLINICAL ONCOLOGY 28.15 (May 20, 2010).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
28
Issue
15
Publish Date
2010

Targeting slow-proliferating ovarian cancer cells.

Advanced ovarian cancer has a high rate of recurrence and mortality despite relative chemosensitivity at the time of initial treatment. Conventional chemotherapeutic agents typically target rapidly dividing cells. Disease relapse may therefore result from the survival and later emergence of latent slow-proliferating and/or quiescent cancer cells. We sought to identify drugs that target this cell population and to investigate the influence of these cells on outcome of patients in remission from advanced ovarian cancer. Drugs with increased efficacy against slower proliferating cells were identified using correlation-based screening of 44,657 compounds tested on the NCI-60 panel of cancer cell lines. Validation of candidates was performed in comparison with Cisplatin or Paclitaxel and by manipulation of proliferation rates by serum deprivation. Cytostatic and cytocidal effects were evaluated using MTT assays and active caspase-3 immunocytochemistry. Ki-67 proliferation indices were determined for tumors from 104 patients in remission. UCN-01 efficacy was correlated with longer doubling time among the NCI-60 cell lines (R = 0.54, p < 0.0001) and in a panel of 24 ovarian cancer cell lines (R = 0.42, p = 0.04), whereas this was not the case for Cisplatin (R = -0.10, p = 0.65) and Paclitaxel efficacy correlated with shorter doubling time (R = -0.52, p = 0.009). Cytostatic and cytocidal effects of UCN-01 were increased in serum-deprived cells. A low proliferation index was associated with presence of persistent disease at second-look surgery (p = 0.01) and poor survival (disease-free survival, p = 0.002; overall survival, p = 0.04). These results suggest that targeting quiescent ovarian cancer cells may be a worthwhile therapeutic approach to improving survival of women with ovarian cancer.

Authors
Kondoh, E; Mori, S; Yamaguchi, K; Baba, T; Matsumura, N; Cory Barnett, J; Whitaker, RS; Konishi, I; Fujii, S; Berchuck, A; Murphy, SK
MLA Citation
Kondoh, E, Mori, S, Yamaguchi, K, Baba, T, Matsumura, N, Cory Barnett, J, Whitaker, RS, Konishi, I, Fujii, S, Berchuck, A, and Murphy, SK. "Targeting slow-proliferating ovarian cancer cells." Int J Cancer 126.10 (May 15, 2010): 2448-2456.
PMID
19795452
Source
pubmed
Published In
International Journal of Cancer
Volume
126
Issue
10
Publish Date
2010
Start Page
2448
End Page
2456
DOI
10.1002/ijc.24919

Association between DNA damage response and repair genes and risk of invasive serous ovarian cancer.

BACKGROUND: We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a population-based, case-control study. METHODS/PRINCIPAL FINDINGS: The analysis was restricted to 364 invasive serous ovarian cancer cases and 761 controls of white, non-Hispanic race. Statistical analysis was two staged: a screen using marginal Bayes factors (BFs) for 484 SNPs and a modeling stage in which we calculated multivariate adjusted posterior probabilities of association for 77 SNPs that passed the screen. These probabilities were conditional on subject age at diagnosis/interview, batch, a DNA quality metric and genotypes of other SNPs and allowed for uncertainty in the genetic parameterizations of the SNPs and number of associated SNPs. Six SNPs had Bayes factors greater than 10 in favor of an association with invasive serous ovarian cancer. These included rs5762746 (median OR(odds ratio)(per allele) = 0.66; 95% credible interval (CI) = 0.44-1.00) and rs6005835 (median OR(per allele) = 0.69; 95% CI = 0.53-0.91) in CHEK2, rs2078486 (median OR(per allele) = 1.65; 95% CI = 1.21-2.25) and rs12951053 (median OR(per allele) = 1.65; 95% CI = 1.20-2.26) in TP53, rs411697 (median OR (rare homozygote) = 0.53; 95% CI = 0.35 - 0.79) in BACH1 and rs10131 (median OR( rare homozygote) = not estimable) in LIG4. The six most highly associated SNPs are either predicted to be functionally significant or are in LD with such a variant. The variants in TP53 were confirmed to be associated in a large follow-up study. CONCLUSIONS/SIGNIFICANCE: Based on our findings, further follow-up of the DNA repair and response pathways in a larger dataset is warranted to confirm these results.

Authors
Schildkraut, JM; Iversen, ES; Wilson, MA; Clyde, MA; Moorman, PG; Palmieri, RT; Whitaker, R; Bentley, RC; Marks, JR; Berchuck, A
MLA Citation
Schildkraut, JM, Iversen, ES, Wilson, MA, Clyde, MA, Moorman, PG, Palmieri, RT, Whitaker, R, Bentley, RC, Marks, JR, and Berchuck, A. "Association between DNA damage response and repair genes and risk of invasive serous ovarian cancer. (Published online)" PLoS One 5.4 (April 8, 2010): e10061-.
Website
http://hdl.handle.net/10161/8883
PMID
20386703
Source
pubmed
Published In
PloS one
Volume
5
Issue
4
Publish Date
2010
Start Page
e10061
DOI
10.1371/journal.pone.0010061

Elevated MAL expression is accompanied by promoter hypomethylation and platinum resistance in epithelial ovarian cancer.

We previously found that the gene encoding the Myelin and Lymphocyte protein, MAL, was among the most highly expressed genes in serous ovarian cancers from short-term survivors (<3 years) relative to those of long-term survivors (>7 years). In the present study, we have found that this difference in expression is partially attributable to differences in DNA methylation at a specific region within the MAL promoter CpG island. While MAL was largely unmethylated at the transcription start site (Region 1; -48 to +73 bp) in primary serous ovarian cancers, methylation of an upstream region (Region 2; -452 to -266 bp) was inversely correlated with MAL transcription in the primary cancers (R = -0.463) and ovarian cancer cell lines (R = -0.444). Following treatment of the OVCA432 cell line with 5-azacytidine, methylation of Region 2 decreased from 73.3% to 34.7% (p = 0.007) while Region 1 was unaffected. This was accompanied by a 10-fold increase in MAL expression. Since MAL transcripts are elevated in tumors from short-term survivors, all of whom were treated with platinum-based therapy, MAL may have a role in cisplatin response. We therefore determined the 50% growth inhibitory dose of cisplatin in 30 ovarian cancer cell lines and compared this to MAL expression. MAL transcript levels were higher in the resistant ovarian cell lines (p = 0.04). MAL methylation status may therefore serve as a marker of platinum sensitivity while MAL protein may be a target for development of novel therapies aimed at enhancing sensitivity to platinum-based drugs in ovarian cancer.

Authors
Lee, PS; Teaberry, VS; Bland, AE; Huang, Z; Whitaker, RS; Baba, T; Fujii, S; Secord, AA; Berchuck, A; Murphy, SK
MLA Citation
Lee, PS, Teaberry, VS, Bland, AE, Huang, Z, Whitaker, RS, Baba, T, Fujii, S, Secord, AA, Berchuck, A, and Murphy, SK. "Elevated MAL expression is accompanied by promoter hypomethylation and platinum resistance in epithelial ovarian cancer." Int J Cancer 126.6 (March 15, 2010): 1378-1389.
PMID
19642140
Source
pubmed
Published In
International Journal of Cancer
Volume
126
Issue
6
Publish Date
2010
Start Page
1378
End Page
1389
DOI
10.1002/ijc.24797

Ovarian cancer tumor infiltrating T-regulatory (T(reg)) cells are associated with a metastatic phenotype.

OBJECTIVE: The objective of this study was to examine the clinicopathologic correlates of T-regulatory (T(reg)) cell infiltration in serous ovarian cancers and to define gene signatures associated with high T(reg)s. METHODS: Tumor infiltrating T(reg) and cytotoxic T-cells (CTLs) were quantitated in 232 primary serous ovarian cancers by immunostaining for FOXP3 and CD8. Expression microarray analysis was performed in a subset of 48 advanced cancers with the highest and lowest numbers of infiltrating T(reg)s and a genomic signature was developed using binary regression. ANOVA analysis was performed to assess the most differentially expressed genes and these genes were further assessed using Ingenuity Pathway Analysis (IPA) software. RESULTS: High T(reg) infiltration in ovarian cancers was associated with high grade (p<0.0001), advanced stage (p=0.004) and suboptimal debulking (p<0.04), but not with survival. In contrast, high tumor infiltrating CD8 CTL infiltration was associated with favorable survival (median survival 48.7 vs. 34.6 months, p=0.01). A microarray-based genomic signature for high tumor-infiltrating T(reg) cells had a 77% predictive accuracy using leave-one-out cross-validation. ANOVA of microarray data revealed the antigen presentation pathway as the most differentially expressed canonical pathway (p<0.00001) between cancers with high and low T(reg) cells. CONCLUSIONS: These data suggest that there may be an association between increased T(reg) cell infiltration in ovarian cancers and advanced stage. Increased T(reg) infiltration is characterized by a genomic signature enriched with several immunologic pathway genes. Therapeutic strategies that reduce tumor infiltrating T(reg) cells are under investigation and may prove useful in ovarian cancers with high numbers of these cells.

Authors
Barnett, JC; Bean, SM; Whitaker, RS; Kondoh, E; Baba, T; Fujii, S; Marks, JR; Dressman, HK; Murphy, SK; Berchuck, A
MLA Citation
Barnett, JC, Bean, SM, Whitaker, RS, Kondoh, E, Baba, T, Fujii, S, Marks, JR, Dressman, HK, Murphy, SK, and Berchuck, A. "Ovarian cancer tumor infiltrating T-regulatory (T(reg)) cells are associated with a metastatic phenotype." Gynecol Oncol 116.3 (March 2010): 556-562.
PMID
20006900
Source
pubmed
Published In
Gynecologic Oncology
Volume
116
Issue
3
Publish Date
2010
Start Page
556
End Page
562
DOI
10.1016/j.ygyno.2009.11.020

Gene expression profiling of invasive serous ovarian cancers from formalin-fixed, paraffin-embedded tissues using DASL

Authors
Sfakianos, G; Yamaguchi, K; Murphy, S; Berchuck, A
MLA Citation
Sfakianos, G, Yamaguchi, K, Murphy, S, and Berchuck, A. "Gene expression profiling of invasive serous ovarian cancers from formalin-fixed, paraffin-embedded tissues using DASL." GYNECOLOGIC ONCOLOGY 116.3 (March 2010): S136-S137.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
116
Issue
3
Publish Date
2010
Start Page
S136
End Page
S137

Adverse events associated with laparoscopy versus laparotomy in the treatment of stage I endometrial cancer

Authors
Barnett, J; Havrilesky, L; Flemming, N; Bland, A; Lee, P; Alvarez-Secord, A; Berchuck, A; Valea, F
MLA Citation
Barnett, J, Havrilesky, L, Flemming, N, Bland, A, Lee, P, Alvarez-Secord, A, Berchuck, A, and Valea, F. "Adverse events associated with laparoscopy versus laparotomy in the treatment of stage I endometrial cancer." GYNECOLOGIC ONCOLOGY 116.3 (March 2010): S147-S147.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
116
Issue
3
Publish Date
2010
Start Page
S147
End Page
S147

Projecting the need for gynecologic oncologists for the next 40 years: Not enough, too many or just right?

Authors
Wallace, A; Havrilesky, L; Valea, F; Barnett, J; Berchuck, A; Myers, E
MLA Citation
Wallace, A, Havrilesky, L, Valea, F, Barnett, J, Berchuck, A, and Myers, E. "Projecting the need for gynecologic oncologists for the next 40 years: Not enough, too many or just right?." GYNECOLOGIC ONCOLOGY 116.3 (March 2010): S52-S53.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
116
Issue
3
Publish Date
2010
Start Page
S52
End Page
S53

Genomic SRC signature and SRC protein expression in ovarian cancers may predict response to the SRC inhibitor dasatinib

Authors
Teoh, D; Ayeni, T; Rubatt, J; Adams, D; Grace, L; Starr, M; Dressman, H; Berchuck, A; Alvarez-Secord, A
MLA Citation
Teoh, D, Ayeni, T, Rubatt, J, Adams, D, Grace, L, Starr, M, Dressman, H, Berchuck, A, and Alvarez-Secord, A. "Genomic SRC signature and SRC protein expression in ovarian cancers may predict response to the SRC inhibitor dasatinib." GYNECOLOGIC ONCOLOGY 116.3 (March 2010): S151-S152.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
116
Issue
3
Publish Date
2010
Start Page
S151
End Page
S152

Genomic analysis defines biological pathway differences between early- and advanced-stage ovarian cancers

Authors
Humphrey, M; Chen, N; Xiong, Y; Marchion, D; Bicaku, E; Chon, H; Berchuck, A; Bansal, N; Apte, S; Wenham, R; Lancaster, J
MLA Citation
Humphrey, M, Chen, N, Xiong, Y, Marchion, D, Bicaku, E, Chon, H, Berchuck, A, Bansal, N, Apte, S, Wenham, R, and Lancaster, J. "Genomic analysis defines biological pathway differences between early- and advanced-stage ovarian cancers." GYNECOLOGIC ONCOLOGY 116.3 (March 2010): S22-S22.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
116
Issue
3
Publish Date
2010
Start Page
S22
End Page
S22

Indolent and aggressive phenotypes of epithelial ovarian cancer: Implications for screening

Authors
Havrilesky, L; Sanders, G; Kulasingam, S; Berchuck, A; Dressman, H; Lancaster, J; Marks, J; Myers, E
MLA Citation
Havrilesky, L, Sanders, G, Kulasingam, S, Berchuck, A, Dressman, H, Lancaster, J, Marks, J, and Myers, E. "Indolent and aggressive phenotypes of epithelial ovarian cancer: Implications for screening." GYNECOLOGIC ONCOLOGY 116.3 (March 2010): S107-S107.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
116
Issue
3
Publish Date
2010
Start Page
S107
End Page
S107

A multicenter, randomized, phase II study evaluating the efficacy and safety of combination docetaxel and carboplatin and sequential therapy with docetaxel then carboplatin in patients with recurrent platinum-sensitive ovarian cancer

Authors
Alvarez-Secord, A; Berchuck, A; Higgins, R; Nycum, L; Kohler, M; Puls, L; Holloway, R; Lewandowski, G; Valea, F; Havrilesky, L
MLA Citation
Alvarez-Secord, A, Berchuck, A, Higgins, R, Nycum, L, Kohler, M, Puls, L, Holloway, R, Lewandowski, G, Valea, F, and Havrilesky, L. "A multicenter, randomized, phase II study evaluating the efficacy and safety of combination docetaxel and carboplatin and sequential therapy with docetaxel then carboplatin in patients with recurrent platinum-sensitive ovarian cancer." GYNECOLOGIC ONCOLOGY 116.3 (March 2010): S3-S3.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
116
Issue
3
Publish Date
2010
Start Page
S3
End Page
S3

Variation at 8q24 and 9p24 and risk of epithelial ovarian cancer.

The chromosome 8q24 region (specifically, 8q24.21.a) is known to harbor variants associated with risk of breast, colorectal, prostate, and bladder cancers. In 2008, variants rs10505477 and rs6983267 in this region were associated with increased risk of invasive ovarian cancer (p < 0.01); however, three subsequent ovarian cancer reports of 8q24 variants were null. Here, we used a multi-site case-control study of 940 ovarian cancer cases and 1,041 controls to evaluate associations between these and other single-nucleotide polymorphisms (SNPs) in this 8q24 region, as well as in the 9p24 colorectal cancer associated-region (specifically, 9p24.1.b). A total of 35 SNPs from previous reports and additional tagging SNPs were assessed using an Illumina GoldenGate array and analyzed using logistic regression models, adjusting for population structure and other potential confounders. We observed no association between genotypes and risk of ovarian cancer considering all cases, invasive cases, or invasive serous cases. For example, at 8q24 SNPs rs10505477 and rs6983267, analyses yielded per-allele invasive cancer odds ratios of 0.95 (95% confidence interval (CI) 0.82-1.09, p trend 0.46) and 0.97 (95% CI 0.84-1.12, p trend 0.69), respectively. Analyses using an approach identical to that of the first positive 8q24 report also yielded no association with risk of ovarian cancer. In the 9p24 region, no SNPs were associated with risk of ovarian cancer overall or with invasive or invasive serous disease (all p values > 0.10). These results indicate that the SNPs studied here are not related to risk of this gynecologic malignancy and that the site-specific nature of 8q24.21.a associations may not include ovarian cancer.

Authors
White, KL; Sellers, TA; Fridley, BL; Vierkant, RA; Phelan, CM; Tsai, Y-Y; Kalli, KR; Berchuck, A; Iversen, ES; Hartmann, LC; Liebow, M; Armasu, S; Fredericksen, Z; Larson, MC; Duggan, D; Couch, FJ; Schildkraut, JM; Cunningham, JM; Goode, EL
MLA Citation
White, KL, Sellers, TA, Fridley, BL, Vierkant, RA, Phelan, CM, Tsai, Y-Y, Kalli, KR, Berchuck, A, Iversen, ES, Hartmann, LC, Liebow, M, Armasu, S, Fredericksen, Z, Larson, MC, Duggan, D, Couch, FJ, Schildkraut, JM, Cunningham, JM, and Goode, EL. "Variation at 8q24 and 9p24 and risk of epithelial ovarian cancer." Twin Res Hum Genet 13.1 (February 2010): 43-56.
PMID
20158306
Source
pubmed
Published In
Twin Research & Human Genetics
Volume
13
Issue
1
Publish Date
2010
Start Page
43
End Page
56
DOI
10.1375/twin.13.1.43

Polymorphism in the GALNT1 gene and epithelial ovarian cancer in non-Hispanic white women: the Ovarian Cancer Association Consortium.

Aberrant glycosylation is a well-described hallmark of cancer. In a previous ovarian cancer case control study that examined polymorphisms in 26 glycosylation-associated genes, we found strong statistical evidence (P = 0.00017) that women who inherited two copies of a single-nucleotide polymorphism in the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase, GALNT1, had decreased ovarian cancer risk. The current study attempted to replicate this observation. The GALNT1 single-nucleotide polymorphism rs17647532 was genotyped in 6,965 cases and 8,377 controls from 14 studies forming the Ovarian Cancer Association Consortium. The fixed effects estimate per rs17647532 allele was null (odds ratio, 0.99; 95% confidence interval, 0.92-1.07). When a recessive model was fit, the results were unchanged. Test for heterogeneity of the odds ratios revealed consistency across the 14 replication sites but significant differences compared with the original study population (P = 0.03). This study underscores the need for replication of putative findings in genetic association studies.

Authors
Phelan, CM; Tsai, Y-Y; Goode, EL; Vierkant, RA; Fridley, BL; Beesley, J; Chen, XQ; Webb, PM; Chanock, S; Cramer, DW; Moysich, K; Edwards, RP; Chang-Claude, J; Garcia-Closas, M; Yang, H; Wang-Gohrke, S; Hein, R; Green, AC; Lissowska, J; Carney, ME; Lurie, G; Wilkens, LR; Ness, RB; Pearce, CL; Wu, AH; Van Den Berg, DJ; Stram, DO; Terry, KL; Whiteman, DC; Whittemore, AS; DiCioccio, RA; McGuire, V; Doherty, JA; Rossing, MA; Anton-Culver, H; Ziogas, A; Hogdall, C; Hogdall, E; Krüger Kjaer, S et al.
MLA Citation
Phelan, CM, Tsai, Y-Y, Goode, EL, Vierkant, RA, Fridley, BL, Beesley, J, Chen, XQ, Webb, PM, Chanock, S, Cramer, DW, Moysich, K, Edwards, RP, Chang-Claude, J, Garcia-Closas, M, Yang, H, Wang-Gohrke, S, Hein, R, Green, AC, Lissowska, J, Carney, ME, Lurie, G, Wilkens, LR, Ness, RB, Pearce, CL, Wu, AH, Van Den Berg, DJ, Stram, DO, Terry, KL, Whiteman, DC, Whittemore, AS, DiCioccio, RA, McGuire, V, Doherty, JA, Rossing, MA, Anton-Culver, H, Ziogas, A, Hogdall, C, Hogdall, E, and Krüger Kjaer, S et al. "Polymorphism in the GALNT1 gene and epithelial ovarian cancer in non-Hispanic white women: the Ovarian Cancer Association Consortium." Cancer Epidemiol Biomarkers Prev 19.2 (February 2010): 600-604.
PMID
20142253
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
19
Issue
2
Publish Date
2010
Start Page
600
End Page
604
DOI
10.1158/1055-9965.EPI-09-0861

Risk of ovarian cancer and inherited variants in relapse-associated genes.

BACKGROUND: We previously identified a panel of genes associated with outcome of ovarian cancer. The purpose of the current study was to assess whether variants in these genes correlated with ovarian cancer risk. METHODS AND FINDINGS: Women with and without invasive ovarian cancer (749 cases, 1,041 controls) were genotyped at 136 single nucleotide polymorphisms (SNPs) within 13 candidate genes. Risk was estimated for each SNP and for overall variation within each gene. At the gene-level, variation within MSL1 (male-specific lethal-1 homolog) was associated with risk of serous cancer (p = 0.03); haplotypes within PRPF31 (PRP31 pre-mRNA processing factor 31 homolog) were associated with risk of invasive disease (p = 0.03). MSL1 rs7211770 was associated with decreased risk of serous disease (OR 0.81, 95% CI 0.66-0.98; p = 0.03). SNPs in MFSD7, BTN3A3, ZNF200, PTPRS, and CCND1A were inversely associated with risk (p<0.05), and there was increased risk at HEXIM1 rs1053578 (p = 0.04, OR 1.40, 95% CI 1.02-1.91). CONCLUSIONS: Tumor studies can reveal novel genes worthy of follow-up for cancer susceptibility. Here, we found that inherited markers in the gene encoding MSL1, part of a complex that modifies the histone H4, may decrease risk of invasive serous ovarian cancer.

Authors
Peedicayil, A; Vierkant, RA; Hartmann, LC; Fridley, BL; Fredericksen, ZS; White, KL; Elliott, EA; Phelan, CM; Tsai, Y-Y; Berchuck, A; Iversen, ES; Couch, FJ; Peethamabaran, P; Larson, MC; Kalli, KR; Kosel, ML; Shridhar, V; Rider, DN; Liebow, M; Cunningham, JM; Schildkraut, JM; Sellers, TA; Goode, EL
MLA Citation
Peedicayil, A, Vierkant, RA, Hartmann, LC, Fridley, BL, Fredericksen, ZS, White, KL, Elliott, EA, Phelan, CM, Tsai, Y-Y, Berchuck, A, Iversen, ES, Couch, FJ, Peethamabaran, P, Larson, MC, Kalli, KR, Kosel, ML, Shridhar, V, Rider, DN, Liebow, M, Cunningham, JM, Schildkraut, JM, Sellers, TA, and Goode, EL. "Risk of ovarian cancer and inherited variants in relapse-associated genes. (Published online)" PLoS One 5.1 (January 27, 2010): e8884-.
Website
http://hdl.handle.net/10161/4525
PMID
20111712
Source
pubmed
Published In
PloS one
Volume
5
Issue
1
Publish Date
2010
Start Page
e8884
DOI
10.1371/journal.pone.0008884

High poly(adenosine diphosphate-ribose) polymerase expression and poor survival in advanced-stage serous ovarian cancer.

OBJECTIVE: To estimate the range of poly(adenosine diphosphate [ADP]-ribose) polymerase expression in serous ovarian cancers and to determine whether expression is associated with response to therapy and outcome. METHODS: Immunostaining for poly(ADP-ribose) polymerase was performed in 186 paraffin-embedded, serous ovarian cancers. Nuclear poly(ADP-ribose) polymerase expression was quantified using a scoring system that assesses both staining intensity and percentage of cells staining. Kaplan-Meier analysis was performed to evaluate the relationship between poly(ADP-ribose) polymerase expression and overall survival. RESULTS: High poly(ADP-ribose) polymerase expression was present in 54% of serous cancers but was not associated with stage or grade. There was no difference in the rate of complete clinical response to primary chemotherapy between cases with low poly(ADP-ribose) polymerase expression (70%) compared with those with high poly(ADP-ribose) polymerase expression (71%). However, high poly(ADP-ribose) polymerase expression was associated with significantly worse median overall survival (36 compared with 43 months, P=.04, hazard ratio 0.71). CONCLUSION: Expression of poly(ADP-ribose) polymerase in ovarian cancers is heterogeneous, and high expression in serous ovarian cancers is associated with worse overall survival. These data suggest that evaluation of poly(ADP-ribose) polymerase expression in the primary cancer could potentially allow selective use of poly(ADP-ribose) polymerase inhibitors in patients most likely to respond. LEVEL OF EVIDENCE: III.

Authors
Barnett, JC; Bean, SM; Nakayama, JM; Kondoh, E; Murphy, SK; Berchuck, A
MLA Citation
Barnett, JC, Bean, SM, Nakayama, JM, Kondoh, E, Murphy, SK, and Berchuck, A. "High poly(adenosine diphosphate-ribose) polymerase expression and poor survival in advanced-stage serous ovarian cancer." Obstet Gynecol 115.1 (January 2010): 49-54.
PMID
20027033
Source
pubmed
Published In
Obstetrics and Gynecology
Volume
115
Issue
1
Publish Date
2010
Start Page
49
End Page
54
DOI
10.1097/AOG.0b013e3181c2d294

ESR1/SYNE1 polymorphism and invasive epithelial ovarian cancer risk: an Ovarian Cancer Association Consortium study.

We genotyped 13 single nucleotide polymorphisms (SNPs) in the estrogen receptor alpha gene (ESR1) region in three population-based case-control studies of epithelial ovarian cancer conducted in the United States, comprising a total of 1,128 and 1,866 non-Hispanic white invasive cases and controls, respectively. A SNP 19 kb downstream of ESR1 (rs2295190, G-to-T change) was associated with invasive ovarian cancer risk, with a per-T-allele odds ratio (OR) of 1.24 [95% confidence interval (CI), 1.06-1.44, P = 0.006]. rs2295190 is a nonsynonymous coding SNP in a neighboring gene called spectrin repeat containing, nuclear envelope 1 (SYNE1), which is involved in nuclear organization and structural integrity, function of the Golgi apparatus, and cytokinesis. An isoform encoded by SYNE1 has been reported to be downregulated in ovarian and other cancers. rs2295190 was genotyped in an additional 12 studies through the Ovarian Cancer Association Consortium, with 5,279 invasive epithelial cases and 7,450 controls. The per-T-allele OR for this 12-study set was 1.09 (95% CI, 1.02-1.17; P = 0.017). Results for the serous subtype in the 15 combined studies were similar to those overall (n = 3,545; OR, 1.09; 95% CI, 1.01-1.18; P = 0.025), and our findings were strongest for the mucinous subtype (n = 447; OR, 1.32; 95% CI, 1.11-1.58; P = 0.002). No association was observed for the endometrioid subtype. In an additional analysis of 1,459 borderline ovarian cancer cases and 7,370 controls, rs2295190 was not associated with risk. These data provide suggestive evidence that the rs2295190 T allele, or another allele in linkage disequilibrium with it, may be associated with increased risk of invasive ovarian cancer.

Authors
Doherty, JA; Rossing, MA; Cushing-Haugen, KL; Chen, C; Van Den Berg, DJ; Wu, AH; Pike, MC; Ness, RB; Moysich, K; Chenevix-Trench, G; Beesley, J; Webb, PM; Chang-Claude, J; Wang-Gohrke, S; Goodman, MT; Lurie, G; Thompson, PJ; Carney, ME; Hogdall, E; Kjaer, SK; Hogdall, C; Goode, EL; Cunningham, JM; Fridley, BL; Vierkant, RA; Berchuck, A; Moorman, PG; Schildkraut, JM; Palmieri, RT; Cramer, DW; Terry, KL; Yang, HP; Garcia-Closas, M; Chanock, S; Lissowska, J; Song, H; Pharoah, PDP; Shah, M et al.
MLA Citation
Doherty, JA, Rossing, MA, Cushing-Haugen, KL, Chen, C, Van Den Berg, DJ, Wu, AH, Pike, MC, Ness, RB, Moysich, K, Chenevix-Trench, G, Beesley, J, Webb, PM, Chang-Claude, J, Wang-Gohrke, S, Goodman, MT, Lurie, G, Thompson, PJ, Carney, ME, Hogdall, E, Kjaer, SK, Hogdall, C, Goode, EL, Cunningham, JM, Fridley, BL, Vierkant, RA, Berchuck, A, Moorman, PG, Schildkraut, JM, Palmieri, RT, Cramer, DW, Terry, KL, Yang, HP, Garcia-Closas, M, Chanock, S, Lissowska, J, Song, H, Pharoah, PDP, and Shah, M et al. "ESR1/SYNE1 polymorphism and invasive epithelial ovarian cancer risk: an Ovarian Cancer Association Consortium study." Cancer Epidemiol Biomarkers Prev 19.1 (January 2010): 245-250.
PMID
20056644
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
19
Issue
1
Publish Date
2010
Start Page
245
End Page
250
DOI
10.1158/1055-9965.EPI-09-0729

Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "Hot-Spot"

We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n = 675) and controls (n = 1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n = 1,233 serous invasive cases; n = 3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. Pper-allele≥0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele = 0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p = 0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus. © 2010 Johnatty et al.

Authors
Johnatty, SE; Beesley, J; Chen, X; Macgregor, S; Duffy, DL; Spurdle, AB; Fazio, AD; Gava, N; Webb, PM; Rossing, MA; Doherty, JA; Goodman, MT; Lurie, G; Thompson, PJ; Wilkens, LR; Ness, RB; Moysich, KB; Chang-Claude, J; Wang-Gohrke, S; Cramer, DW; Terry, KL; Hankinson, SE; Tworoger, SS; Garcia-Closas, M; Yang, H; Lissowska, J; Chanock, SJ; Pharoah, PD; Song, H; Whitemore, AS; Pearce, CL; Stram, DO; Wu, AH; Pike, MC; Gayther, SA; Ramus, SJ; Menon, U; Gentry-Maharaj, A; Anton-Culver, H; Ziogas, A et al.
MLA Citation
Johnatty, SE, Beesley, J, Chen, X, Macgregor, S, Duffy, DL, Spurdle, AB, Fazio, AD, Gava, N, Webb, PM, Rossing, MA, Doherty, JA, Goodman, MT, Lurie, G, Thompson, PJ, Wilkens, LR, Ness, RB, Moysich, KB, Chang-Claude, J, Wang-Gohrke, S, Cramer, DW, Terry, KL, Hankinson, SE, Tworoger, SS, Garcia-Closas, M, Yang, H, Lissowska, J, Chanock, SJ, Pharoah, PD, Song, H, Whitemore, AS, Pearce, CL, Stram, DO, Wu, AH, Pike, MC, Gayther, SA, Ramus, SJ, Menon, U, Gentry-Maharaj, A, Anton-Culver, H, and Ziogas, A et al. "Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "Hot-Spot"." PLoS Genetics 6.7 (2010): 1-10.
Source
scival
Published In
PLoS genetics
Volume
6
Issue
7
Publish Date
2010
Start Page
1
End Page
10
DOI
10.1371/journal.pgen.1001016

Secondary Malignancy after Radiation for Endometrial Cancer: Comparing No Radiation, External Beam, and Brachytherapy

Authors
Chino, JP; Havrilesky, L; Berchuck, A; Jones, E
MLA Citation
Chino, JP, Havrilesky, L, Berchuck, A, and Jones, E. "Secondary Malignancy after Radiation for Endometrial Cancer: Comparing No Radiation, External Beam, and Brachytherapy." 2010.
Source
wos-lite
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
78
Issue
3
Publish Date
2010
Start Page
S404
End Page
S404

Association between the N-terminally truncated (DeltaN) p63alpha (DeltaNp63alpha) isoform and debulking status, VEGF expression and progression-free survival in previously untreated, advanced stage epithelial ovarian cancer: A Gynecologic Oncology Group study.

OBJECTIVES: The Gynecologic Oncology Group (GOG) examined the association between the relative expression of the DeltaNp63alpha isoform and clinicopathologic variables, p53 status, angiogenic markers, progression-free survival (PFS) and overall survival (OS) in epithelial ovarian cancer (EOC). METHODS: Immunoblot analysis was used to determine the relative expression of DeltaNp63alpha to beta-actin in lysates of frozen primary tumor from women with previously untreated, advanced stage EOC who participated in a GOG specimen banking protocol and a randomized phase III treatment protocol. RESULTS: DeltaNp63alpha was detected in 49/56 (87.5%) cases with relative expression ranging from 0 to 4.55 (median=0.325). A correlation was observed between the relative expression of DeltaNp63alpha and debulking status (Spearman's correlation coefficient=0.303; p=0.025) and the relative expression of vascular endothelial growth factor (VEGF) (Spearman's correlation coefficient=0.303; p=0.045), but not with p53 status (overexpression or mutation), immunoblot expression of MASPIN, or the relative expression of thrombospondin-1, basic fibroblast growth factor or VEGF receptor-1. A 1.4-fold increase was observed in the risk of disease progression for each unit increase in the relative expression of DeltaNp63alpha using an unadjusted (hazard ratio [HR]=1.459; 95% confidence interval [CI]=1.096-1.942; p=0.010), a full (HR=1.483; 95% CI=1.060-2.076; p=0.021) and a reduced (HR=1.387; 95% CI=1.025-1.877; p=0.034) Cox regression model. The relative expression of DeltaNp63alpha was not associated with OS using an unadjusted, a full or a reduced Cox model. CONCLUSIONS: The relative expression DeltaNp63alpha appears to be associated with debulking status and the relative expression of VEGF and PFS, and to be an independent prognostic factor for disease progression in EOC.

Authors
Jewell, EL; Darcy, KM; Hutson, A; Lee, PS; Havrilesky, LJ; Grace, LA; Berchuck, A; Secord, AA
MLA Citation
Jewell, EL, Darcy, KM, Hutson, A, Lee, PS, Havrilesky, LJ, Grace, LA, Berchuck, A, and Secord, AA. "Association between the N-terminally truncated (DeltaN) p63alpha (DeltaNp63alpha) isoform and debulking status, VEGF expression and progression-free survival in previously untreated, advanced stage epithelial ovarian cancer: A Gynecologic Oncology Group study." Gynecol Oncol 115.3 (December 2009): 424-429.
PMID
19767063
Source
pubmed
Published In
Gynecologic Oncology
Volume
115
Issue
3
Publish Date
2009
Start Page
424
End Page
429
DOI
10.1016/j.ygyno.2009.07.035

Cell cycle genes and ovarian cancer susceptibility: a tagSNP analysis.

BACKGROUND: Dysregulation of the cell cycle is a hallmark of many cancers including ovarian cancer, a leading cause of gynaecologic cancer mortality worldwide. METHODS: We examined single nucleotide polymorphisms (SNPs) (n=288) from 39 cell cycle regulation genes, including cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors, in a two-stage study. White, non-Hispanic cases (n=829) and ovarian cancer-free controls (n=941) were genotyped using an Illumina assay. RESULTS: Eleven variants in nine genes (ABL1, CCNB2, CDKN1A, CCND3, E2F2, CDK2, E2F3, CDC2, and CDK7) were associated with risk of ovarian cancer in at least one genetic model. Seven SNPs were then assessed in four additional studies with 1689 cases and 3398 controls. Association between risk of ovarian cancer and ABL1 rs2855192 found in the original population [odds ratio, OR(BB vs AA) 2.81 (1.29-6.09), P=0.01] was also observed in a replication population, and the association remained suggestive in the combined analysis [OR(BB vs AA) 1.59 (1.08-2.34), P=0.02]. No other SNP associations remained suggestive in the replication populations. CONCLUSION: ABL1 has been implicated in multiple processes including cell division, cell adhesion and cellular stress response. These results suggest that characterization of the function of genetic variation in this gene in other ovarian cancer populations is warranted.

Authors
Cunningham, JM; Vierkant, RA; Sellers, TA; Phelan, C; Rider, DN; Liebow, M; Schildkraut, J; Berchuck, A; Couch, FJ; Wang, X; Fridley, BL; Ovarian Cancer Association Consortium, ; Gentry-Maharaj, A; Menon, U; Hogdall, E; Kjaer, S; Whittemore, A; DiCioccio, R; Song, H; Gayther, SA; Ramus, SJ; Pharaoh, PDP; Goode, EL
MLA Citation
Cunningham, JM, Vierkant, RA, Sellers, TA, Phelan, C, Rider, DN, Liebow, M, Schildkraut, J, Berchuck, A, Couch, FJ, Wang, X, Fridley, BL, Ovarian Cancer Association Consortium, , Gentry-Maharaj, A, Menon, U, Hogdall, E, Kjaer, S, Whittemore, A, DiCioccio, R, Song, H, Gayther, SA, Ramus, SJ, Pharaoh, PDP, and Goode, EL. "Cell cycle genes and ovarian cancer susceptibility: a tagSNP analysis." Br J Cancer 101.8 (October 20, 2009): 1461-1468.
PMID
19738611
Source
pubmed
Published In
British Journal of Cancer
Volume
101
Issue
8
Publish Date
2009
Start Page
1461
End Page
1468
DOI
10.1038/sj.bjc.6605284

Robotic-assisted laparoscopic gynecologic procedures in a fellowship training program.

BACKGROUND AND OBJECTIVE: The robotic surgical platform is an alternative technique to traditional laparoscopy and requires the development of new surgical skills for both the experienced surgeon and trainee. Our goal was to perform an early evaluation of the feasibility of training fellows in robotic-assisted gynecologic procedures at the outset of our incorporation of this technology into clinical practice. METHODS: A systematic approach to fellow training included (1) didactic and hands-on training with the robotic system, (2) instructional videos, (3) assistance at the operating table, and (4) performance of segments of gynecologic procedures in tandem with the attending physician. Time to complete the entire procedure, individual segments, rate of conversion to laparotomy, and complications were recorded. RESULTS: Twenty-one robotic-assisted gynecologic procedures were performed from April 2006 to January 2007. Fellows participated as the console surgeon in 14/21 cases. Thirteen patients (62%) had prior abdominal surgery. Median values with ranges were age 51 years (range, 33 to 90); BMI 28 (range, 19.4 to 43.8); EBL 25 mL (range, 25 to 250); and hospital stay 1 day (range, 1 to 4). No significant difference existed between fellow and attending mean total operative and individual segment times. One conversion to laparotomy was necessary. No major surgical complications occurred. CONCLUSION: These data suggest that it is feasible to incorporate a systematic approach to robotic-assisted laparoscopic training for trainees at the outset of incorporation of this technology into current practice.

Authors
Lee, PS; Bland, A; Valea, FA; Havrilesky, LJ; Berchuck, A; Secord, AA
MLA Citation
Lee, PS, Bland, A, Valea, FA, Havrilesky, LJ, Berchuck, A, and Secord, AA. "Robotic-assisted laparoscopic gynecologic procedures in a fellowship training program." JSLS 13.4 (October 2009): 467-472.
PMID
20202385
Source
pubmed
Published In
JSLS : Journal of the Society of Laparoendoscopic Surgeons / Society of Laparoendoscopic Surgeons
Volume
13
Issue
4
Publish Date
2009
Start Page
467
End Page
472
DOI
10.4293/108680809X12589998403921

Ovarian cancer risk factors in African-American and white women.

Ovarian cancer is the most lethal gynecologic malignancy in both African-American and white women. Although prevalences of many ovarian cancer risk factors differ markedly between African Americans and whites, there has been little research on how the relative contributions of risk factors may vary between racial/ethnic groups. Using data from a North Carolina case-control study (1999-2008), the authors conducted unconditional logistic regression analyses to calculate odds ratios and 95% confidence intervals for ovarian cancer risk factors in African-American (143 cases, 189 controls) and white (943 cases, 868 controls) women and to test for interactions by race/ethnicity. They also calculated attributable fractions within each racial/ethnic group for the modifiable factors of pregnancy, oral contraceptive use, tubal ligation, and body mass index. Many risk factors showed similar relations across racial/ethnic groups, but tubal ligation and family history of breast or ovarian cancer showed stronger associations among African Americans. Younger age at menarche was associated with risk only in white women. Attributable fractions associated with tubal ligation, oral contraceptive use, and obesity were markedly higher for African Americans. The relative importance of ovarian cancer risk factors may differ for African-American women, but conclusions were limited by the small sample. There is a clear need for further research on etiologic factors for ovarian cancer in African-American women.

Authors
Moorman, PG; Palmieri, RT; Akushevich, L; Berchuck, A; Schildkraut, JM
MLA Citation
Moorman, PG, Palmieri, RT, Akushevich, L, Berchuck, A, and Schildkraut, JM. "Ovarian cancer risk factors in African-American and white women." Am J Epidemiol 170.5 (September 1, 2009): 598-606.
PMID
19605513
Source
pubmed
Published In
American Journal of Epidemiology
Volume
170
Issue
5
Publish Date
2009
Start Page
598
End Page
606
DOI
10.1093/aje/kwp176

A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2.

Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk. We performed a genome-wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817 cases and 2,353 controls from the UK and approximately 2 million imputed SNPs. We genotyped the 22,790 top ranked SNPs in 4,274 cases and 4,809 controls of European ancestry from Europe, USA and Australia. We identified 12 SNPs at 9p22 associated with disease risk (P < 10(-8)). The most significant SNP (rs3814113; P = 2.5 x 10(-17)) was genotyped in a further 2,670 ovarian cancer cases and 4,668 controls, confirming its association (combined data odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.79-0.86, P(trend) = 5.1 x 10(-19)). The association differs by histological subtype, being strongest for serous ovarian cancers (OR 0.77, 95% CI 0.73-0.81, P(trend) = 4.1 x 10(-21)).

Authors
Song, H; Ramus, SJ; Tyrer, J; Bolton, KL; Gentry-Maharaj, A; Wozniak, E; Anton-Culver, H; Chang-Claude, J; Cramer, DW; DiCioccio, R; Dörk, T; Goode, EL; Goodman, MT; Schildkraut, JM; Sellers, T; Baglietto, L; Beckmann, MW; Beesley, J; Blaakaer, J; Carney, ME; Chanock, S; Chen, Z; Cunningham, JM; Dicks, E; Doherty, JA; Dürst, M; Ekici, AB; Fenstermacher, D; Fridley, BL; Giles, G; Gore, ME; De Vivo, I; Hillemanns, P; Hogdall, C; Hogdall, E; Iversen, ES; Jacobs, IJ; Jakubowska, A; Li, D et al.
MLA Citation
Song, H, Ramus, SJ, Tyrer, J, Bolton, KL, Gentry-Maharaj, A, Wozniak, E, Anton-Culver, H, Chang-Claude, J, Cramer, DW, DiCioccio, R, Dörk, T, Goode, EL, Goodman, MT, Schildkraut, JM, Sellers, T, Baglietto, L, Beckmann, MW, Beesley, J, Blaakaer, J, Carney, ME, Chanock, S, Chen, Z, Cunningham, JM, Dicks, E, Doherty, JA, Dürst, M, Ekici, AB, Fenstermacher, D, Fridley, BL, Giles, G, Gore, ME, De Vivo, I, Hillemanns, P, Hogdall, C, Hogdall, E, Iversen, ES, Jacobs, IJ, Jakubowska, A, and Li, D et al. "A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2." Nat Genet 41.9 (September 2009): 996-1000.
PMID
19648919
Source
pubmed
Published In
Nature Genetics
Volume
41
Issue
9
Publish Date
2009
Start Page
996
End Page
1000
DOI
10.1038/ng.424

MLH1 expression sensitises ovarian cancer cells to cell death mediated by XIAP inhibition.

BACKGROUND: The X-linked inhibitor of apoptosis protein (XIAP), an endogenous apoptosis suppressor, can determine the level of caspase accumulation and the resultant response to apoptosis-inducing agents such as cisplatin in epithelial ovarian cancer (EOC). In addition, the mismatch repair protein, hMLH1, has been linked to DNA damage-induced apoptosis by cisplatin by both p53-dependent and -independent mechanisms. METHODS: In this study, hMLH1 expression was correlated with clinical response to platinum drugs and survival in advanced stage (III-IV) EOC patients. We then investigated whether MLH1 loss was a determinant in anti-apoptosis response to cisplatin mediated by XIAP in isogenic and established EOC cell lines with differential p53 status. RESULTS: The percentage of cells undergoing cisplatin-induced cell killing was higher in MLH1-proficient cells than in MLH1-defective cells. In addition, the presence of wild-type hMLH1 or hMLH1 re-expression significantly increased sensitivity to 6-thioguanine, a MMR-dependent agent. Cell-death response to 6-thioguanine and cisplatin was associated with significant proteolysis of MLH1, with XIAP destabilisation and increased caspase-3 activity. The siRNA-mediated inhibition of XIAP increased MLH1 proteolysis and cell death in MLH1-proficient cells but not in MLH1-defective cells. CONCLUSION: These data suggest that XIAP inhibitors may prove to be an effective means of sensitising EOC to MLH1-dependent apoptosis.

Authors
Ding, X; Mohd, AB; Huang, Z; Baba, T; Bernardini, MQ; Lyerly, HK; Berchuck, A; Murphy, SK; Buermeyer, AB; Devi, GR
MLA Citation
Ding, X, Mohd, AB, Huang, Z, Baba, T, Bernardini, MQ, Lyerly, HK, Berchuck, A, Murphy, SK, Buermeyer, AB, and Devi, GR. "MLH1 expression sensitises ovarian cancer cells to cell death mediated by XIAP inhibition." Br J Cancer 101.2 (July 21, 2009): 269-277.
PMID
19603033
Source
pubmed
Published In
British Journal of Cancer
Volume
101
Issue
2
Publish Date
2009
Start Page
269
End Page
277
DOI
10.1038/sj.bjc.6605180

Evaluation of two management strategies for preoperative grade 1 endometrial cancer.

OBJECTIVE: To compare the practices, adjuvant treatment, and outcomes of patients with preoperatively assessed grade 1 endometrioid endometrial cancer between two academic gynecologic oncology centers that use different treatment strategies. METHODS: A retrospective analysis was performed at Duke University Medical Center (Duke) and the Toronto Sunnybrook Regional Cancer Center (Sunnybrook) between 1991 and 2007. Patients at Duke generally underwent surgical staging unless intraoperative assessment identified a negligible risk of nodal disease. Patients at Sunnybrook generally did not undergo surgical staging. RESULTS: A total of 494 patients (272 from Duke and 222 from Sunnybrook were identified with preoperative, central-review-confirming, grade 1, endometrioid, endometrial cancer. Groups were similar in grade, final histology, type of hysterectomy, and length of hospital stay. Patients from Sunnybrook were older (aged 62 years compared with 59 years, P=.001) and were more likely to have capillary lymphatic space involvement (18.2% compared with 8.3%, P=.003) and cervical involvement (12.2% compared with 3.7%, P<.001). Approximately 2% of cases were upgraded to high grade on final specimen. Lymphadenectomy was performed on 49.4% of patients at Duke compared with 11.7% of patients at Sunnybrook. Overall 3-year survival was 96% at Duke and 96% at Sunnybrook (P=.217). Three-year recurrence-free survival was 96% at Duke and 95% at Sunnybrook (P=.327). CONCLUSION: Despite differences in practice and slight differences in patient populations, the recurrence-free and overall survival of women with preoperative centrally reviewed grade 1 endometrial cancer is excellent and without statistically significant difference between the two centers. LEVEL OF EVIDENCE: III

Authors
Bernardini, MQ; May, T; Khalifa, MA; Bland, AE; Nofech-Mozes, S; Berchuck, A; Covens, A; Havrilesky, L
MLA Citation
Bernardini, MQ, May, T, Khalifa, MA, Bland, AE, Nofech-Mozes, S, Berchuck, A, Covens, A, and Havrilesky, L. "Evaluation of two management strategies for preoperative grade 1 endometrial cancer." Obstet Gynecol 114.1 (July 2009): 7-15.
PMID
19546752
Source
pubmed
Published In
Obstetrics & Gynecology (Elsevier)
Volume
114
Issue
1
Publish Date
2009
Start Page
7
End Page
15
DOI
10.1097/AOG.0b013e3181aa97fc

Microarray analysis of gene expression in gynecologic cancers--still only the beginning.

Authors
Berchuck, A
MLA Citation
Berchuck, A. "Microarray analysis of gene expression in gynecologic cancers--still only the beginning." Gynecol Oncol 114.1 (July 2009): 1-2.
PMID
19497432
Source
pubmed
Published In
Gynecologic Oncology
Volume
114
Issue
1
Publish Date
2009
Start Page
1
End Page
2
DOI
10.1016/j.ygyno.2009.05.002

Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study.

Because both ovarian and breast cancer are hormone-related and are known to have some predisposition genes in common, we evaluated 11 of the most significant hits (six with confirmed associations with breast cancer) from the breast cancer genome-wide association study for association with invasive ovarian cancer. Eleven SNPs were initially genotyped in 2927 invasive ovarian cancer cases and 4143 controls from six ovarian cancer case-control studies. Genotype frequencies in cases and controls were compared using a likelihood ratio test in a logistic regression model stratified by study. Initially, three SNPs (rs2107425 in MRPL23, rs7313833 in PTHLH, rs3803662 in TNRC9) were weakly associated with ovarian cancer risk and one SNP (rs4954956 in NXPH2) was associated with serous ovarian cancer in non-Hispanic white subjects (P-trend < 0.1). These four SNPs were then genotyped in an additional 4060 cases and 6308 controls from eight independent studies. Only rs4954956 was significantly associated with ovarian cancer risk both in the replication study and in combined analyses. This association was stronger for the serous histological subtype [per minor allele odds ratio (OR) 1.07 95% CI 1.01-1.13, P-trend = 0.02 for all types of ovarian cancer and OR 1.14 95% CI 1.07-1.22, P-trend = 0.00017 for serous ovarian cancer]. In conclusion, we found that rs4954956 was associated with increased ovarian cancer risk, particularly for serous ovarian cancer. However, none of the six confirmed breast cancer susceptibility variants we tested was associated with ovarian cancer risk. Further work will be needed to identify the causal variant associated with rs4954956 or elucidate its function.

Authors
Song, H; Ramus, SJ; Kjaer, SK; DiCioccio, RA; Chenevix-Trench, G; Pearce, CL; Hogdall, E; Whittemore, AS; McGuire, V; Hogdall, C; Blaakaer, J; Wu, AH; Van Den Berg, DJ; Stram, DO; Menon, U; Gentry-Maharaj, A; Jacobs, IJ; Webb, PM; Beesley, J; Chen, X; Australian Cancer (Ovarian) Study, ; Australian Ovarian Cancer Study Group, ; Rossing, MA; Doherty, JA; Chang-Claude, J; Wang-Gohrke, S; Goodman, MT; Lurie, G; Thompson, PJ; Carney, ME; Ness, RB; Moysich, K; Goode, EL; Vierkant, RA; Cunningham, JM et al.
MLA Citation
Song, H, Ramus, SJ, Kjaer, SK, DiCioccio, RA, Chenevix-Trench, G, Pearce, CL, Hogdall, E, Whittemore, AS, McGuire, V, Hogdall, C, Blaakaer, J, Wu, AH, Van Den Berg, DJ, Stram, DO, Menon, U, Gentry-Maharaj, A, Jacobs, IJ, Webb, PM, Beesley, J, Chen, X, Australian Cancer (Ovarian) Study, , Australian Ovarian Cancer Study Group, , Rossing, MA, Doherty, JA, Chang-Claude, J, Wang-Gohrke, S, Goodman, MT, Lurie, G, Thompson, PJ, Carney, ME, Ness, RB, Moysich, K, Goode, EL, Vierkant, RA, and Cunningham, JM et al. "Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study." Hum Mol Genet 18.12 (June 15, 2009): 2297-2304.
PMID
19304784
Source
pubmed
Published In
Human Molecular Genetics
Volume
18
Issue
12
Publish Date
2009
Start Page
2297
End Page
2304
DOI
10.1093/hmg/ddp138

UCN-01 is effective in targeting ovarian cancer spheroids

Authors
Kondoh, E; Baba, T; Matsumura, N; Konishi, I; Fujii, S; Berchuck, A; Murphy, S
MLA Citation
Kondoh, E, Baba, T, Matsumura, N, Konishi, I, Fujii, S, Berchuck, A, and Murphy, S. "UCN-01 is effective in targeting ovarian cancer spheroids." CANCER RESEARCH 69 (May 1, 2009).
Source
wos-lite
Published In
Cancer Research
Volume
69
Publish Date
2009

CTCF binding at a novel intragenic binding site is associated with elevated IGF2 expression in serous epithelial ovarian cancer

Authors
Huang, Z; Wen, Y; Simel, L; Price, T; Berchuck, A; Murphy, SK
MLA Citation
Huang, Z, Wen, Y, Simel, L, Price, T, Berchuck, A, and Murphy, SK. "CTCF binding at a novel intragenic binding site is associated with elevated IGF2 expression in serous epithelial ovarian cancer." CANCER RESEARCH 69 (May 1, 2009).
Source
wos-lite
Published In
Cancer Research
Volume
69
Publish Date
2009

Association between serous invasive ovarian cancer and variants in candidate DNA damage response genes

Authors
Schildkraut, J; Iversen, E; Marks, J; Wilson, M; Clyde, M; Palmieri, R; Moorman, P; Berchuck, A
MLA Citation
Schildkraut, J, Iversen, E, Marks, J, Wilson, M, Clyde, M, Palmieri, R, Moorman, P, and Berchuck, A. "Association between serous invasive ovarian cancer and variants in candidate DNA damage response genes." CANCER RESEARCH 69 (May 1, 2009).
Source
wos-lite
Published In
Cancer Research
Volume
69
Publish Date
2009

In vitro characterization of the antitumor effects of dasatinib (BMS-354825) in combination with paclitaxel and carboplatin in human ovarian cancer cell lines

Authors
Teoh, D; Ayeni, T; Rubatt, J; Whitaker, R; Dressman, H; Berchuck, A; Secord, A
MLA Citation
Teoh, D, Ayeni, T, Rubatt, J, Whitaker, R, Dressman, H, Berchuck, A, and Secord, A. "In vitro characterization of the antitumor effects of dasatinib (BMS-354825) in combination with paclitaxel and carboplatin in human ovarian cancer cell lines." CANCER RESEARCH 69 (May 1, 2009).
Source
wos-lite
Published In
Cancer Research
Volume
69
Publish Date
2009

Microarray analysis of early stage serous ovarian cancers shows profiles predictive of favorable outcome.

PURPOSE: Although few women with advanced serous ovarian cancer are cured, detection of the disease at an early stage is associated with a much higher likelihood of survival. We previously used gene expression array analysis to distinguish subsets of advanced cancers based on disease outcome. In the present study, we report on gene expression of early-stage cancers and validate our prognostic model for advanced-stage cancers. EXPERIMENTAL DESIGN: Frozen specimens from 39 stage I/II, 42 stage III/IV, and 20 low malignant potential cancers were obtained from four different sites. A linear discriminant model was used to predict survival based upon array data. RESULTS: We validated the late-stage survival model and show that three of the most differentially expressed genes continue to be predictive of outcome. Most early-stage cancers (38 of 39 invasive, 15 of 20 low malignant potential) were classified as long-term survivors (median probabilities 0.97 and 0.86). MAL, the most differentially expressed gene, was further validated at the protein level and found to be an independent predictor of poor survival in an unselected group of advanced serous cancers (P = 0.0004). CONCLUSIONS: These data suggest that serous ovarian cancers detected at an early stage generally have a favorable underlying biology similar to advanced-stage cases that are long-term survivors. Conversely, most late-stage ovarian cancers seem to have a more virulent biology. This insight suggests that if screening approaches are to succeed it will be necessary to develop approaches that are able to detect these virulent cancers at an early stage.

Authors
Berchuck, A; Iversen, ES; Luo, J; Clarke, JP; Horne, H; Levine, DA; Boyd, J; Alonso, MA; Secord, AA; Bernardini, MQ; Barnett, JC; Boren, T; Murphy, SK; Dressman, HK; Marks, JR; Lancaster, JM
MLA Citation
Berchuck, A, Iversen, ES, Luo, J, Clarke, JP, Horne, H, Levine, DA, Boyd, J, Alonso, MA, Secord, AA, Bernardini, MQ, Barnett, JC, Boren, T, Murphy, SK, Dressman, HK, Marks, JR, and Lancaster, JM. "Microarray analysis of early stage serous ovarian cancers shows profiles predictive of favorable outcome." Clin Cancer Res 15.7 (April 1, 2009): 2448-2455.
PMID
19318476
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
7
Publish Date
2009
Start Page
2448
End Page
2455
DOI
10.1158/1078-0432.CCR-08-2430

Role of genetic polymorphisms and ovarian cancer susceptibility.

The value of identifying women with an inherited predisposition to epithelial ovarian cancer has become readily apparent with the identification of the BRCA1, and BRCA2 genes. Women who inherit a deleterious mutation in either of these genes have a very high lifetime risk of ovarian cancer (10-60%) and to some extent, increased risks of fallopian tube and peritoneal cancer. These highly lethal cancers are almost completely prevented by prophylactic salpingoophorectomy. BRCA1/2 mutation testing has become the accepted standard of care in families with a strong history of breast and/or ovarian cancer. This approach has the potential to reduce ovarian cancer mortality by about 10%. Although the ability to perform genetic testing for BRCA1 and 2 represents a significant clinical advance, the frequency of mutations in these high penetrance ovarian cancer susceptibility genes is low in most populations. There is evidence to suggest that ovarian cancer susceptibility might be affected by common low penetrance genetic polymorphisms like it was shown for several common disorders like diabetes or breast cancer. Although such polymorphisms would increase risk to a lesser degree, they could contribute to the development of a greater proportion of ovarian cancers by virtue of their higher frequencies in the population. It has been shown that the most powerful approach to studying low penetrance genes is an association study rather than a linkage study design. This review describes the efforts that have been made in this field by individual case-control studies and through multi-center collaborations as part of international consortia such as the Ovarian Cancer Association Consortium (OCAC).

Authors
Fasching, PA; Gayther, S; Pearce, L; Schildkraut, JM; Goode, E; Thiel, F; Chenevix-Trench, G; Chang-Claude, J; Wang-Gohrke, S; Ramus, S; Pharoah, P; Berchuck, A; OCAC (Ovarian Cancer Association Consortium),
MLA Citation
Fasching, PA, Gayther, S, Pearce, L, Schildkraut, JM, Goode, E, Thiel, F, Chenevix-Trench, G, Chang-Claude, J, Wang-Gohrke, S, Ramus, S, Pharoah, P, Berchuck, A, and OCAC (Ovarian Cancer Association Consortium), . "Role of genetic polymorphisms and ovarian cancer susceptibility." Mol Oncol 3.2 (April 2009): 171-181. (Review)
PMID
19383379
Source
pubmed
Published In
Molecular Oncology
Volume
3
Issue
2
Publish Date
2009
Start Page
171
End Page
181
DOI
10.1016/j.molonc.2009.01.008

Single nucleotide polymorphisms in the TP53 region and susceptibility to invasive epithelial ovarian cancer.

The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (BF) for genotype associations. Five SNPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r(2) = 0.62) SNPs: rs2287498 (median per allele OR, 1.30; 95% PI, 1.07-1.57) and rs12951053 (median per allele OR, 1.19; 95% PI, 1.01-1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TP53 region.

Authors
Schildkraut, JM; Goode, EL; Clyde, MA; Iversen, ES; Moorman, PG; Berchuck, A; Marks, JR; Lissowska, J; Brinton, L; Peplonska, B; Cunningham, JM; Vierkant, RA; Rider, DN; Chenevix-Trench, G; Webb, PM; Beesley, J; Chen, X; Phelan, C; Sutphen, R; Sellers, TA; Pearce, L; Wu, AH; Van Den Berg, D; Conti, D; Elund, CK; Anderson, R; Goodman, MT; Lurie, G; Carney, ME; Thompson, PJ; Gayther, SA; Ramus, SJ; Jacobs, I; Krüger Kjaer, S; Hogdall, E; Blaakaer, J; Hogdall, C; Easton, DF; Song, H; Pharoah, PDP et al.
MLA Citation
Schildkraut, JM, Goode, EL, Clyde, MA, Iversen, ES, Moorman, PG, Berchuck, A, Marks, JR, Lissowska, J, Brinton, L, Peplonska, B, Cunningham, JM, Vierkant, RA, Rider, DN, Chenevix-Trench, G, Webb, PM, Beesley, J, Chen, X, Phelan, C, Sutphen, R, Sellers, TA, Pearce, L, Wu, AH, Van Den Berg, D, Conti, D, Elund, CK, Anderson, R, Goodman, MT, Lurie, G, Carney, ME, Thompson, PJ, Gayther, SA, Ramus, SJ, Jacobs, I, Krüger Kjaer, S, Hogdall, E, Blaakaer, J, Hogdall, C, Easton, DF, Song, H, and Pharoah, PDP et al. "Single nucleotide polymorphisms in the TP53 region and susceptibility to invasive epithelial ovarian cancer." Cancer Res 69.6 (March 15, 2009): 2349-2357.
PMID
19276375
Source
pubmed
Published In
Cancer Research
Volume
69
Issue
6
Publish Date
2009
Start Page
2349
End Page
2357
DOI
10.1158/0008-5472.CAN-08-2902

Independent prognostic relevance of microvessel density in advanced epithelial ovarian cancer and associations between CD31, CD105, p53 status, and angiogenic marker expression: A Gynecologic Oncology Group study.

OBJECTIVES: The aims of this study were to examine prognostic significance of microvessel density (MVD) in previously-untreated, advanced epithelial ovarian cancer (EOC) and explore associations between MVD and factors that affect angiogenesis. METHODS: MVD was determined by immunohistochemical expression of CD31 or CD105 in tumor sections from 106 women treated on GOG randomized phase III trials. Average MVD hotspots were quantified by light microscopy at high power (x400) and categorized as low (or=upper quartile). Immunoblot expression of MASPIN, THBS-1, bFGF, VEGF, VEGFR-1 and p53 status (mutation and overexpression) was previously determined. RESULTS: Of 106 evaluable cases, 25% exhibited high CD31-MVD (>24.25 vessels/high power field [HPF]) or high CD105-MVD (>19.25 vessels/HPF). After adjusting for age and stratifying by GOG performance status, stage, cell type, grade, debulking status and treatment regimen, high versus low CD105-MVD was associated with increased risk of disease progression (hazard ratio [HR]=1.873; 95% confidence interval [CI]: 1.102-3.184; p=0.020), but not death (HR=1.125; 95% CI: 0.654-1.935; p=0.670) whereas CD31-MVD was not associated with risk of disease progression (HR=1.578; 95% CI=0.918-2.711; p=0.099) or death (HR=1.678; 95% CI=0.957-2.943; p=0.071). CD31-MVD was correlated with CD105-MVD (p=0.001) and MASPIN (p=0.016). Neither CD31-MVD nor CD105-MVD was associated with p53 status, THBS-1, bFGF, VEGF or VEGFR-1. CONCLUSIONS: High MVD assessed using CD105, a marker of proliferating endothelial cells and neoangiogenesis, but not CD31 a pan-endothelial marker, appeared to be an independent prognostic factor for worse progression-free survival in women with advanced EOC after adjusting for prognostic clinical covariates.

Authors
Rubatt, JM; Darcy, KM; Hutson, A; Bean, SM; Havrilesky, LJ; Grace, LA; Berchuck, A; Secord, AA
MLA Citation
Rubatt, JM, Darcy, KM, Hutson, A, Bean, SM, Havrilesky, LJ, Grace, LA, Berchuck, A, and Secord, AA. "Independent prognostic relevance of microvessel density in advanced epithelial ovarian cancer and associations between CD31, CD105, p53 status, and angiogenic marker expression: A Gynecologic Oncology Group study." Gynecol Oncol 112.3 (March 2009): 469-474.
PMID
19135712
Source
pubmed
Published In
Gynecologic Oncology
Volume
112
Issue
3
Publish Date
2009
Start Page
469
End Page
474
DOI
10.1016/j.ygyno.2008.11.030

Yin yang 1 modulates taxane response in epithelial ovarian cancer.

Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein, we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary serous epithelial ovarian cancer and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using small interfering RNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in ovarian cancer and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule-stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA cross-linking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1 knockdown in ovarian cancer cell lines results in inhibition of anchorage-independent growth, motility, and proliferation but also increases resistance to taxanes, with no effect on cisplatin sensitivity. These results, together with the prior demonstration of augmentation of microtubule-related genes by E2F3, suggest that enhanced taxane sensitivity in tumors with high YY1/E2F activity may be mediated by modulation of putative target genes with microtubule function.

Authors
Matsumura, N; Huang, Z; Baba, T; Lee, PS; Barnett, JC; Mori, S; Chang, JT; Kuo, W-L; Gusberg, AH; Whitaker, RS; Gray, JW; Fujii, S; Berchuck, A; Murphy, SK
MLA Citation
Matsumura, N, Huang, Z, Baba, T, Lee, PS, Barnett, JC, Mori, S, Chang, JT, Kuo, W-L, Gusberg, AH, Whitaker, RS, Gray, JW, Fujii, S, Berchuck, A, and Murphy, SK. "Yin yang 1 modulates taxane response in epithelial ovarian cancer." Mol Cancer Res 7.2 (February 2009): 210-220.
PMID
19208743
Source
pubmed
Published In
Molecular cancer research : MCR
Volume
7
Issue
2
Publish Date
2009
Start Page
210
End Page
220
DOI
10.1158/1541-7786.MCR-08-0255

Ovarian adenocarcinomas in the laying hen and women share similar alterations in p53, ras, and HER-2/neu.

We examined alterations in the p53 tumor suppressor gene and the ras and HER-2/neu oncogenes in chicken ovarian cancers to determine if these tumors have genetic alterations similar to those in human ovarian adenocarcinomas. Mutations in the p53 tumor suppressor gene and the H-ras and K-ras oncogenes were assessed by direct sequencing in 172 ovarian cancers obtained from 4-year-old birds enrolled at age 2 in two separate 2-year chemoprevention trials. Birds in trial B had approximately twice as many lifetime ovulations as those in trial A. Immunohistochemical staining for the HER-2/neu oncogene was done on a subset of avian ovarian and oviductal adenocarcinomas. Alterations in p53 were detected in 48% of chicken ovarian cancers. Incidence of p53 alterations varied according to the number of lifetime ovulations, ranging from 14% in trial A to 96% in trial B (P < 0.01). No mutations were seen in H-ras, and only 2 of 172 (1.2%) tumors had K-ras mutations. Significant HER-2/neu staining was noted in 10 of 19 ovarian adenocarcinomas but in only 1 of 17 oviductal adenocarcinomas. Similar to human ovarian cancers, p53 alterations are common in chicken ovarian adenocarcinomas and correlate with the number of lifetime ovulations. Ras mutations are rare, similar to high-grade human ovarian cancers. HER-2/neu overexpression is common and may represent a marker to exclude an oviductal origin in cancers involving both the ovary and oviduct.

Authors
Hakim, AA; Barry, CP; Barnes, HJ; Anderson, KE; Petitte, J; Whitaker, R; Lancaster, JM; Wenham, RM; Carver, DK; Turbov, J; Berchuck, A; Kopelovich, L; Rodriguez, GC
MLA Citation
Hakim, AA, Barry, CP, Barnes, HJ, Anderson, KE, Petitte, J, Whitaker, R, Lancaster, JM, Wenham, RM, Carver, DK, Turbov, J, Berchuck, A, Kopelovich, L, and Rodriguez, GC. "Ovarian adenocarcinomas in the laying hen and women share similar alterations in p53, ras, and HER-2/neu." Cancer Prev Res (Phila) 2.2 (February 2009): 114-121.
PMID
19174584
Source
pubmed
Published In
Cancer Prevention Research
Volume
2
Issue
2
Publish Date
2009
Start Page
114
End Page
121
DOI
10.1158/1940-6207.CAPR-08-0065

High poly (ADP-ribose) polymerase (PARP) expression is associated with poor survival in advanced-stage serous ovarian cancer

Authors
Barnett, JC; Kondoh, E; Whitaker, R; Murphy, SK; Berchuck, A
MLA Citation
Barnett, JC, Kondoh, E, Whitaker, R, Murphy, SK, and Berchuck, A. "High poly (ADP-ribose) polymerase (PARP) expression is associated with poor survival in advanced-stage serous ovarian cancer." GYNECOLOGIC ONCOLOGY 112.2 (February 2009): S107-S107.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
112
Issue
2
Publish Date
2009
Start Page
S107
End Page
S107

Genomic predictors of ovarian cancer response to salvage therapy

Authors
Cragun, J; Xiong, Y; Boren, TP; Indermaur, MD; Sayer, R; Humphrey, MM; Cottrill, HM; Kamath, S; Hakam, A; Apte, SM; Wenham, RM; Berchuck, A; Lancaster, JM
MLA Citation
Cragun, J, Xiong, Y, Boren, TP, Indermaur, MD, Sayer, R, Humphrey, MM, Cottrill, HM, Kamath, S, Hakam, A, Apte, SM, Wenham, RM, Berchuck, A, and Lancaster, JM. "Genomic predictors of ovarian cancer response to salvage therapy." GYNECOLOGIC ONCOLOGY 112.2 (February 2009): S133-S133.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
112
Issue
2
Publish Date
2009
Start Page
S133
End Page
S133

7-hydroxystaurosporine (UCN-01) is effective in targeting ovarian cancer spheroids

Authors
Kondoh, E; Baba, T; Malsumura, N; Konishi, I; Fujii, S; Berchuck, A; Murphy, SK
MLA Citation
Kondoh, E, Baba, T, Malsumura, N, Konishi, I, Fujii, S, Berchuck, A, and Murphy, SK. "7-hydroxystaurosporine (UCN-01) is effective in targeting ovarian cancer spheroids." GYNECOLOGIC ONCOLOGY 112.2 (February 2009): S161-S162.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
112
Issue
2
Publish Date
2009
Start Page
S161
End Page
S162

Gene signature specific for ovarian clear cell carcinoma is induced by the contents of endometriotic cysts

Authors
Yamaguchi, K; Mandai, M; Matsumura, N; Baba, T; Oura, T; Matsui, S; Murphy, SK; Berchuck, A; Fujii, S; Konishi, I
MLA Citation
Yamaguchi, K, Mandai, M, Matsumura, N, Baba, T, Oura, T, Matsui, S, Murphy, SK, Berchuck, A, Fujii, S, and Konishi, I. "Gene signature specific for ovarian clear cell carcinoma is induced by the contents of endometriotic cysts." GYNECOLOGIC ONCOLOGY 112.2 (February 2009): S132-S132.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
112
Issue
2
Publish Date
2009
Start Page
S132
End Page
S132

Ovarian cancer tumor-infiltrating regulatory T cells are associated with a metastatic phenotype

Authors
Barnett, JC; Whitaker, R; Kondoh, E; Baba, T; Murphy, SK; Berchuck, A
MLA Citation
Barnett, JC, Whitaker, R, Kondoh, E, Baba, T, Murphy, SK, and Berchuck, A. "Ovarian cancer tumor-infiltrating regulatory T cells are associated with a metastatic phenotype." GYNECOLOGIC ONCOLOGY 112.2 (February 2009): S11-S11.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
112
Issue
2
Publish Date
2009
Start Page
S11
End Page
S11

Loss of GPR54 correlates with stem cell activity in high-grade endometrial cancer

Authors
Baba, T; Kang, HS; Matsumura, N; Hamanishi, J; Mandai, M; Berchuck, A; Murphy, SK; Konishi, I
MLA Citation
Baba, T, Kang, HS, Matsumura, N, Hamanishi, J, Mandai, M, Berchuck, A, Murphy, SK, and Konishi, I. "Loss of GPR54 correlates with stem cell activity in high-grade endometrial cancer." GYNECOLOGIC ONCOLOGY 112.2 (February 2009): S78-S78.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
112
Issue
2
Publish Date
2009
Start Page
S78
End Page
S78

Intragenic methylation at a novel CTCF binding site is associated with elevated IGF2 expression in serous epithelial ovarian cancer

Authors
Murphy, SK; Huang, Z; Wen, Y; Simel, LR; Price, TM; Berchuck, A
MLA Citation
Murphy, SK, Huang, Z, Wen, Y, Simel, LR, Price, TM, and Berchuck, A. "Intragenic methylation at a novel CTCF binding site is associated with elevated IGF2 expression in serous epithelial ovarian cancer." GYNECOLOGIC ONCOLOGY 112.2 (February 2009): S138-S138.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
112
Issue
2
Publish Date
2009
Start Page
S138
End Page
S138

Validation of the MAL gene as a predictor of survival in advanced-stage high-grade serous ovarian cancer

Authors
Barnett, JC; Iverson, E; Dressman, H; Whitaker, R; Murphy, SK; Lancaster, J; Berchuck, A
MLA Citation
Barnett, JC, Iverson, E, Dressman, H, Whitaker, R, Murphy, SK, Lancaster, J, and Berchuck, A. "Validation of the MAL gene as a predictor of survival in advanced-stage high-grade serous ovarian cancer." GYNECOLOGIC ONCOLOGY 112.2 (February 2009): S123-S124.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
112
Issue
2
Publish Date
2009
Start Page
S123
End Page
S124

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Authors
Pearce, CL; Near, AM; Van Den Berg, DJ; Ramus, SJ; Gentry-Maharaj, A; Menon, U; Gayther, SA; Anderson, AR; Edlund, CK; Wu, AH; Chen, X; Beesley, J; Webb, PM; Holt, SK; Chen, C; Doherty, JA; Rossing, MA; Whittemore, AS; McGuire, V; DiCioccio, RA; Goodman, MT; Lurie, G; Carney, ME; Wilkens, LR; Ness, RB; Moysich, KB; Edwards, R; Jennison, E; Kjaer, SK; Hogdall, E; Hogdall, CK; Goode, EL; Sellers, TA; Vierkant, RA; Cunningham, JM; Schildkraut, JM; Berchuck, A; Moorman, PG; Iversen, ES; Cramer, DW et al.
MLA Citation
Pearce, CL, Near, AM, Van Den Berg, DJ, Ramus, SJ, Gentry-Maharaj, A, Menon, U, Gayther, SA, Anderson, AR, Edlund, CK, Wu, AH, Chen, X, Beesley, J, Webb, PM, Holt, SK, Chen, C, Doherty, JA, Rossing, MA, Whittemore, AS, McGuire, V, DiCioccio, RA, Goodman, MT, Lurie, G, Carney, ME, Wilkens, LR, Ness, RB, Moysich, KB, Edwards, R, Jennison, E, Kjaer, SK, Hogdall, E, Hogdall, CK, Goode, EL, Sellers, TA, Vierkant, RA, Cunningham, JM, Schildkraut, JM, Berchuck, A, Moorman, PG, Iversen, ES, and Cramer, DW et al. "Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium." Br J Cancer 100.2 (January 27, 2009): 412-420.
PMID
19127255
Source
pubmed
Published In
British Journal of Cancer
Volume
100
Issue
2
Publish Date
2009
Start Page
412
End Page
420
DOI
10.1038/sj.bjc.6604820

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium

Authors
Pearce, CL; Near, AM; Van Den Berg, DJ; Ramus, SJ; Gentry-Maharaj, A; Menon, U; Gayther, SA; Anderson, AR; Edlund, CK; Wu, AH; Chen, X; Beesley, J; Webb, PM; Holt, SK; Chen, C; Doherty, JA; Rossing, MA; Whittemore, AS; McGuire, V; DiCioccio, RA; Goodman, MT; Lurie, G; Carney, ME; Wilkens, LR; Ness, RB; Moysich, KB; Edwards, R; Jennison, E; Kjaer, SK; Hogdall, E; Hogdall, CK; Goode, EL; Sellers, TA; Vierkant, RA; Cunningham, JC; Schildkraut, JM; Berchuck, A; Moorman, PG; Iversen, ES; Cramer, DW et al.
MLA Citation
Pearce, CL, Near, AM, Van Den Berg, DJ, Ramus, SJ, Gentry-Maharaj, A, Menon, U, Gayther, SA, Anderson, AR, Edlund, CK, Wu, AH, Chen, X, Beesley, J, Webb, PM, Holt, SK, Chen, C, Doherty, JA, Rossing, MA, Whittemore, AS, McGuire, V, DiCioccio, RA, Goodman, MT, Lurie, G, Carney, ME, Wilkens, LR, Ness, RB, Moysich, KB, Edwards, R, Jennison, E, Kjaer, SK, Hogdall, E, Hogdall, CK, Goode, EL, Sellers, TA, Vierkant, RA, Cunningham, JC, Schildkraut, JM, Berchuck, A, Moorman, PG, Iversen, ES, and Cramer, DW et al. "Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium." BRITISH JOURNAL OF CANCER 100.2 (January 22, 2009): 412-420.
Source
wos-lite
Published In
British Journal of Cancer
Volume
100
Issue
2
Publish Date
2009
Start Page
412
End Page
420
DOI
10.1038/sj.bjc.6604820

Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells.

The cancer stem cell hypothesis posits that malignant growth arises from a rare population of progenitor cells within a tumor that provide it with unlimited regenerative capacity. Such cells also possess increased resistance to chemotherapeutic agents. Resurgence of chemoresistant disease after primary therapy typifies epithelial ovarian cancer and may be attributable to residual cancer stem cells, or cancer-initiating cells, that survive initial treatment. As the cell surface marker CD133 identifies cancer-initiating cells in a number of other malignancies, we sought to determine the potential role of CD133+ cells in epithelial ovarian cancer. We detected CD133 on ovarian cancer cell lines, in primary cancers and on purified epithelial cells from ascitic fluid of ovarian cancer patients. We found CD133+ ovarian cancer cells generate both CD133+ and CD133- daughter cells, whereas CD133- cells divide symmetrically. CD133+ cells exhibit enhanced resistance to platinum-based therapy, drugs commonly used as first-line agents for the treatment of ovarian cancer. Sorted CD133+ ovarian cancer cells also form more aggressive tumor xenografts at a lower inoculum than their CD133- progeny. Epigenetic changes may be integral to the behavior of cancer progenitor cells and their progeny. In this regard, we found that CD133 transcription is controlled by both histone modifications and promoter methylation. Sorted CD133- ovarian cancer cells treated with DNA methyltransferase and histone deacetylase inhibitors show a synergistic increase in cell surface CD133 expression. Moreover, DNA methylation at the ovarian tissue active P2 promoter is inversely correlated with CD133 transcription. We also found that promoter methylation increases in CD133- progeny of CD133+ cells, with CD133+ cells retaining a less methylated or unmethylated state. Taken together, our results show that CD133 expression in ovarian cancer is directly regulated by epigenetic modifications and support the idea that CD133 demarcates an ovarian cancer-initiating cell population. The activity of these cells may be epigenetically detected and such cells might serve as pertinent chemotherapeutic targets for reducing disease recurrence.

Authors
Baba, T; Convery, PA; Matsumura, N; Whitaker, RS; Kondoh, E; Perry, T; Huang, Z; Bentley, RC; Mori, S; Fujii, S; Marks, JR; Berchuck, A; Murphy, SK
MLA Citation
Baba, T, Convery, PA, Matsumura, N, Whitaker, RS, Kondoh, E, Perry, T, Huang, Z, Bentley, RC, Mori, S, Fujii, S, Marks, JR, Berchuck, A, and Murphy, SK. "Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells." Oncogene 28.2 (January 15, 2009): 209-218.
PMID
18836486
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
28
Issue
2
Publish Date
2009
Start Page
209
End Page
218
DOI
10.1038/onc.2008.374

Relationship between tamoxifen use and high risk endometrial cancer histologic types.

OBJECTIVES: We wished to determine whether a pre-existing diagnosis of breast cancer or the use of tamoxifen among patients with pre-existing breast cancer influences the histologic type of subsequently diagnosed endometrial carcinoma, the interval between these diagnoses, or survival. METHODS: A single institution retrospective review was performed of all patients who underwent primary surgery for endometrial carcinoma from 1995-2005. We compared the histologic type of endometrial carcinoma among patients with a prior history of breast cancer to those without. Patients with a previous diagnosis of breast cancer were further analyzed by comparing histologic type, progression-free and overall survival between tamoxifen users and non-users. RESULTS: Among 732 women with endometrial carcinoma, 59 patients (8%) had a previous diagnosis of breast cancer, of whom 29 (49%) had used tamoxifen. Women with a history of breast cancer were more likely to have a high risk uterine histologic type (grade 3 endometrioid, papillary serous, or clear cell) (18/59; 31%) than those without this prior malignancy (120/670, 18%; p=0.024). Breast cancer survivors whose endometrial carcinoma was of a high risk histologic type had a longer median duration of prior tamoxifen use compared to those with lower risk histologic types (60 versus 46 months, p=0.034). CONCLUSIONS: Among women with endometrial carcinoma, those with a history of breast cancer are more likely to harbor a high risk uterine histologic subtype. Tamoxifen use of at least 60 months is associated with high risk uterine histologic subtypes when compared to no tamoxifen use. This study adds to existing data suggesting a relationship between tamoxifen use and development of endometrial carcinoma of more aggressive histologic types.

Authors
Bland, AE; Calingaert, B; Secord, AA; Lee, PS; Valea, FA; Berchuck, A; Soper, JT; Havrilesky, L
MLA Citation
Bland, AE, Calingaert, B, Secord, AA, Lee, PS, Valea, FA, Berchuck, A, Soper, JT, and Havrilesky, L. "Relationship between tamoxifen use and high risk endometrial cancer histologic types." Gynecol Oncol 112.1 (January 2009): 150-154.
PMID
18937966
Source
pubmed
Published In
Gynecologic Oncology
Volume
112
Issue
1
Publish Date
2009
Start Page
150
End Page
154
DOI
10.1016/j.ygyno.2008.08.035

Erratum: Validating genetic risk associations for ovarian cancer through the International Ovarian Cancer Association Consortium (British Journal of Cancer (2009) 100 (412-420) DOI: 10.1038/sj.bjc.6604820 www.bjcancer.com)

Authors
Pearce, CL; Near, AM; Berg, DJVD; Ramus, SJ; Gentry-Maharaj, A; Menon, U; Gayther, SA; Anderson, AR; Edlund, CK; Wu, AH; Chen, X; Beesley, J; Webb, PM; Holt, SK; Chen, C; Doherty, JA; Rossing, MA; Whittemore, AS; McGuire, V; Dicioccio, RA; Goodman, MT; Lurie, G; Carney, ME; Wilkens, LR; Ness, RB; Moysich, KB; Edwards, R; Jennison, E; Kjaer, SK; Hogdall, E; Hogdall, CK; Goode, EL; Sellers, TA; Vierkant, RA; Cunningham, JM; Schildkraut, JM; Berchuck, A; Moorman, PG; Iversen, ES; Cramer, DW et al.
MLA Citation
Pearce, CL, Near, AM, Berg, DJVD, Ramus, SJ, Gentry-Maharaj, A, Menon, U, Gayther, SA, Anderson, AR, Edlund, CK, Wu, AH, Chen, X, Beesley, J, Webb, PM, Holt, SK, Chen, C, Doherty, JA, Rossing, MA, Whittemore, AS, McGuire, V, Dicioccio, RA, Goodman, MT, Lurie, G, Carney, ME, Wilkens, LR, Ness, RB, Moysich, KB, Edwards, R, Jennison, E, Kjaer, SK, Hogdall, E, Hogdall, CK, Goode, EL, Sellers, TA, Vierkant, RA, Cunningham, JM, Schildkraut, JM, Berchuck, A, Moorman, PG, Iversen, ES, and Cramer, DW et al. "Erratum: Validating genetic risk associations for ovarian cancer through the International Ovarian Cancer Association Consortium (British Journal of Cancer (2009) 100 (412-420) DOI: 10.1038/sj.bjc.6604820 www.bjcancer.com)." British Journal of Cancer 101.10 (2009): 1805--.
Source
scival
Published In
British Journal of Cancer
Volume
101
Issue
10
Publish Date
2009
Start Page
1805-
DOI
10.1038/sj.bjc.6605431

Polymorphism in the IL18 gene and epithelial ovarian cancer in non-Hispanic white women.

Over 22,000 cases of ovarian cancer were diagnosed in 2007 in the United States, but only a fraction of them can be attributed to mutations in highly penetrant genes such as BRCA1. To determine whether low-penetrance genetic variants contribute to ovarian cancer risk, we genotyped 1,536 single nucleotide polymorphisms (SNP) in several candidate gene pathways in 848 epithelial ovarian cancer cases and 798 controls in the North Carolina Ovarian Cancer Study (NCO) using a customized Illumina array. The inflammation gene interleukin-18 (IL18) showed the strongest evidence for association with epithelial ovarian cancer in a gene-by-gene analysis (P = 0.002) with a <25% chance of being a false-positive finding (q value = 0.240). Using a multivariate model search algorithm over 11 IL18 tagging SNPs, we found that the association was best modeled by rs1834481. Further, this SNP uniquely tagged a significantly associated IL18 haplotype and there was an increased risk of epithelial ovarian cancer per rs1834481 allele (odds ratio, 1.24; 95% confidence interval, 1.06-1.45). In a replication stage, 12 independent studies from the Ovarian Cancer Association Consortium (OCAC) genotyped rs1834481 in an additional 5,877 cases and 7,791 controls. The fixed effects estimate per rs1834481 allele was null (odds ratio, 0.99; 95% confidence interval, 0.94-1.05) when data from the 12 OCAC studies were combined. The effect estimate remained unchanged with the addition of the initial North Carolina Ovarian Cancer Study data. This analysis shows the importance of consortia, like the OCAC, in either confirming or refuting the validity of putative findings in studies with smaller sample sizes. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3567-72).

Authors
Palmieri, RT; Wilson, MA; Iversen, ES; Clyde, MA; Calingaert, B; Moorman, PG; Poole, C; Anderson, AR; Anderson, S; Anton-Culver, H; Beesley, J; Hogdall, E; Brewster, W; Carney, ME; Chen, X; Chenevix-Trench, G; Chang-Claude, J; Cunningham, JM; Dicioccio, RA; Doherty, JA; Easton, DF; Edlund, CK; Gayther, SA; Gentry-Maharaj, A; Goode, EL; Goodman, MT; Kjaer, SK; Hogdall, CK; Hopkins, MP; Jenison, EL; Blaakaer, J; Lurie, G; McGuire, V; Menon, U; Moysich, KB; Ness, RB; Pearce, CL; Pharoah, PDP et al.
MLA Citation
Palmieri, RT, Wilson, MA, Iversen, ES, Clyde, MA, Calingaert, B, Moorman, PG, Poole, C, Anderson, AR, Anderson, S, Anton-Culver, H, Beesley, J, Hogdall, E, Brewster, W, Carney, ME, Chen, X, Chenevix-Trench, G, Chang-Claude, J, Cunningham, JM, Dicioccio, RA, Doherty, JA, Easton, DF, Edlund, CK, Gayther, SA, Gentry-Maharaj, A, Goode, EL, Goodman, MT, Kjaer, SK, Hogdall, CK, Hopkins, MP, Jenison, EL, Blaakaer, J, Lurie, G, McGuire, V, Menon, U, Moysich, KB, Ness, RB, Pearce, CL, and Pharoah, PDP et al. "Polymorphism in the IL18 gene and epithelial ovarian cancer in non-Hispanic white women." Cancer Epidemiol Biomarkers Prev 17.12 (December 2008): 3567-3572.
PMID
19064572
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
17
Issue
12
Publish Date
2008
Start Page
3567
End Page
3572
DOI
10.1158/1055-9965.EPI-08-0548

Evaluation of biomarker panels for early stage ovarian cancer detection and monitoring for disease recurrence.

OBJECTIVE: To determine the utility of novel combinations of biomarkers, using both a one-step and two-step assay format, to distinguish serum of early ovarian cancer patients from that of healthy controls and to discern the utility of these biomarkers in a monitoring capacity. METHODS: For ovarian cancer detection, HE4, Glycodelin, MMP7, SLPI, Plau-R, MUC1, Inhibin A, PAI-1, and CA125 were evaluated in a cohort of 200 women with ovarian cancer and 396 healthy age-matched controls. Each biomarker was assessed by serum-based immunoassays utilizing novel monoclonal antibody pairs or commercial kits. For detection of disease recurrence, HE4, Glycodelin, MMP7 and CA125 were evaluated in 260 samples from 30 patients with OC monitored longitudinally after diagnosis. RESULTS: Based upon ROC curve analysis, the sensitivity/specificity of specific biomarker combination algorithms ranged from 59.0%/99.7% to 80.5%/96.5% for detection of early stage ovarian cancer and 76.9%/99.7% to 89.2%/97.2% for detection of late stage cancer. In monitoring evaluation of 27 patients who experienced recurrence of OC, sensitivity for predicting recurrence was 100% for the biomarker panel and 96% for CA125. At least one of the panel biomarkers was elevated earlier (range 6-69 weeks) than CA125 and prior to clinical evidence of recurrence in 14/27 (52%) patients. CONCLUSIONS: We have developed and demonstrated the utility of several one- and two-step multi-marker combinations with acceptable test characteristics for possible use in an ovarian cancer screening population. A subset of this panel may also provide adjunctive information to rising CA125 levels in disease monitoring.

Authors
Havrilesky, LJ; Whitehead, CM; Rubatt, JM; Cheek, RL; Groelke, J; He, Q; Malinowski, DP; Fischer, TJ; Berchuck, A
MLA Citation
Havrilesky, LJ, Whitehead, CM, Rubatt, JM, Cheek, RL, Groelke, J, He, Q, Malinowski, DP, Fischer, TJ, and Berchuck, A. "Evaluation of biomarker panels for early stage ovarian cancer detection and monitoring for disease recurrence." Gynecol Oncol 110.3 (September 2008): 374-382.
PMID
18584856
Source
pubmed
Published In
Gynecologic Oncology
Volume
110
Issue
3
Publish Date
2008
Start Page
374
End Page
382
DOI
10.1016/j.ygyno.2008.04.041

Consortium analysis of 7 candidate SNPs for ovarian cancer.

The Ovarian Cancer Association Consortium selected 7 candidate single nucleotide polymorphisms (SNPs), for which there is evidence from previous studies of an association with variation in ovarian cancer or breast cancer risks. The SNPs selected for analysis were F31I (rs2273535) in AURKA, N372H (rs144848) in BRCA2, rs2854344 in intron 17 of RB1, rs2811712 5' flanking CDKN2A, rs523349 in the 3' UTR of SRD5A2, D302H (rs1045485) in CASP8 and L10P (rs1982073) in TGFB1. Fourteen studies genotyped 4,624 invasive epithelial ovarian cancer cases and 8,113 controls of white non-Hispanic origin. A marginally significant association was found for RB1 when all studies were included [ordinal odds ratio (OR) 0.88 (95% confidence interval (CI) 0.79-1.00) p = 0.041 and dominant OR 0.87 (95% CI 0.76-0.98) p = 0.025]; when the studies that originally suggested an association were excluded, the result was suggestive although no longer statistically significant (ordinal OR 0.92, 95% CI 0.79-1.06). This SNP has also been shown to have an association with decreased risk in breast cancer. There was a suggestion of an association for AURKA, when one study that caused significant study heterogeneity was excluded [ordinal OR 1.10 (95% CI 1.01-1.20) p = 0.027; dominant OR 1.12 (95% CI 1.01-1.24) p = 0.03]. The other 5 SNPs in BRCA2, CDKN2A, SRD5A2, CASP8 and TGFB1 showed no association with ovarian cancer risk; given the large sample size, these results can also be considered to be informative. These null results for SNPs identified from relatively large initial studies shows the importance of replicating associations by a consortium approach.

Authors
Ramus, SJ; Vierkant, RA; Johnatty, SE; Pike, MC; Van Den Berg, DJ; Wu, AH; Pearce, CL; Menon, U; Gentry-Maharaj, A; Gayther, SA; DiCioccio, RA; McGuire, V; Whittemore, AS; Song, H; Easton, DF; Pharoah, PDP; Garcia-Closas, M; Chanock, S; Lissowska, J; Brinton, L; Terry, KL; Cramer, DW; Tworoger, SS; Hankinson, SE; Berchuck, A; Moorman, PG; Schildkraut, JM; Cunningham, JM; Liebow, M; Kjaer, SK; Hogdall, E; Hogdall, C; Blaakaer, J; Ness, RB; Moysich, KB; Edwards, RP; Carney, ME; Lurie, G et al.
MLA Citation
Ramus, SJ, Vierkant, RA, Johnatty, SE, Pike, MC, Van Den Berg, DJ, Wu, AH, Pearce, CL, Menon, U, Gentry-Maharaj, A, Gayther, SA, DiCioccio, RA, McGuire, V, Whittemore, AS, Song, H, Easton, DF, Pharoah, PDP, Garcia-Closas, M, Chanock, S, Lissowska, J, Brinton, L, Terry, KL, Cramer, DW, Tworoger, SS, Hankinson, SE, Berchuck, A, Moorman, PG, Schildkraut, JM, Cunningham, JM, Liebow, M, Kjaer, SK, Hogdall, E, Hogdall, C, Blaakaer, J, Ness, RB, Moysich, KB, Edwards, RP, Carney, ME, and Lurie, G et al. "Consortium analysis of 7 candidate SNPs for ovarian cancer." Int J Cancer 123.2 (July 15, 2008): 380-388.
PMID
18431743
Source
pubmed
Published In
International Journal of Cancer
Volume
123
Issue
2
Publish Date
2008
Start Page
380
End Page
388
DOI
10.1002/ijc.23448

Scientific innovation--pathway to progress in women's cancer.

Authors
Berchuck, A
MLA Citation
Berchuck, A. "Scientific innovation--pathway to progress in women's cancer." Gynecol Oncol 109.3 (June 2008): 316-322.
PMID
18534249
Source
pubmed
Published In
Gynecologic Oncology
Volume
109
Issue
3
Publish Date
2008
Start Page
316
End Page
322
DOI
10.1016/j.ygyno.2008.04.020

Gene expression determinants of ovarian cancer platinum-response in older women.

22059 Background: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, and more than half of new ovarian cancer cases arise in women over age 65. Although older women with EOC have poorer overall prognosis compared to younger women, the exact molecular basis to this difference remains unclear. The goal of this study is to improve our understanding of the molecular underpinnings of advanced stage EOC in older women and identify genes associated with chemo-response in older women such that therapy may be tailored to individual patients. METHODS: We performed Affymetrix microarray gene expression analysis on 122 primary advanced stage epithelial ovarian cancers resected from 73 younger (<65 years) and 49 older (>65 years) women. For each age group, gene expression data was compared using Significance Analysis of Microarrays (SAM), between patients who demonstrated a complete-response (>65 years, n=38; <65 years, n=48) and incomplete-response (>65 years, n=11; <65 years, n=25) to primary platinum-based chemotherapy. Differential expression was determined by two class unpaired t-tests (false discovery rate, 0%), and results ranked according to d score. RESULTS: We identified 317 genes associated with platinum-response in cancers from younger women, and 264 genes associated with platinum-response in cancers from older women. Six genes (JRKL, LRP8, OVOL2, PKP4, SRD5A1, TMEM1) demonstrated differential expression associated with platinum-response in cancers from both age groups. Genes associated with platinum-response in older, but not younger, women have functional links to apoptosis regulation, programmed cell death, and cell growth. In contrast, genes associated with platinum-response in younger women have functional links to DNA repair. CONCLUSIONS: We have identified genes associated with response to platinum-based therapy in younger and older women with EOC. Our data provides insights into biologic functions that may underlie differences in chemo-responsiveness in older versus younger women with EOC. Identifying the molecular underpinnings that drive response to chemotherapy in older women may enable clinicians to tailor therapy and identify potential novel therapeutic targets. No significant financial relationships to disclose.

Authors
Cragun, JM; Boren, T; Xiong, Y; Indermaur, M; Kamath, S; Cottrill, H; Balducci, L; Sayer, R; Dressman, HK; Berchuck, A; Lancaster, J
MLA Citation
Cragun, JM, Boren, T, Xiong, Y, Indermaur, M, Kamath, S, Cottrill, H, Balducci, L, Sayer, R, Dressman, HK, Berchuck, A, and Lancaster, J. "Gene expression determinants of ovarian cancer platinum-response in older women." J Clin Oncol 26.15_suppl (May 20, 2008): 22059-.
PMID
27950659
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
22059

Gene expression determinants of ovarian cancer platinum-response in older women

Authors
Cragun, JM; Boren, T; Xiong, Y; Indermaur, M; Kamath, S; Cottrill, H; Balducci, L; Sayer, R; Dressman, HK; Berchuck, A; Lancaster, J
MLA Citation
Cragun, JM, Boren, T, Xiong, Y, Indermaur, M, Kamath, S, Cottrill, H, Balducci, L, Sayer, R, Dressman, HK, Berchuck, A, and Lancaster, J. "Gene expression determinants of ovarian cancer platinum-response in older women." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Hormonal risk factors for ovarian cancer in premenopausal and postmenopausal women.

Ovarian cancer is most frequently diagnosed in postmenopausal women; however, the strongest risk predictors, pregnancy and oral contraceptive use, occur in most women in their twenties and thirties. Relatively few studies have examined how reproductive risk factors vary between pre- and postmenopausal ovarian cancer. The authors used data from a population-based, case-control study of ovarian cancer (896 cases, 967 controls) conducted in North Carolina from 1999 to 2006. Odds ratios and 95% confidence intervals were calculated by using unconditional logistic regression. Inverse associations with ovarian cancer were observed with duration of oral contraceptive use, later age at last use, and more recent use among premenopausal women; no significant associations were found for postmenopausal women. Analyses limited to oral contraceptive users showed that duration was a more significant predictor of risk than was timing of use. Parity was inversely associated with premenopausal but not postmenopausal ovarian cancer. Later age at pregnancy was associated with reduced risk for both pre- and postmenopausal women. Analyses among parous women showed that pregnancy timing was a stronger risk predictor than number of pregnancies. Findings suggest that associations between ovarian cancer and reproductive characteristics vary by menopausal status. Additional research is needed to further elucidate risk factors for postmenopausal disease.

Authors
Moorman, PG; Calingaert, B; Palmieri, RT; Iversen, ES; Bentley, RC; Halabi, S; Berchuck, A; Schildkraut, JM
MLA Citation
Moorman, PG, Calingaert, B, Palmieri, RT, Iversen, ES, Bentley, RC, Halabi, S, Berchuck, A, and Schildkraut, JM. "Hormonal risk factors for ovarian cancer in premenopausal and postmenopausal women." Am J Epidemiol 167.9 (May 1, 2008): 1059-1069.
PMID
18303003
Source
pubmed
Published In
American Journal of Epidemiology
Volume
167
Issue
9
Publish Date
2008
Start Page
1059
End Page
1069
DOI
10.1093/aje/kwn006

A multi-institutional evaluation of factors predictive of toxicity and efficacy of bevacizumab for recurrent ovarian cancer.

While bevacizumab has shown activity in recurrent ovarian cancer, a higher than expected incidence of bowel perforations has been reported in recent trials. We sought to determine factors associated with toxicity and tumor response in patients with relapsed ovarian cancer treated with bevacizumab. A retrospective review of patients with recurrent ovarian cancer treated with bevacizumab was undertaken. Response was determined radiographically and through CA125 measurements. Statistical analysis to determine factors associated with toxicity and response was performed. Sixty-two eligible patients were identified. The cohort had received a median of 5 prior chemotherapy regimens. Single-agent bevacizumab was administered to 12 (19%), while 50 (81%) received the drug in combination with a cytotoxic agent. Grade 3-5 toxicities occurred in 15 (24%) patients, including grade 3-4 hypertension in 4 (7%), gastrointestinal perforations in 7%, and chylous ascites in 5%. Development of chylous ascites and gastrointestinal perforations appeared to correlate with tumor response. The overall response rate was 36% (4 complete response, 17 partial response), with stable disease in 40%. A higher objective response rate was seen in the bevacizumab combination group compared to single-agent treatment (43% vs 10%) (P = 0.07). However, 29 grade 3-5 toxic episodes were seen in the combination group vs only 1 in the single-agent bevacizumab cohort (P = 0.071). We conclude that bevacizumab demonstrates promising activity in recurrent ovarian cancer. The addition of a cytotoxic agent to bevacizumab improved response rates at the cost of increased toxicity. Gastrointestinal perforations occurred in 7%. The perforations occurred in heavily pretreated patients who were responding to therapy.

Authors
Wright, JD; Secord, AA; Numnum, TM; Rocconi, RP; Powell, MA; Berchuck, A; Alvarez, RD; Gibb, RK; Trinkaus, K; Rader, JS; Mutch, DG
MLA Citation
Wright, JD, Secord, AA, Numnum, TM, Rocconi, RP, Powell, MA, Berchuck, A, Alvarez, RD, Gibb, RK, Trinkaus, K, Rader, JS, and Mutch, DG. "A multi-institutional evaluation of factors predictive of toxicity and efficacy of bevacizumab for recurrent ovarian cancer." Int J Gynecol Cancer 18.3 (May 2008): 400-406.
PMID
17645510
Source
pubmed
Published In
International Journal of Gynecological Cancer
Volume
18
Issue
3
Publish Date
2008
Start Page
400
End Page
406
DOI
10.1111/j.1525-1438.2007.01027.x

Cyclin E overexpression in epithelial ovarian cancer characterizes an etiologic subgroup.

BACKGROUND: The objective of this study was to determine whether cyclin E overexpression defines an etiologically distinct subgroup of ovarian cancer. METHODS: We analyzed data from 538 epithelial ovarian cancer cases and 629 controls enrolled in a population-based case-control study. Cyclin E protein overexpression was assessed using immunohistochemistry. Case-control and case-case comparisons were done to evaluate the relationship between cyclin E overexpression and epidemiologic risk factors. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) while adjusting for potential confounders. RESULTS: Case-control comparisons showed ovarian cancers with and without cyclin E overexpression have different associations with several epidemiologic risk factors. A dose-response relationship was observed between lifetime ovulatory cycles (LOC) and ovarian cancer that overexpressed cyclin E [OR, 1.8; 95% CI, 1.1-3.0 for moderately high LOC (265-390 cycles) and OR, 2.7; 95% CI, 1.6-4.5 for high LOC (>390 cycles) compared with low LOC (<265 cycles)], but no relationship was seen with cancers that lacked overexpression. The most important components of the LOC variable contributing to the differences in the association with the cyclin E subgroups of ovarian cancer were months of oral contraceptive use and months pregnant. CONCLUSIONS: Cyclin E overexpression is associated with a high number of LOC, largely influenced by oral contraceptive use and pregnancy. This suggests that cyclin E overexpression is a molecular signature characteristic of ovarian cancer cases that may arise via a pathway that involves ovulation-induced alterations.

Authors
Schildkraut, JM; Moorman, PG; Bland, AE; Halabi, S; Calingaert, B; Whitaker, R; Lee, PS; Elkins-Williams, T; Bentley, RC; Marks, JR; Berchuck, A
MLA Citation
Schildkraut, JM, Moorman, PG, Bland, AE, Halabi, S, Calingaert, B, Whitaker, R, Lee, PS, Elkins-Williams, T, Bentley, RC, Marks, JR, and Berchuck, A. "Cyclin E overexpression in epithelial ovarian cancer characterizes an etiologic subgroup." Cancer Epidemiol Biomarkers Prev 17.3 (March 2008): 585-593.
PMID
18349276
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
17
Issue
3
Publish Date
2008
Start Page
585
End Page
593
DOI
10.1158/1055-9965.EPI-07-0596

Prognostic relevance of microvessel density in previously untreated, advanced-stage epithelial ovarian cancer and associations between CD31, CD105, p53 status, and angiogenic marker expression: A Gynecologic Oncology Group study

Authors
Rubatt, JM; Darcy, KM; Hutson, A; Bean, SM; Havrilesky, LJ; Lee, PS; Grace, LA; Berchuck, A; Secord, AA
MLA Citation
Rubatt, JM, Darcy, KM, Hutson, A, Bean, SM, Havrilesky, LJ, Lee, PS, Grace, LA, Berchuck, A, and Secord, AA. "Prognostic relevance of microvessel density in previously untreated, advanced-stage epithelial ovarian cancer and associations between CD31, CD105, p53 status, and angiogenic marker expression: A Gynecologic Oncology Group study." GYNECOLOGIC ONCOLOGY 108.3 (March 2008): S20-S20.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
108
Issue
3
Publish Date
2008
Start Page
S20
End Page
S20

The prognostic significance of p53 and cyclin E overexpression in ovarian cancer: A population-based study

Authors
Barnett, JC; Bland, A; Whitaker, R; Calingaert, B; Bentley, RC; Lee, PS; Moorman, PC; Schildkraut, JM; Berchuck, A
MLA Citation
Barnett, JC, Bland, A, Whitaker, R, Calingaert, B, Bentley, RC, Lee, PS, Moorman, PC, Schildkraut, JM, and Berchuck, A. "The prognostic significance of p53 and cyclin E overexpression in ovarian cancer: A population-based study." GYNECOLOGIC ONCOLOGY 108.3 (March 2008): S125-S125.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
108
Issue
3
Publish Date
2008
Start Page
S125
End Page
S125

Stem cell marker CD133 (PROMININ-1) is epigenetically regulated in ovarian cancer

Authors
Baba, T; Convery, PA; Matsumura, N; Whitaker, RS; Perry, T; Huang, Z; Mori, S; Kondoh, E; Bentley, RC; Fujii, S; Marks, JR; Berchuck, A; Murphy, SK
MLA Citation
Baba, T, Convery, PA, Matsumura, N, Whitaker, RS, Perry, T, Huang, Z, Mori, S, Kondoh, E, Bentley, RC, Fujii, S, Marks, JR, Berchuck, A, and Murphy, SK. "Stem cell marker CD133 (PROMININ-1) is epigenetically regulated in ovarian cancer." March 2008.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
108
Issue
3
Publish Date
2008
Start Page
S104
End Page
S104

Gene expression analysis of stage I serous and endornetrioid endometrial cancers

Authors
Risinger, JI; Allard, J; Day, R; Chandran, U; Litzi, T; Rose, G; Berchuck, A; Maxwell, G
MLA Citation
Risinger, JI, Allard, J, Day, R, Chandran, U, Litzi, T, Rose, G, Berchuck, A, and Maxwell, G. "Gene expression analysis of stage I serous and endornetrioid endometrial cancers." GYNECOLOGIC ONCOLOGY 108.3 (March 2008): S76-S76.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
108
Issue
3
Publish Date
2008
Start Page
S76
End Page
S76

Targeting dormant ovarian cancer cells

Authors
Kondoh, E; Baba, T; Matsurnura, N; Fujii, S; Berchuck, A; Murphy, SK
MLA Citation
Kondoh, E, Baba, T, Matsurnura, N, Fujii, S, Berchuck, A, and Murphy, SK. "Targeting dormant ovarian cancer cells." GYNECOLOGIC ONCOLOGY 108.3 (March 2008): S13-S14.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
108
Issue
3
Publish Date
2008
Start Page
S13
End Page
S14

Microarray analysis of microdissected stage I endometrial cancers reveals gene expression patterns associated with inflammation

Authors
Allard, J; Risinger, JI; Day, R; Chandran, U; Litzi, T; Rose, G; Berchuck, A; Maxwell, G
MLA Citation
Allard, J, Risinger, JI, Day, R, Chandran, U, Litzi, T, Rose, G, Berchuck, A, and Maxwell, G. "Microarray analysis of microdissected stage I endometrial cancers reveals gene expression patterns associated with inflammation." GYNECOLOGIC ONCOLOGY 108.3 (March 2008): S80-S81.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
108
Issue
3
Publish Date
2008
Start Page
S80
End Page
S81

Ovarian Cancer Association Consortium analysis of seven candidate ovarian cancer susceptibility polymorphisms

Authors
Ramus, SJ; Vierkant, RA; Jonhatty, S; Schildkraut, JM; Pharoah, PD; Chenevix-Trench, G; Pearce, CL; Berchuck, A; Goode, EL
MLA Citation
Ramus, SJ, Vierkant, RA, Jonhatty, S, Schildkraut, JM, Pharoah, PD, Chenevix-Trench, G, Pearce, CL, Berchuck, A, and Goode, EL. "Ovarian Cancer Association Consortium analysis of seven candidate ovarian cancer susceptibility polymorphisms." GYNECOLOGIC ONCOLOGY 108.3 (March 2008): S29-S30.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
108
Issue
3
Publish Date
2008
Start Page
S29
End Page
S30

Regulation of angiogenic gene expression in p53 wild type and mutant ovarian cancer cells by hypoxia and radiation

Authors
Rubatt, JM; Secord, AA; Iversen, E; Grace, L; Soper, W; Berchuck, A
MLA Citation
Rubatt, JM, Secord, AA, Iversen, E, Grace, L, Soper, W, and Berchuck, A. "Regulation of angiogenic gene expression in p53 wild type and mutant ovarian cancer cells by hypoxia and radiation." GYNECOLOGIC ONCOLOGY 108.3 (March 2008): S84-S84.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
108
Issue
3
Publish Date
2008
Start Page
S84
End Page
S84

Methylation in ovarian cancer is related to poor prognosis and suppression of the transforming growth factor signaling pathway

Authors
Matsumura, N; Huang, Z; Perry, T; Kroyer, D; Baba, T; Mori, S; Fujii, S; Berchuck, A; Murphy, SK
MLA Citation
Matsumura, N, Huang, Z, Perry, T, Kroyer, D, Baba, T, Mori, S, Fujii, S, Berchuck, A, and Murphy, SK. "Methylation in ovarian cancer is related to poor prognosis and suppression of the transforming growth factor signaling pathway." GYNECOLOGIC ONCOLOGY 108.3 (March 2008): S104-S104.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
108
Issue
3
Publish Date
2008
Start Page
S104
End Page
S104

Microarray analysis defines patterns of gene expression associated with mutation of TP53 in ovarian cancer

Authors
Bernardini, MQ; Lee, P; Baba, T; Whitaker, RS; Murphy, SK; Berchuck, A
MLA Citation
Bernardini, MQ, Lee, P, Baba, T, Whitaker, RS, Murphy, SK, and Berchuck, A. "Microarray analysis defines patterns of gene expression associated with mutation of TP53 in ovarian cancer." GYNECOLOGIC ONCOLOGY 108.3 (March 2008): S84-S84.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
108
Issue
3
Publish Date
2008
Start Page
S84
End Page
S84

Microarray analysis identifies NSC668814 as a potentially active chemotherapeutic agent for platinum-resistant ovarian cancers with TP53 mutations

Authors
Baba, T; Mori, S; Matsumura, N; Bernardini, M; Fujii, S; Berchuck, A; Murphy, SK
MLA Citation
Baba, T, Mori, S, Matsumura, N, Bernardini, M, Fujii, S, Berchuck, A, and Murphy, SK. "Microarray analysis identifies NSC668814 as a potentially active chemotherapeutic agent for platinum-resistant ovarian cancers with TP53 mutations." GYNECOLOGIC ONCOLOGY 108.3 (March 2008): S72-S72.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
108
Issue
3
Publish Date
2008
Start Page
S72
End Page
S72

MAL, a gene associated with survival in epithelial ovarian cancer, is epigenetically regulated

Authors
Lee, PS; Teaberry, V; Bland, AE; Huang, Z; Secord, AA; Berchuck, A; Murphy, SK
MLA Citation
Lee, PS, Teaberry, V, Bland, AE, Huang, Z, Secord, AA, Berchuck, A, and Murphy, SK. "MAL, a gene associated with survival in epithelial ovarian cancer, is epigenetically regulated." GYNECOLOGIC ONCOLOGY 108.3 (March 2008): S125-S125.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
108
Issue
3
Publish Date
2008
Start Page
S125
End Page
S125

Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the Ovarian Cancer Association Consortium pooled analysis.

There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3' variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case-control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01-1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62-1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.

Authors
Pearce, CL; Wu, AH; Gayther, SA; Bale, AE; Australian Cancer Study (Ovarian Cancer) and Australian Cancer Study Group, ; Beck, PA; Beesley, J; Chanock, S; Cramer, DW; DiCioccio, R; Edwards, R; Fredericksen, ZS; Garcia-Closas, M; Goode, EL; Green, AC; Hartmann, LC; Hogdall, E; Kjaer, SK; Lissowska, J; McGuire, V; Modugno, F; Moysich, K; Ness, RB; Ramus, SJ; Risch, HA; Sellers, TA; Song, H; Stram, DO; Terry, KL; Webb, PM; Whiteman, DC; Whittemore, AS; Zheng, W; Pharoah, PDP; Chenevix-Trench, G et al.
MLA Citation
Pearce, CL, Wu, AH, Gayther, SA, Bale, AE, Australian Cancer Study (Ovarian Cancer) and Australian Cancer Study Group, , Beck, PA, Beesley, J, Chanock, S, Cramer, DW, DiCioccio, R, Edwards, R, Fredericksen, ZS, Garcia-Closas, M, Goode, EL, Green, AC, Hartmann, LC, Hogdall, E, Kjaer, SK, Lissowska, J, McGuire, V, Modugno, F, Moysich, K, Ness, RB, Ramus, SJ, Risch, HA, Sellers, TA, Song, H, Stram, DO, Terry, KL, Webb, PM, Whiteman, DC, Whittemore, AS, Zheng, W, Pharoah, PDP, and Chenevix-Trench, G et al. "Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the Ovarian Cancer Association Consortium pooled analysis." Br J Cancer 98.2 (January 29, 2008): 282-288.
PMID
18219286
Source
pubmed
Published In
British Journal of Cancer
Volume
98
Issue
2
Publish Date
2008
Start Page
282
End Page
288
DOI
10.1038/sj.bjc.6604170

Role of genetic polymorphisms in ovarian cancer susceptibility: Development of an international ovarian cancer association consortium

Authors
Berchuck, A; Schildkraut, JM; Pearce, CL; Chenevix-Trench, G; Pharoah, PD
MLA Citation
Berchuck, A, Schildkraut, JM, Pearce, CL, Chenevix-Trench, G, and Pharoah, PD. "Role of genetic polymorphisms in ovarian cancer susceptibility: Development of an international ovarian cancer association consortium." Advances in Experimental Medicine and Biology 622 (2008): 53-67.
Source
scival
Published In
Advances in experimental medicine and biology
Volume
622
Publish Date
2008
Start Page
53
End Page
67
DOI
10.1007/978-0-387-68969-2_5

Cyclin E overexpression relates to ovarian cancer histology but not to risk factors [2]

Authors
Schildraut, JM; Moorman, PG; Calingaert, B; Berchuck, A
MLA Citation
Schildraut, JM, Moorman, PG, Calingaert, B, and Berchuck, A. "Cyclin E overexpression relates to ovarian cancer histology but not to risk factors [2]." Cancer Epidemiology Biomarkers and Prevention 17.7 (2008): 1841-1842.
Source
scival
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
17
Issue
7
Publish Date
2008
Start Page
1841
End Page
1842
DOI
10.1158/1055-9965.EPI-08-0491

Role of genetic polymorphisms in ovarian cancer susceptibility: development of an international ovarian cancer association consortium.

Authors
Berchuck, A; Schildkraut, JM; Pearce, CL; Chenevix-Trench, G; Pharoah, PD
MLA Citation
Berchuck, A, Schildkraut, JM, Pearce, CL, Chenevix-Trench, G, and Pharoah, PD. "Role of genetic polymorphisms in ovarian cancer susceptibility: development of an international ovarian cancer association consortium." Adv Exp Med Biol 622 (2008): 53-67. (Review)
PMID
18546618
Source
pubmed
Published In
Advances in experimental medicine and biology
Volume
622
Publish Date
2008
Start Page
53
End Page
67
DOI
10.1007/978-0-387-68969-2_5

Corrigendum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12, (1294-1300))

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Corrigendum: Genomic signatures to guide the use of chemotherapeutics (Nature Medicine (2006) 12, (1294-1300))." Nature Medicine 14.8 (2008): 889--.
Source
scival
Published In
Nature Medicine
Volume
14
Issue
8
Publish Date
2008
Start Page
889-
DOI
10.1038/nm0808-889

Foreword

Authors
Berchuck, A
MLA Citation
Berchuck, A. "Foreword." Gynecologic Oncology 108.3 SUPPL. (2008): S1-.
Source
scival
Published In
Gynecologic Oncology
Volume
108
Issue
3 SUPPL.
Publish Date
2008
Start Page
S1
DOI
10.1016/j.ygyno.2007.11.040

Stem cell marker CD133 (PROMININ-1) is epigenetically regulated in ovarian cancer

Authors
Baba, T; Convey, P; Matsumura, N; Whitaker, RS; Perry, T; Huang, Z; Mori, S; Kondoh, E; Bentley, RC; Fujii, S; Berchuck, A; Murphy, SK; Marks, JR
MLA Citation
Baba, T, Convey, P, Matsumura, N, Whitaker, RS, Perry, T, Huang, Z, Mori, S, Kondoh, E, Bentley, RC, Fujii, S, Berchuck, A, Murphy, SK, and Marks, JR. "Stem cell marker CD133 (PROMININ-1) is epigenetically regulated in ovarian cancer." 2008.
Source
wos-lite
Published In
Cancer biomarkers : section A of Disease markers
Volume
4
Issue
3
Publish Date
2008
Start Page
175
End Page
176

Combining multiple serum tumor markers improves detection of stage I epithelial ovarian cancer.

OBJECTIVE: Currently available tumor markers for ovarian cancer are still inadequate in both sensitivity and specificity to be used for population-based screening. Artificial neural network (ANN) as a modeling tool has demonstrated its ability to assimilate information from multiple sources and to detect subtle and complex patterns. In this paper, an ANN model was evaluated for its performance in detecting early stage epithelial ovarian cancer using multiple serum markers. METHODS: Serum specimens collected at four institutions in the US, The Netherlands and the United Kingdom were analyzed for CA 125II, CA 72-4, CA 15-3 and macrophage colony stimulating factor (M-CSF). The four tumor marker values were then used as inputs to an ANN derived using a training set from 100 apparently healthy women, 45 women with benign conditions arising from the ovary and 55 invasive epithelial ovarian cancer patients (including 27 stage I/II cases). A separate validation set from 27 apparently healthy women, 56 women with benign conditions and 35 women with various types of malignant pelvic masses was used to monitor the ANN's performance during training. An independent test data set from 98 apparently healthy women and 52 early stage epithelial ovarian cancer patients (38 stage I and 4 stage II invasive cases and 10 stage I borderline ovarian tumor cases) was used to evaluate the ANN. RESULTS: ROC analysis confirmed the overall superiority of the ANN-derived composite index over CA 125II alone (p=0.0333). At a fixed specificity of 98%, the sensitivities for ANN and CA 125II alone were 71% (37/52) and 46% (24/52) (p=0.047), respectively, for detecting early stage epithelial ovarian cancer, and 71% (30/42) and 43% (18/42) (p=0.040), respectively, for detecting invasive early stage epithelial ovarian cancer. CONCLUSIONS: The combined use of multiple tumor markers through an ANN improves the overall accuracy to discern healthy women from patients with early stage ovarian cancer. Analysis of multiple markers with an ANN may be a better choice than the use of CA 125II alone in a two-step approach for population screening in which a secondary test such as ultrasound is used to keep the overall specificity at an acceptable level.

Authors
Zhang, Z; Yu, Y; Xu, F; Berchuck, A; van Haaften-Day, C; Havrilesky, LJ; de Bruijn, HWA; van der Zee, AGJ; Woolas, RP; Jacobs, IJ; Skates, S; Chan, DW; Bast, RC
MLA Citation
Zhang, Z, Yu, Y, Xu, F, Berchuck, A, van Haaften-Day, C, Havrilesky, LJ, de Bruijn, HWA, van der Zee, AGJ, Woolas, RP, Jacobs, IJ, Skates, S, Chan, DW, and Bast, RC. "Combining multiple serum tumor markers improves detection of stage I epithelial ovarian cancer." Gynecol Oncol 107.3 (December 2007): 526-531.
PMID
17920110
Source
pubmed
Published In
Gynecologic Oncology
Volume
107
Issue
3
Publish Date
2007
Start Page
526
End Page
531
DOI
10.1016/j.ygyno.2007.08.009

The role of multi-modality adjuvant chemotherapy and radiation in women with advanced stage endometrial cancer.

OBJECTIVE: : The optimal adjuvant therapy for women with stages III and IV endometrial cancer following surgical staging and cytoreductive surgery is controversial. We sought to determine the outcome of patients with advanced stage endometrial cancer treated with postoperative chemotherapy+/-radiation to determine whether there was an advantage to combining treatment modalities. METHODS: : A retrospective analysis of patients with surgical stages III and IV endometrial cancer from 1975 to 2006 was conducted at Duke University and the University of North Carolina. Inclusion criteria were comprehensive staging procedure including hysterectomy, bilateral salpingo-oophorectomy, +/-selective pelvic/aortic lymphadenectomy, surgical debulking, and treatment with adjuvant chemotherapy and/or radiotherapy. Progression-free (PFS) and overall survival (OS) were analyzed using Kaplan-Meier method and Cox proportional hazards model. RESULTS: : 356 Patients with advanced stage endometrial cancer were identified who received postoperative adjuvant therapies; 48% (n=171) radiotherapy alone, 29% (n=102) chemotherapy alone, 23% (n=83) chemotherapy and radiation. The median age was 66 years; 38% had endometrioid tumors; and 83% were optimally debulked. There was a significant difference between the adjuvant treatment groups for both OS and PFS (p<0.001), with those receiving chemotherapy alone having poorer 3-year OS (33%) and PFS (19%) compared to either radiotherapy alone (70% and 59%) or combination therapy (79% and 62%). After adjusting for stage, age, grade, and debulking status the hazard ratio (HR) for OS was 1.60 (95% CI, 0.88 to 2.89; p=0.122) for chemotherapy alone and 2.01 (95% CI, 1.17 to 3.48; p=0.012) for radiotherapy alone, compared to combination therapy. When the analysis was restricted to optimally debulked patients the adjusted HR for patients who were treated with either chemotherapy or radiation alone indicated a significantly higher risk for disease progression [HR=1.84 (95% CI, 1.03 to 3.27; p=0.038); HR=1.80 (95% CI, 1.10 to 2.95; p=0.020)] and death [HR=2.33 (95% CI, 1.12 to 4.86; p=0.024); HR=2.64 (95% CI, 1.38 to 5.07; p=0.004)], respectively, compared to patients who received combination therapy. CONCLUSION: : Combined adjuvant chemotherapy and radiation was associated with improved survival in patients with advanced stage disease compared to either modality alone. Future clinical trials are needed to prospectively evaluate multi-modality adjuvant therapy in women with advanced staged endometrial cancer to determine the appropriate sequencing and types of chemotherapy and radiation.

Authors
Alvarez Secord, A; Havrilesky, LJ; Bae-Jump, V; Chin, J; Calingaert, B; Bland, A; Rutledge, TL; Berchuck, A; Clarke-Pearson, DL; Gehrig, PA
MLA Citation
Alvarez Secord, A, Havrilesky, LJ, Bae-Jump, V, Chin, J, Calingaert, B, Bland, A, Rutledge, TL, Berchuck, A, Clarke-Pearson, DL, and Gehrig, PA. "The role of multi-modality adjuvant chemotherapy and radiation in women with advanced stage endometrial cancer." Gynecol Oncol 107.2 (November 2007): 285-291.
PMID
17688923
Source
pubmed
Published In
Gynecologic Oncology
Volume
107
Issue
2
Publish Date
2007
Start Page
285
End Page
291
DOI
10.1016/j.ygyno.2007.06.014

Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions.

Women with germline mutations in the cancer susceptibility genes, BRCA1 or BRCA2, associated with Hereditary Breast/Ovarian Cancer syndrome, have up to an 85% lifetime risk of breast cancer and up to a 46% lifetime risk ovarian cancer. Similarly, women with mutations in the DNA mismatch repair genes, MLH1, MSH2 or MSH6, associated with the Lynch/Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome, have up to a 40-60% lifetime risk of both endometrial and colorectal cancer as well as a 9-12% lifetime risk of ovarian cancer. Genetic risk assessment enables physicians to provide individualized evaluation of the likelihood of having one of these gynecologic cancer predisposition syndromes, as well the opportunity to provide tailored screening and prevention strategies such as surveillance, chemoprevention, and prophylactic surgery that may reduce the morbidity and mortality associated with these syndromes. Hereditary cancer risk assessment is a process that includes assessment of risk, education and counseling conducted by a provider with expertise in cancer genetics, and may include genetic testing after appropriate consent is obtained. This commentary provides guidance on identification of patients who may benefit from hereditary cancer risk assessment for Hereditary Breast/Ovarian Cancer and the Lynch/Hereditary Non-Polyposis Colorectal Cancer syndrome.

Authors
Lancaster, JM; Powell, CB; Kauff, ND; Cass, I; Chen, L-M; Lu, KH; Mutch, DG; Berchuck, A; Karlan, BY; Herzog, TJ; Society of Gynecologic Oncologists Education Committee,
MLA Citation
Lancaster, JM, Powell, CB, Kauff, ND, Cass, I, Chen, L-M, Lu, KH, Mutch, DG, Berchuck, A, Karlan, BY, Herzog, TJ, and Society of Gynecologic Oncologists Education Committee, . "Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions." Gynecol Oncol 107.2 (November 2007): 159-162.
PMID
17950381
Source
pubmed
Published In
Gynecologic Oncology
Volume
107
Issue
2
Publish Date
2007
Start Page
159
End Page
162
DOI
10.1016/j.ygyno.2007.09.031

Overexpression of folate binding protein is associated with shortened progression-free survival in uterine adenocarcinomas.

OBJECTIVES: Oligonucleotide array and tissue microarray analysis (TMA) by our group has revealed that folate binding protein (FOLR1) is overexpressed in some types of uterine cancer, particularly tumors with serous histology. Since FOLR1 overexpression is a frequent event in some types of endometrial carcinoma, we examined the relationship between FOLR1 overexpression and clinical and pathologic features to determine its prognostic relevance. METHODS: A tissue microarray (TMA) comprised of primary tumor specimens from 485 patients diagnosed with endometrial adenocarcinoma was used to identify cases characterized by FOLR1 overexpression. A proportional hazards model was used to evaluate the association of FOLR1 overexpression with progression-free survival while accounting for confounding influences. RESULTS: Overexpression of FOLR1 was observed in 50/292 (17%) cases and was seen more often in poorly differentiated cancers (22/90 [24%], p=0.051) and tumors with serous histology (16/32 [50%], p<0.001). A shorter progression-free survival was noted in patients with FOLR1 overexpression (log-rank p=0.016) that persisted when the data were limited to patients with stage III/IV disease (log-rank p=0.021) or serous tumors (log-rank p=0.020). Multivariate Cox regression analysis revealed that patients with FOLR1 overexpression had a shorter progression-free survival (H.R. 2.14; 95% CI 1.07-4.28) even when controlling for stage, grade, myometrial invasion and adjuvant chemotherapy. CONCLUSIONS: Our data show that FOLR1 overexpression is not only a biomarker associated with endometrial cancer, but it also appears to be a prognostic factor associated with adverse outcome. These findings suggest that FOLR1 may be an appealing target for biological therapies in some types of endometrial carcinomas.

Authors
Allard, JE; Risinger, JI; Morrison, C; Young, G; Rose, GS; Fowler, J; Berchuck, A; Maxwell, GL
MLA Citation
Allard, JE, Risinger, JI, Morrison, C, Young, G, Rose, GS, Fowler, J, Berchuck, A, and Maxwell, GL. "Overexpression of folate binding protein is associated with shortened progression-free survival in uterine adenocarcinomas." Gynecol Oncol 107.1 (October 2007): 52-57.
PMID
17582475
Source
pubmed
Published In
Gynecologic Oncology
Volume
107
Issue
1
Publish Date
2007
Start Page
52
End Page
57
DOI
10.1016/j.ygyno.2007.05.018

Chemotherapy administration for ovarian cancer by gynecologic oncologists and medical oncologists.

Authors
Berchuck, A
MLA Citation
Berchuck, A. "Chemotherapy administration for ovarian cancer by gynecologic oncologists and medical oncologists." J Clin Oncol 25.23 (August 10, 2007): 3552-. (Letter)
PMID
17687164
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
23
Publish Date
2007
Start Page
3552
DOI
10.1200/JCO.2007.12.2960

Co-expression of angiogenic markers and associations with prognosis in advanced epithelial ovarian cancer: a Gynecologic Oncology Group study.

OBJECTIVES: The aim of this study was to explore the co-expression and prognostic relevance of thrombospondin-1 (THBS-1), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and VEGF receptor 1 (VEGFR-1) in epithelial ovarian cancer (EOC). METHODS: Frozen tumor specimens with defined p53 status were obtained from 67 patients with previously untreated advanced-stage EOC who participated in a Gynecologic Oncology Group specimen-banking protocol and a phase III treatment protocol. Relative expression of the angiogenic markers was quantified by immunoblot analysis and categorized at the median angiogenic marker/actin ratio. p-values are provided as an indication of confidence in the results and to prioritize further testing. RESULTS: An association was observed between categorized VEGF and p53 overexpression (p=0.022), and between VEGFR-1 and race (p=0.027) or histologic subtype (p=0.007). Unadjusted Cox regression analyses indicated that high compared with low THBS-1, but not VEGF or VEGFR-1, was associated with an increased risk of disease progression (hazard ratio [HR]=2.19; 95% confidence interval [CI]=1.29-3.71; p=0.004) and death (HR=1.93; 95% CI=1.12-3.32; p=0.018) whereas bFGF was associated with a reduced risk of disease progression (HR=0.60; 95% CI=0.36-0.99; p=0.046) and death (HR=0.54; 95% CI=0.32-0.93; p=0.026). After adjusting for prognostic factors including clinical characteristics and p53 overexpression, THBS-1 but not bFGF, VEGF or VEGFR-1 was associated with progression-free and overall survival. CONCLUSIONS: These data suggest that high THBS-1 is an independent predictor of worse progression-free and overall survival in women with advanced-stage EOC. A larger prospective study is warranted for validation of these findings.

Authors
Secord, AA; Darcy, KM; Hutson, A; Lee, PS; Havrilesky, LJ; Grace, LA; Berchuck, A; Gynecologic Oncology Group study,
MLA Citation
Secord, AA, Darcy, KM, Hutson, A, Lee, PS, Havrilesky, LJ, Grace, LA, Berchuck, A, and Gynecologic Oncology Group study, . "Co-expression of angiogenic markers and associations with prognosis in advanced epithelial ovarian cancer: a Gynecologic Oncology Group study." Gynecol Oncol 106.1 (July 2007): 221-232.
PMID
17481705
Source
pubmed
Published In
Gynecologic Oncology
Volume
106
Issue
1
Publish Date
2007
Start Page
221
End Page
232
DOI
10.1016/j.ygyno.2007.03.021

The role of genetic testing for cancer susceptibility in gynecologic practice.

Genetic counseling and testing for inherited disorders are part of every obstetrician-gynecologist's practice. Family history, ethnicity, and race are routinely evaluated as a part of the prenatal assessment. The discovery of genes responsible for inherited cancer susceptibility and the wide availability of clinical genetic testing for mutations in these genes have made similar assessments an integral part of gynecologic practice as well. The indications for genetic testing for mutations in BRCA1, BRCA2, and the mismatch repair genes responsible for the hereditary nonpolyposis colon cancer (HNPCC) syndrome need to be individualized. As in obstetrics, genetic counseling can provide critical assessment of the family history to help determine the likelihood of an inherited cancer susceptibility syndrome and the appropriateness of genetic testing. The subsequent clinical recommendations for mutation carriers need to take into account the patient's age, desire for future childbearing, and other medical history when prescribing screening interventions or prophylactic surgery. Practical applications of genetic testing for cancer susceptibility have the ability to reduce the burden of hereditary cancers by saving lives, decreasing medical morbidities, and reducing psychological stress.

Authors
Karlan, BY; Berchuck, A; Mutch, D
MLA Citation
Karlan, BY, Berchuck, A, and Mutch, D. "The role of genetic testing for cancer susceptibility in gynecologic practice." Obstet Gynecol 110.1 (July 2007): 155-167. (Review)
PMID
17601911
Source
pubmed
Published In
Obstetrics & Gynecology (Elsevier)
Volume
110
Issue
1
Publish Date
2007
Start Page
155
End Page
167
DOI
10.1097/01.AOG.0000269050.79143.84

Outcomes in surgical stage I uterine papillary serous carcinoma.

OBJECTIVE: The optimal management of patients with stage I uterine papillary serous carcinoma (UPSC) is unclear. We sought to determine whether outcomes of women with surgical stage I UPSC differ with and without adjuvant therapy. METHODS: Retrospective multi-institution analysis of women with stage I UPSC surgically staged from 1976 to 2006. INCLUSION CRITERIA: comprehensive staging procedure including hysterectomy, bilateral salpingo-oophorectomy, selective pelvic/aortic lymphadenectomy, peritoneal cytology. Recurrence and survival were analyzed using Kaplan-Meier method. RESULTS: Of 83 women with stage I UPSC, 36 (43%) received adjuvant therapies (23% radiotherapy, 3% chemotherapy, 15% chemotherapy and radiotherapy, 2% progestins). Three-year overall (OS) and progression-free survival (PFS) were 80% and 68%, respectively. Three-year OS and PFS by adjuvant treatment were observation (N=47) 86% and 78%, radiotherapy (N=17) 63% and 44%, chemotherapy with or without radiotherapy (N=17) 92% and 76%, respectively. Of the 18 recurrences, 9 (50%) included an extrapelvic component. Local recurrence was 2/30 (7%) following adjuvant radiotherapy and 7/53 (13%) without radiotherapy (p=0.48). Recurrence was higher in stage IB/IC (15/51, 29%) compared to stage IA (3/32, 9%). There has been one recurrence (5%) among the 22 women observed with stage IA disease. CONCLUSION: In this largest reported series of women with surgical stage I UPSC, the high recurrence (29%) among patients with stage IB/IC disease highlights the need for clinical trials to test new therapeutic approaches. Surgically staged patients with IA disease had good prognosis. These data suggest that radiotherapy alone is not effective, that systemic therapy is needed, and that observation could be considered in patients with stage IA disease.

Authors
Havrilesky, LJ; Secord, AA; Bae-Jump, V; Ayeni, T; Calingaert, B; Clarke-Pearson, DL; Berchuck, A; Gehrig, PA
MLA Citation
Havrilesky, LJ, Secord, AA, Bae-Jump, V, Ayeni, T, Calingaert, B, Clarke-Pearson, DL, Berchuck, A, and Gehrig, PA. "Outcomes in surgical stage I uterine papillary serous carcinoma." Gynecol Oncol 105.3 (June 2007): 677-682.
PMID
17355889
Source
pubmed
Published In
Gynecologic Oncology
Volume
105
Issue
3
Publish Date
2007
Start Page
677
End Page
682
DOI
10.1016/j.ygyno.2007.01.041

Overexpression of folate binding protein and mesothelin are associated with uterine serous carcinoma.

PURPOSE: Folate receptor alpha (FOLR1) is a membrane bound receptor involved in the transport of folate as well as other regulatory cellular processes. The purpose of this study was to examine the expression of FOLR1 in uterine cancers and to identify changes in gene expression that are associated with overexpression of FOLR1. EXPERIMENTAL DESIGN: Fifty-eight frozen uterine cancer specimens were stained for FOLR1 using immunohistochemistry and results were correlated with transcript expression noted on quantitative PCR. Total RNA from 16 cases of uterine serous carcinoma (USC) was analyzed for gene expression using the Affymetrix HG-U133A and HG-U133B GeneChip set. USCs overexpressing FOLR1 were compared to cancers with an absence of FOLR1 using binary comparison and template matching of data was used to identify genes that correlate with FOLR1 expression. Selected targets from this analysis were evaluated by quantitative PCR as well as in an independent set of USC represented in quadruplicate on a tissue microarray (TMA). RESULTS: Overexpression of FOLR1 was observed in 11/16 (69%) of USC and 0/10 normal endometrium cases using frozen tissue specimens. Binary comparison between FOLR1 positive and negative cases identified 121 genes altered by 2-fold at p<0.01 of which 45 are well correlated with FOLR1 expression pattern. Using quantitative PCR, both mesothelin (MSLN) and PTGS1 (COX1) were significantly increased in FOLR1 overexpressing tumors (p=0.014 and p=0.006 respectively). TMA confirmed that overexpression of FOLR1 and MSLN respectively occurred in 23/48 (48%) and 17/54 (32%) of pure USC. CONCLUSION: Both FOLR1 and MSLN are cell surface targets that are co-expressed at high levels in USC and are appealing targets for biologic therapy.

Authors
Dainty, LA; Risinger, JI; Morrison, C; Chandramouli, GVR; Bidus, MA; Zahn, C; Rose, GS; Fowler, J; Berchuck, A; Maxwell, GL
MLA Citation
Dainty, LA, Risinger, JI, Morrison, C, Chandramouli, GVR, Bidus, MA, Zahn, C, Rose, GS, Fowler, J, Berchuck, A, and Maxwell, GL. "Overexpression of folate binding protein and mesothelin are associated with uterine serous carcinoma." Gynecol Oncol 105.3 (June 2007): 563-570.
PMID
17400285
Source
pubmed
Published In
Gynecologic Oncology
Volume
105
Issue
3
Publish Date
2007
Start Page
563
End Page
570
DOI
10.1016/j.ygyno.2006.10.063

Regulation of the metastasis suppressor gene MKK4 in ovarian cancer.

OBJECTIVES: MKK4 is a metastasis suppressor that is downregulated in some ovarian cancers. We sought to investigate whether promoter methylation, loss of heterozygosity, or changes in phosphorylation are involved in MKK4 dysregulation during ovarian carcinogenesis. METHODS: Bisulfite sequencing was used to determine MKK4 promoter methylation. PCR analysis of tumor/normal DNA was performed to determine LOH at the MKK4 locus. Normal human ovarian surface epithelium (HOSE) and SKOV-3 cells were serum starved and treated with EGF, TGFbeta, or wortmannin. Western blotting was performed using antibodies that detect total and phosphorylated MKK4. RESULTS: No MKK4 promoter hypermethylation was detected in 21 ovarian cancers. LOH was detected at the MKK4 intragenic marker D17S969 in 35% of cases and at D17S1303 in 20%. MKK4 protein was detected in 97% of ovarian tumors. The inactivated phosphoserine 80 (ser-80) form comprised 62% of phosphorylated MKK4 protein in ovarian tumors. Treatment of HOSE or SKOV-3 cells with EGF induced a 1.7- to 4.2-fold increase in phosphorylation of ser-80 MKK4 without altering total MKK4 protein. TGFbeta increased MKK4 ser-80 phosphorylation by 5.4-fold above baseline. The PI3K/Akt pathway inhibitor wortmannin decreased the amount of ser-80 MKK4 by 50%, and inhibited EGF stimulation of MKK4 ser-80 phosphorylation by 60%. CONCLUSIONS: LOH of MKK4 occurs in some ovarian cancers, but without loss of MKK4 protein. MKK4 expression does not appear to be downregulated by promoter methylation. Peptide growth factors induce MKK4 ser-80 phosphorylation, which downregulates its activity. PI3K/Akt pathway inhibitors can partially block ser-80 phosphorylation and this may have therapeutic implications.

Authors
Spillman, MA; Lacy, J; Murphy, SK; Whitaker, RS; Grace, L; Teaberry, V; Marks, JR; Berchuck, A
MLA Citation
Spillman, MA, Lacy, J, Murphy, SK, Whitaker, RS, Grace, L, Teaberry, V, Marks, JR, and Berchuck, A. "Regulation of the metastasis suppressor gene MKK4 in ovarian cancer." Gynecol Oncol 105.2 (May 2007): 312-320.
PMID
17276500
Source
pubmed
Published In
Gynecologic Oncology
Volume
105
Issue
2
Publish Date
2007
Start Page
312
End Page
320
DOI
10.1016/j.ygyno.2006.12.017

Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer.

High-risk susceptibility genes explain <40% of the excess risk of familial ovarian cancer. Therefore, other ovarian cancer susceptibility genes are likely to exist. We have used a single nucleotide polymorphism (SNP)-tagging approach to evaluate common variants in 13 genes involved in cell cycle control-CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D-and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark ( approximately 1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States ( approximately 2,000 cases and approximately 3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85-0.98) for rs3731257; and OR, 0.93 (0.87-0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies.

Authors
Gayther, SA; Song, H; Ramus, SJ; Kjaer, SK; Whittemore, AS; Quaye, L; Tyrer, J; Shadforth, D; Hogdall, E; Hogdall, C; Blaeker, J; DiCioccio, R; McGuire, V; Webb, PM; Beesley, J; Green, AC; Whiteman, DC; Australian Ovarian Cancer Study Group, ; Goodman, MT; Lurie, G; Carney, ME; Modugno, F; Ness, RB; Edwards, RP; Moysich, KB; Goode, EL; Couch, FJ; Cunningham, JM; Sellers, TA; Wu, AH; Pike, MC; Iversen, ES; Marks, JR; Garcia-Closas, M; Brinton, L; Lissowska, J; Peplonska, B; Easton, DF; Jacobs, I et al.
MLA Citation
Gayther, SA, Song, H, Ramus, SJ, Kjaer, SK, Whittemore, AS, Quaye, L, Tyrer, J, Shadforth, D, Hogdall, E, Hogdall, C, Blaeker, J, DiCioccio, R, McGuire, V, Webb, PM, Beesley, J, Green, AC, Whiteman, DC, Australian Ovarian Cancer Study Group, , Goodman, MT, Lurie, G, Carney, ME, Modugno, F, Ness, RB, Edwards, RP, Moysich, KB, Goode, EL, Couch, FJ, Cunningham, JM, Sellers, TA, Wu, AH, Pike, MC, Iversen, ES, Marks, JR, Garcia-Closas, M, Brinton, L, Lissowska, J, Peplonska, B, Easton, DF, and Jacobs, I et al. "Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer." Cancer Res 67.7 (April 1, 2007): 3027-3035.
PMID
17409409
Source
pubmed
Published In
Cancer Research
Volume
67
Issue
7
Publish Date
2007
Start Page
3027
End Page
3035
DOI
10.1158/0008-5472.CAN-06-3261

Global expression analysis of cancer/testis genes in uterine cancers reveals a high incidence of BORIS expression.

PURPOSE: Cancer/testis (CT) genes predominantly expressed in the testis (germ cells) and generally not in other normal tissues are aberrantly expressed in human cancers. This highly restricted expression provides a unique opportunity to use these CT genes for diagnostics, immunotherapeutic, or other targeted therapies. The purpose of this study was to identify those CT genes with the greatest incidence of expression in uterine cancers. EXPERIMENTAL DESIGN: We queried the expression of known and putative CT gene transcripts (representing 79 gene loci) using whole genome gene expression arrays. Specifically, the global gene expressions of uterine cancers (n = 122) and normal uteri (n = 10) were determined using expression data from the Affymetrix HG-U133A and HG-U133B chips. Additionally, we also examined the brother of the regulator of imprinted sites (BORIS) transcript by reverse transcription-PCR and quantitative PCR because its transcript was not represented on the array. RESULTS: Global microarray analysis detected many CT genes expressed in various uterine cancers; however, no individual CT gene was expressed in more than 25% of all cancers. The expression of the two most commonly expressed CT genes on the arrays, MAGEA9 (24 of 122 cancers and 0 of 10 normal tissues) and Down syndrome critical region 8 (DSCR8)/MMA1 (16 if 122 cancers and 0 of 10 normal tissues), was confirmed by reverse transcription-PCR methods, validating the array screening approach. In contrast to the relatively low incidence of expression of the other CT genes, BORIS expression was detected in 73 of 95 (77%) endometrial cancers and 24 of 31 (77%) uterine mixed mesodermal tumors. CONCLUSIONS: These data provide the first extensive survey of multiple CT genes in uterine cancers. Importantly, we detected a high frequency of BORIS expression in uterine cancers, suggesting its potential as an immunologic or diagnostic target for these cancers. Given the high incidence of BORIS expression and its possible regulatory role, an examination of BORIS function in the etiology of these cancers is warranted.

Authors
Risinger, JI; Chandramouli, GVR; Maxwell, GL; Custer, M; Pack, S; Loukinov, D; Aprelikova, O; Litzi, T; Schrump, DS; Murphy, SK; Berchuck, A; Lobanenkov, V; Barrett, JC
MLA Citation
Risinger, JI, Chandramouli, GVR, Maxwell, GL, Custer, M, Pack, S, Loukinov, D, Aprelikova, O, Litzi, T, Schrump, DS, Murphy, SK, Berchuck, A, Lobanenkov, V, and Barrett, JC. "Global expression analysis of cancer/testis genes in uterine cancers reveals a high incidence of BORIS expression." Clin Cancer Res 13.6 (March 15, 2007): 1713-1719.
PMID
17363524
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
13
Issue
6
Publish Date
2007
Start Page
1713
End Page
1719
DOI
10.1158/1078-0432.CCR-05-2569

Trinucleotide repeat polymorphisms in the androgen receptor gene and risk of ovarian cancer.

INTRODUCTION: Androgens may play a role in the development of ovarian cancers. Two trinucleotide repeat polymorphisms have been described in exon 1 of the androgen receptor (AR) gene that may affect its function. Previous studies of ovarian cancer and AR repeat polymorphisms have been inconsistent. METHODS: We analyzed CAG and GGC repeat length polymorphisms in the AR gene using data from a population-based case-control study of ovarian cancer that included 594 cases and 681 controls. Repeat lengths were determined by fluorescent DNA fragment analysis using ABI GeneScan software. Change point models were used to determine appropriate repeat length cutoff points by race (African American versus Caucasian) for both the shorter and longer CAG and GGC repeats. RESULTS: No relationship was observed between CAG repeat length and ovarian cancer among Caucasians. Among African Americans, having a short repeat length on either allele was associated with a 2-fold increase in ovarian cancer risk (age-adjusted odds ratio, 2.2; 95% confidence interval, 1.1-4.1). Having short CAG repeat lengths for both alleles was associated with a 5-fold increased risk for developing ovarian cancer (age-adjusted odds ratio, 5.4; 95% confidence interval, 1.4-1.7). No relationship with the GGC repeat length polymorphisms was observed. CONCLUSION: These results suggest that having a short CAG repeat length in AR increases ovarian cancer risk in African Americans. The failure to observe this relationship in Caucasians may be due to the rarity of such short CAG alleles in this population or could reflect racial differences in disease etiology.

Authors
Schildkraut, JM; Murphy, SK; Palmieri, RT; Iversen, E; Moorman, PG; Huang, Z; Halabi, S; Calingaert, B; Gusberg, A; Marks, JR; Berchuck, A
MLA Citation
Schildkraut, JM, Murphy, SK, Palmieri, RT, Iversen, E, Moorman, PG, Huang, Z, Halabi, S, Calingaert, B, Gusberg, A, Marks, JR, and Berchuck, A. "Trinucleotide repeat polymorphisms in the androgen receptor gene and risk of ovarian cancer." Cancer Epidemiol Biomarkers Prev 16.3 (March 2007): 473-480.
PMID
17372242
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
16
Issue
3
Publish Date
2007
Start Page
473
End Page
480
DOI
10.1158/1055-9965.EPI-06-0868

Most early-stage serous ovarian cancers have gene expression profiles predictive of long-term survival

Authors
Berchuck, A; Lancaster, JM; Iversen, ES; Luo, J; Levine, DA; Boyd, J; Secord, AA; Marks, JR; Nevins, JR; Dressman, H
MLA Citation
Berchuck, A, Lancaster, JM, Iversen, ES, Luo, J, Levine, DA, Boyd, J, Secord, AA, Marks, JR, Nevins, JR, and Dressman, H. "Most early-stage serous ovarian cancers have gene expression profiles predictive of long-term survival." March 2007.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
104
Issue
3
Publish Date
2007
Start Page
S15
End Page
S16

Preclinical evaluation of biomarkers for ovarian cancer detection and monitoring for disease recurrence

Authors
Havrilesky, LJ; Whitehead, C; Rubatt, J; Cheek, RL; Groelke, J; He, Q; Malinowski, DP; Fischer, TJ; Berchuck, A
MLA Citation
Havrilesky, LJ, Whitehead, C, Rubatt, J, Cheek, RL, Groelke, J, He, Q, Malinowski, DP, Fischer, TJ, and Berchuck, A. "Preclinical evaluation of biomarkers for ovarian cancer detection and monitoring for disease recurrence." GYNECOLOGIC ONCOLOGY 104.3 (March 2007): S12-S12.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
104
Issue
3
Publish Date
2007
Start Page
S12
End Page
S12

The role of multimodality adjuvant chemotherapy and radiation in women with advanced-stage endometrial cancer

Authors
Alvarez Secord, A; Gehrig, PA; Havrilesky, LJ; Bae-Jump, V; Chin, J; Calingaert, B; Bland, A; Rutledge, T; Berchuck, A; Clarke-Pearson, DL
MLA Citation
Alvarez Secord, A, Gehrig, PA, Havrilesky, LJ, Bae-Jump, V, Chin, J, Calingaert, B, Bland, A, Rutledge, T, Berchuck, A, and Clarke-Pearson, DL. "The role of multimodality adjuvant chemotherapy and radiation in women with advanced-stage endometrial cancer." GYNECOLOGIC ONCOLOGY 104.3 (March 2007): S6-S6.
Source
wos-lite
Published In
Gynecologic Oncology
Volume
104
Issue
3
Publish Date
2007
Start Page
S6
End Page
S6

An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer.

PURPOSE: The purpose of this study was to develop an integrated genomic-based approach to personalized treatment of patients with advanced-stage ovarian cancer. We have used gene expression profiles to identify patients likely to be resistant to primary platinum-based chemotherapy and also to identify alternate targeted therapeutic options for patients with de novo platinum-resistant disease. PATIENTS AND METHODS: A gene expression model that predicts response to platinum-based therapy was developed using a training set of 83 advanced-stage serous ovarian cancers and tested on a 36-sample external validation set. In parallel, expression signatures that define the status of oncogenic signaling pathways were evaluated in 119 primary ovarian cancers and 12 ovarian cancer cell lines. In an effort to increase chemotherapy sensitivity, pathways shown to be activated in platinum-resistant cancers were subject to targeted therapy in ovarian cancer cell lines. RESULTS: Gene expression profiles identified patients with ovarian cancer likely to be resistant to primary platinum-based chemotherapy with greater than 80% accuracy. In patients with platinum-resistant disease, we identified expression signatures consistent with activation of Src and Rb/E2F pathways, components of which were successfully targeted to increase response in ovarian cancer cell lines. CONCLUSION: We have defined a strategy for treatment of patients with advanced-stage ovarian cancer that uses therapeutic stratification based on predictions of response to chemotherapy, coupled with prediction of oncogenic pathway deregulation, as a method to direct the use of targeted agents.

Authors
Dressman, HK; Berchuck, A; Chan, G; Zhai, J; Bild, A; Sayer, R; Cragun, J; Clarke, J; Whitaker, RS; Li, L; Gray, J; Marks, J; Ginsburg, GS; Potti, A; West, M; Nevins, JR; Lancaster, JM
MLA Citation
Dressman, HK, Berchuck, A, Chan, G, Zhai, J, Bild, A, Sayer, R, Cragun, J, Clarke, J, Whitaker, RS, Li, L, Gray, J, Marks, J, Ginsburg, GS, Potti, A, West, M, Nevins, JR, and Lancaster, JM. "An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer." J Clin Oncol 25.5 (February 10, 2007): 517-525.
PMID
17290060
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
5
Publish Date
2007
Start Page
517
End Page
525
DOI
10.1200/JCO.2006.06.3743

Magellan: a web based system for the integrated analysis of heterogeneous biological data and annotations; application to DNA copy number and expression data in ovarian cancer.

Recent advances in high throughput biological methods allow researchers to generate enormous amounts of data from a single experiment. In order to extract meaningful conclusions from this tidal wave of data, it will be necessary to develop analytical methods of sufficient power and utility. It is particularly important that biologists themselves be able to perform many of these analyses, such that their background knowledge of the experimental system under study can be used to interpret results and direct further inquiries. We have developed a web-based system, Magellan, which allows the upload, storage, and analysis of multivariate data and textual or numerical annotations. Data and annotations are treated as abstract entities, to maximize the different types of information the system can store and analyze. Annotations can be used in analyses/visualizations, as a means of subsetting data to reduce dimensionality, or as a means of projecting variables from one data type or data set to another. Analytical methods are deployed within Magellan such that new functionalities can be added in a straightforward fashion. Using Magellan, we performed an integrated analysis of genome-wide comparative genomic hybridization (CGH), mRNA expression, and clinical data from ovarian tumors. Analyses included the use of permutation-based methods to identify genes whose mRNA expression levels correlated with patient survival, a nearest neighbor classifier to predict patient survival from CGH data, and curated annotations such as genomic position and derived annotations such as statistical computations to explore the quantitative relationship between CGH and mRNA expression data.

Authors
Kingsley, CB; Kuo, W-L; Polikoff, D; Berchuck, A; Gray, JW; Jain, AN
MLA Citation
Kingsley, CB, Kuo, W-L, Polikoff, D, Berchuck, A, Gray, JW, and Jain, AN. "Magellan: a web based system for the integrated analysis of heterogeneous biological data and annotations; application to DNA copy number and expression data in ovarian cancer. (Published online)" Cancer Inform 2 (February 5, 2007): 10-21.
PMID
19458754
Source
pubmed
Published In
Cancer Informatics
Volume
2
Publish Date
2007
Start Page
10
End Page
21

Weekly low-dose paclitaxel and carboplatin in the treatment of advanced or recurrent cervical and endometrial cancer.

BACKGROUND: The purpose of this study was to evaluate the toxicity profile of weekly low-dose paclitaxel and carboplatin in patients with gynecologic malignancies. METHODS: Patients had measurable disease defined by clinical examination or radiographic studies. Each cycle of treatment consisted of carboplatin at an AUC of 2 and paclitaxel at 80 mg/m2 on days 1, 8, and 15 of a 28-day cycle. RESULTS: Twenty-eight patients with advanced or recurrent cervical and endometrial cancers were included in this study. The overall response rate (ORR) was 39% (2 CR, 9 PR). Among the 15 cervical cancers the ORR was 20%, while the 13 endometrial cancers had a 62% ORR. Median time to progression and overall survival was 3.4 and 7.6 months for those with cervical cancer and 5.5 and 15.4 months for those with endometrial cancer. Grade 3 or 4 hematologic toxicity was uncommon (7% grade 3 anemia, 21% grade 3 or 4 neutropenia, 7% grade 3 or 4 thrombocytopenia). CONCLUSION: A regimen of weekly low-dose paclitaxel and carboplatin has an acceptable toxicity profile that is easily managed by dose adjustment and the use of erythropoietic therapy. This regimen appears to have activity in advanced or recurrent endometrial cancer which warrants further evaluation.

Authors
Secord, AA; Havrilesky, LJ; Carney, ME; Soper, JT; Clarke-Pearson, DL; Rodriguez, GC; Berchuck, A
MLA Citation
Secord, AA, Havrilesky, LJ, Carney, ME, Soper, JT, Clarke-Pearson, DL, Rodriguez, GC, and Berchuck, A. "Weekly low-dose paclitaxel and carboplatin in the treatment of advanced or recurrent cervical and endometrial cancer." Int J Clin Oncol 12.1 (February 2007): 31-36.
PMID
17380438
Source
pubmed
Published In
International Journal of Clinical Oncology
Volume
12
Issue
1
Publish Date
2007
Start Page
31
End Page
36
DOI
10.1007/s10147-006-0619-9

The prognostic significance of positive peritoneal cytology and adnexal/serosal metastasis in stage IIIA endometrial cancer.

OBJECTIVE: The clinical significance and optimal management of patients with stage IIIA endometrial cancer are controversial. We sought to determine whether recurrence and survival of patients with stage IIIA endometrial cancer differ with surgical pathologic findings (positive peritoneal cytology versus positive adnexae or serosa) and adjuvant treatment. METHODS: Retrospective single institution analysis of patients surgically staged for IIIA endometrial cancer at Duke University Medical Center from 1973 to 2002. Stage IIIA patients were stratified into positive cytology alone (group IIIA1, n=37) and positive adnexae or uterine serosa (group IIIA2, n=20). Comparison was made with previously reported group of 467 patients with surgical stage I/II disease. Recurrence and survival were analyzed using Kaplan-Meier estimations and Cox proportional hazards model. RESULTS: Mean age of 57 patients with stage IIIA endometrial cancer was 63. Adjuvant therapies were administered to 89% patients (74% radiotherapy, 4% chemotherapy, 19% progestins). Five-year overall (OS) and recurrence-free disease-specific survival (RFDSS) were 64% and 76%, respectively. Survival was similar comparing IIIA1 (62%) and IIIA2 (68%, p=0.999). RFDSS by adjuvant therapy was: external beam radiotherapy 89% (n=10), intraperitoneal P32 84% (n=21), progestins 78% (n=9), none 75% (n=6). 61% recurrences included extrapelvic component. In multivariable analysis of stage I-IIIA patients (n=517), positive cytology but not adnexal/serosal metastasis was predictive of death (HR 1.70, 95% CI 1.06-2.73) and disease recurrence (HR 1.70, 95% CI 1.07-2.71). CONCLUSION: Among patients with stage IIIA endometrial cancer, metastasis to adnexae or serosa does not appear to confer worse prognosis than positive cytology alone. Positive cytology is an independent predictor of prognosis among patients with stage I-IIIA endometrial cancer. While optimal adjuvant therapy for these groups remains unclear, recurrence patterns suggest that systemic therapies are appropriate.

Authors
Havrilesky, LJ; Cragun, JM; Calingaert, B; Alvarez Secord, A; Valea, FA; Clarke-Pearson, DL; Berchuck, A; Soper, JT
MLA Citation
Havrilesky, LJ, Cragun, JM, Calingaert, B, Alvarez Secord, A, Valea, FA, Clarke-Pearson, DL, Berchuck, A, and Soper, JT. "The prognostic significance of positive peritoneal cytology and adnexal/serosal metastasis in stage IIIA endometrial cancer." Gynecol Oncol 104.2 (February 2007): 401-405.
PMID
17014898
Source
pubmed
Published In
Gynecologic Oncology
Volume
104
Issue
2
Publish Date
2007
Start Page
401
End Page
405
DOI
10.1016/j.ygyno.2006.08.027

Comparison of gracilis and rectus abdominis myocutaneous flap neovaginal reconstruction performed during radical pelvic surgery: flap-specific morbidity.

To compare flap-specific complications of gracilis myocutaneous (GM) and rectus abdominis myocutaneous (RAM) flap neovaginal reconstructions after radical pelvic surgery. The study was a single-institution retrospective review of patients undergoing concurrent radical pelvic surgery with GM or RAM neovaginal reconstructions performed on a gynecological oncology service, 1978-2003. Flap-specific complications were compared between the techniques. Forty-four GM and 32 RAM neovaginal reconstructions were analyzed: plastic surgeons developed 12 (27%) GM and 4 (13%) RAM flaps, with all other flaps performed by gynecological oncologists. Primary procedures included 54 (71%) total pelvic exenterations, with partial exenterations or radical vulvovaginectomies in 16 (21%) and 6 (8%) patients, respectively. Forty (53%) patients had received radiation and 28 (36%) received chemoradiation before radical surgery. There were no significant differences in patient characteristics, other than more frequent use of continent urinary conduits (P < 0.001) and a trend for more frequent sidewall radiation (P < 0.1) in the RAM group, reflecting use in more recent patients (P < 0.001). Median follow-up is 28 months (range: 2 weeks to 216 months), with 5% acute operative mortality. Flap-specific complications were significantly increased in GM patients (P < 0.03). Overall flap loss was significantly increased in GM patients (P < 0.02). Thirty (59%) of 51 patients surviving for more than 12 months reported coitus, with no significant difference between the groups. Because of lower overall incidence of flap-specific complications and significantly lower incidence of flap loss compared with GM flap, RAM flap has become our technique of choice for neovaginal reconstruction concurrent with radical pelvic surgery.

Authors
Soper, JT; Secord, AA; Havrilesky, LJ; Berchuck, A; Clarke-Pearson, DL
MLA Citation
Soper, JT, Secord, AA, Havrilesky, LJ, Berchuck, A, and Clarke-Pearson, DL. "Comparison of gracilis and rectus abdominis myocutaneous flap neovaginal reconstruction performed during radical pelvic surgery: flap-specific morbidity." Int J Gynecol Cancer 17.1 (January 2007): 298-303.
PMID
17291272
Source
pubmed
Published In
International Journal of Gynecological Cancer
Volume
17
Issue
1
Publish Date
2007
Start Page
298
End Page
303
DOI
10.1111/j.1525-1438.2007.00784.x

Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature (2006) 12, (1294-1300))

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Erratum: Genomic signatures to guide the use of chemotherapeutics (Nature (2006) 12, (1294-1300))." Nature Medicine 13.11 (2007): 1388--.
Source
scival
Published In
Nature Medicine
Volume
13
Issue
11
Publish Date
2007
Start Page
1388-
DOI
10.1038/nm1107-1388

Society of gynecologic oncologists

Authors
Berchuck, A
MLA Citation
Berchuck, A. "Society of gynecologic oncologists." Journal of Oncology Practice 3.2 (2007): 108-109.
Source
scival
Published In
Journal of Oncology Practice
Volume
3
Issue
2
Publish Date
2007
Start Page
108
End Page
109
DOI
10.1200/JOP.0728001

Gene expression patterns identify patients with non-small cell lung cancer (NSCLC) and ovarian cancer who are at increased risk for venous thromboembolism (VTE).

Authors
Ramiah, VS; Potti, A; Peterson, R; Harpole, D; Berchuck, A; Ortel, TL
MLA Citation
Ramiah, VS, Potti, A, Peterson, R, Harpole, D, Berchuck, A, and Ortel, TL. "Gene expression patterns identify patients with non-small cell lung cancer (NSCLC) and ovarian cancer who are at increased risk for venous thromboembolism (VTE)." November 16, 2006.
Source
wos-lite
Published In
Blood
Volume
108
Issue
11
Publish Date
2006
Start Page
425A
End Page
425A

Genomic signatures to guide the use of chemotherapeutics.

Using in vitro drug sensitivity data coupled with Affymetrix microarray data, we developed gene expression signatures that predict sensitivity to individual chemotherapeutic drugs. Each signature was validated with response data from an independent set of cell line studies. We further show that many of these signatures can accurately predict clinical response in individuals treated with these drugs. Notably, signatures developed to predict response to individual agents, when combined, could also predict response to multidrug regimens. Finally, we integrated the chemotherapy response signatures with signatures of oncogenic pathway deregulation to identify new therapeutic strategies that make use of all available drugs. The development of gene expression profiles that can predict response to commonly used cytotoxic agents provides opportunities to better use these drugs, including using them in combination with existing targeted therapies.

Authors
Potti, A; Dressman, HK; Bild, A; Riedel, RF; Chan, G; Sayer, R; Cragun, J; Cottrill, H; Kelley, MJ; Petersen, R; Harpole, D; Marks, J; Berchuck, A; Ginsburg, GS; Febbo, P; Lancaster, J; Nevins, JR
MLA Citation
Potti, A, Dressman, HK, Bild, A, Riedel, RF, Chan, G, Sayer, R, Cragun, J, Cottrill, H, Kelley, MJ, Petersen, R, Harpole, D, Marks, J, Berchuck, A, Ginsburg, GS, Febbo, P, Lancaster, J, and Nevins, JR. "Genomic signatures to guide the use of chemotherapeutics." Nat Med 12.11 (November 2006): 1294-1300.
PMID
17057710
Source
pubmed
Published In
Nature Medicine
Volume
12
Issue
11
Publish Date
2006
Start Page
1294
End Page
1300
DOI
10.1038/nm1491

Progestin and estrogen potency of combination oral contraceptives and endometrial cancer risk.

OBJECTIVE: Using data from a case-control study of endometrial cancer, we investigated the relationship between the progestin and estrogen potency in combination oral contraceptives (OCs) and the risk of developing endometrial cancer. METHODS: Subjects included 434 endometrial cancer cases and 2,557 controls identified from the Cancer and Steroid Hormone (CASH) study. OCs were classified into four categories according to the individual potencies of each hormonal constituent (high versus low estrogen or progestin potency). Logistic regression was used to evaluate associations between endometrial cancer risk and combination OC formulations. RESULTS: With non-users as the referent group, use of OCs with either high potency progestin [odds ratio for endometrial cancer (OR)=0.21, 95% confidence interval (CI)=0.10 to 0.43] or with low potency progestin (OR=0.39, 95% CI=0.25 to 0.60) were both associated with a decreased risk of endometrial cancer. Overall high progestin potency OCs did not confer significantly more protection than low progestin potency OCs (OR=0.52, 95% CI=0.24 to 1.14). However, among women with a body mass index of 22.1 kg/m2 or higher, those who used high progestin potency oral contraceptives had a lower risk of endometrial cancer than those who used low progestin potency oral contraceptives (OR=0.31, 95% CI=0.11 to 0.92) while those with a BMI below 22.1 kg/m2 did not (OR=1.36, 95% CI=0.39 to 4.70). CONCLUSION: The potency of the progestin in most OCs appears adequate to provide a protective effect against endometrial cancer. Higher progestin-potency OCs may be more protective than lower progestin potency OCs among women with a larger body habitus.

Authors
Maxwell, GL; Schildkraut, JM; Calingaert, B; Risinger, JI; Dainty, L; Marchbanks, PA; Berchuck, A; Barrett, JC; Rodriguez, GC
MLA Citation
Maxwell, GL, Schildkraut, JM, Calingaert, B, Risinger, JI, Dainty, L, Marchbanks, PA, Berchuck, A, Barrett, JC, and Rodriguez, GC. "Progestin and estrogen potency of combination oral contraceptives and endometrial cancer risk." Gynecol Oncol 103.2 (November 2006): 535-540.
PMID
16740300
Source
pubmed
Published In
Gynecologic Oncology
Volume
103
Issue
2
Publish Date
2006
Start Page
535
End Page
540
DOI
10.1016/j.ygyno.2006.03.046

ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes.

Although the etiology of solid cancers is multifactorial, with environmental and genetic factors playing a variable role, a significant portion of the burden of cancer is accounted for by a heritable component. Increasingly, the heritable component of cancer predispositions has been linked to mutations in specific genes, and clinical interventions have been formulated for mutation carriers within affected families. The primary interventions for mutations carriers for highly penetrant syndromes such as multiple endocrine neoplasias, familial adenomatous polyposis, hereditary nonpolyposis colon cancer, and hereditary breast and ovarian cancer syndromes are primarily surgical. For that reason, the American Society of Clinical Oncology (ASCO) and the Society of Surgical Oncology (SSO) have undertaken an educational effort within the oncology community. A joint ASCO/SSO Task Force was charged with presenting an educational symposium on the surgical management of hereditary cancer syndromes at the annual ASCO and SSO meetings, resulting in an educational position article on this topic. Both the content of the symposium and the article were developed as a consensus statement by the Task Force, with the intent of summarizing the current standard of care. This article is divided into four sections addressing breast, colorectal, ovarian and endometrial cancers, and multiple endocrine neoplasia. For each, a brief introduction on the genetics and natural history of the disease is provided, followed by a detailed description of modern surgical approaches, including a description of the clinical and genetic indications and timing of prophylactic surgery, and the efficacy of prophylactic surgery when known. Although a number of recent reviews have addressed the role of genetic testing for cancer susceptibility, including the richly illustrated Cancer Genetics and Cancer Predisposition Testing curriculum by the ASCO Cancer Genetics Working Group (available through http://www.asco.org), this article focuses on the issues surrounding the why, how, and when of surgical prophylaxis for inherited forms of cancer. This is a complex process, which requires a clear understanding of the natural history of the disease and variance of penetrance, a realistic appreciation of the potential benefit and risk of a risk-reducing procedure in a potentially otherwise healthy individual, the long-term sequelae of such surgical intervention, as well as the individual patient and family's perception of surgical risk and anticipated benefit.

Authors
Guillem, JG; Wood, WC; Moley, JF; Berchuck, A; Karlan, BY; Mutch, DG; Gagel, RF; Weitzel, J; Morrow, M; Weber, BL; Giardiello, F; Rodriguez-Bigas, MA; Church, J; Gruber, S; Offit, K; ASCO, ; SSO,
MLA Citation
Guillem, JG, Wood, WC, Moley, JF, Berchuck, A, Karlan, BY, Mutch, DG, Gagel, RF, Weitzel, J, Morrow, M, Weber, BL, Giardiello, F, Rodriguez-Bigas, MA, Church, J, Gruber, S, Offit, K, ASCO, , and SSO, . "ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes." J Clin Oncol 24.28 (October 1, 2006): 4642-4660. (Review)
PMID
17008706
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
28
Publish Date
2006
Start Page
4642
End Page
4660
DOI
10.1200/JCO.2005.04.5260

Genomic tests for ovarian cancer detection and management.

OBJECTIVES: To assess the evidence that the use of genomic tests for ovarian cancer screening, diagnosis, and treatment leads to improved outcomes. DATA SOURCES: PubMed and reference lists of recent reviews. REVIEW METHODS: We evaluated tests for: (a) single gene products; (b) genetic variations affecting risk of ovarian cancer; (c) gene expression; and (d) proteomics. For tests covered in recent evidence reports (cancer antigen 125 [CA-125] and breast cancer genes 1 and 2 [BRCA1/2]), we added studies published subsequent to the reports. We sought evidence on: (a) the analytic performance of tests in clinical laboratories; (b) the sensitivity and specificity of tests in different patient populations; (c) the clinical impact of testing in asymptomatic women, women with suspected ovarian cancer, and women with diagnosed ovarian cancer; (d) the harms of genomic testing; and (e) the impact of direct-to-consumer and direct-to-physician advertising on appropriate use of tests. We also constructed a computer simulation model to test the impact of different assumptions about ovarian cancer natural history on the relative effectiveness of different strategies. RESULTS: There are reasonable data on the clinical laboratory performance of most radioimmunoassays, but the majority of the data on other genomic tests comes from research laboratories. Genomic test sensitivity/specificity estimates are limited by small sample sizes, spectrum bias, and unrealistically large prevalences of ovarian cancer; in particular, estimates of positive predictive values derived from most of the studies are substantially higher than would be expected in most screening or diagnostic settings. We found no evidence relevant to the question of the impact of genomic tests on health outcomes in asymptomatic women. Although there is a relatively large literature on the association of test results and various clinical outcomes, the clinical utility of changing management based on these results has not been evaluated. We found no evidence that genomic tests for ovarian cancer have unique harms beyond those common to other tests for genetic susceptibility or other tests used in screening, diagnosis, and management of ovarian cancer. Studies of a direct-to-consumer campaign for BRCA1/2 testing suggest increased utilization, but the effect on "appropriateness" was unclear. Model simulations suggest that annual screening, even with a highly sensitive test, will not reduce ovarian cancer mortality by more than 50 percent; frequent screening has a very low positive predictive value, even with a highly specific test. CONCLUSIONS: Although research remains promising, adaptation of genomic tests into clinical practice must await appropriately designed and powered studies in relevant clinical settings.

Authors
Myers, ER; Havrilesky, LJ; Kulasingam, SL; Sanders, GD; Cline, KE; Gray, RN; Berchuck, A; McCrory, DC
MLA Citation
Myers, ER, Havrilesky, LJ, Kulasingam, SL, Sanders, GD, Cline, KE, Gray, RN, Berchuck, A, and McCrory, DC. "Genomic tests for ovarian cancer detection and management." Evid Rep Technol Assess (Full Rep) 145 (October 2006): 1-100. (Review)
PMID
17764207
Source
pubmed
Published In
Evidence report/technology assessment
Issue
145
Publish Date
2006
Start Page
1
End Page
100

ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes.

BACKGROUND: A significant portion of cancers are accounted for by a heritable component, which has increasingly been linked to mutations in specific genes. Clinical interventions have been formulated for mutation carriers within affected families. The primary interventions for mutation carriers of highly penetrant syndromes are surgical. METHODS: The American Society of Clinical Oncology and the Society of Surgical Oncology formed a task force charged with presenting an educational symposium on surgical management of hereditary cancer syndromes at annual society meetings, and this resulted in a position paper on this topic. The content of both the symposium and the position paper was developed as a consensus statement. RESULTS: This article addresses hereditary breast, colorectal, ovarian/endometrial, and multiple endocrine neoplasias. A brief introduction on the genetics and natural history of each disease is provided, followed by detailed descriptions of modern surgical approaches, clinical and genetic indications, timing of prophylactic surgery, and the efficacy of surgery (when known). Although several recent reviews have addressed the role of genetic testing for cancer susceptibility, this article focuses on the issues surrounding surgical technique, timing, and indications for surgical prophylaxis. CONCLUSIONS: Risk-reducing surgical treatment of hereditary cancer is a complex undertaking. It requires a clear understanding of the natural history of the disease, realistic appreciation of the potential benefits and risks of these procedures in potentially otherwise healthy individuals, and the long-term sequelae of such interventions, as well as the individual patient's and family's perceptions of surgical risk and anticipated benefit.

Authors
Guillem, JG; Wood, WC; Moley, JF; Berchuck, A; Karlan, BY; Mutch, DG; Gagel, RF; Weitzel, J; Morrow, M; Weber, BL; Giardiello, F; Rodriguez-Bigas, MA; Church, J; Gruber, S; Offit, K
MLA Citation
Guillem, JG, Wood, WC, Moley, JF, Berchuck, A, Karlan, BY, Mutch, DG, Gagel, RF, Weitzel, J, Morrow, M, Weber, BL, Giardiello, F, Rodriguez-Bigas, MA, Church, J, Gruber, S, and Offit, K. "ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes." Ann Surg Oncol 13.10 (October 2006): 1296-1321. (Review)
PMID
16990987
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
13
Issue
10
Publish Date
2006
Start Page
1296
End Page
1321
DOI
10.1245/s10434-006-9036-6

Identification of genes associated with ovarian cancer metastasis using microarray expression analysis.

Although the transition from early- to advanced-stage ovarian cancer is a critical determinant of survival, little is known about the molecular underpinnings of ovarian metastasis. We hypothesize that microarray analysis of global gene expression patterns in primary ovarian cancer and metastatic omental implants can identify genes that underlie the metastatic process in epithelial ovarian cancer. We utilized Affymetrix U95Av2 microarrays to characterize the molecular alterations that underlie omental metastasis from 47 epithelial ovarian cancer samples collected from multiple sites in 20 patients undergoing primary surgical cytoreduction for advanced-stage (IIIC/IV) serous ovarian cancer. Fifty-six genes demonstrated differential expression between ovarian and omental samples (P < 0.01), and twenty of these 56 differentially expressed genes have previously been implicated in metastasis, cell motility, or cytoskeletal function. Ten of the 56 genes are involved in p53 gene pathways. A Bayesian statistical tree analysis was used to identify a 27-gene expression pattern that could accurately predict the site of tumor (ovary versus omentum). This predictive model was evaluated using an external data set. Nine of the 27 predictive genes have previously been shown to be involved in oncogenesis and/or metastasis, and 10/27 genes have been implicated in p53 pathways. Microarray findings were validated by real-time quantitative PCR. We conclude that gene expression patterns that distinguish omental metastasis from primary epithelial ovarian cancer can be identified and that many of the genes have functions that are biologically consistent with a role in oncogenesis, metastasis, and p53 gene networks.

Authors
Lancaster, JM; Dressman, HK; Clarke, JP; Sayer, RA; Martino, MA; Cragun, JM; Henriott, AH; Gray, J; Sutphen, R; Elahi, A; Whitaker, RS; West, M; Marks, JR; Nevins, JR; Berchuck, A
MLA Citation
Lancaster, JM, Dressman, HK, Clarke, JP, Sayer, RA, Martino, MA, Cragun, JM, Henriott, AH, Gray, J, Sutphen, R, Elahi, A, Whitaker, RS, West, M, Marks, JR, Nevins, JR, and Berchuck, A. "Identification of genes associated with ovarian cancer metastasis using microarray expression analysis." Int J Gynecol Cancer 16.5 (September 2006): 1733-1745.
PMID
17009964
Source
pubmed
Published In
International Journal of Gynecological Cancer
Volume
16
Issue
5
Publish Date
2006
Start Page
1733
End Page
1745
DOI
10.1111/j.1525-1438.2006.00660.x

Pelvic lymph node count is an important prognostic variable for FIGO stage I and II endometrial carcinoma with high-risk histology.

OBJECTIVE: To determine whether pelvic lymph node count is associated with patterns of recurrence or survival in patients with FIGO stage I and II endometrial cancer. METHODS: Single institution retrospective study of 467 patients with FIGO stage I and II endometrial cancer treated with primary surgery including lymph node dissection. Analysis included pelvic lymph node count, histology, stage, age, race, BMI, year of surgery, depth of myometrial invasion, and adjuvant radiation. Kaplan-Meier life-tables were used to calculate survival; the Cox proportional hazards model was used to identify prognostic factors independently associated with survival. RESULTS: Mean pelvic lymph node count was 12.6 (SD +/- 8). Distant recurrence was associated with decreased pelvic lymph node count, high-risk histology, and postoperative pelvic radiation. Pelvic lymph node count was not associated with survival by univariate analysis, however, overall (OS) and progression-free (PFS) survival were significantly better with pelvic lymph node counts >or=12 among women with high-risk histology (P < 0.001), but not among women with low-risk histology. Multivariable Cox proportional hazards regression identified increasing age, non-Caucasian race, and high-risk histology as independent negative prognostic factors for both OS and PFI. Among patients with high-risk histology, pelvic lymph node count remained an independent prognostic factor for both overall (OS) and progression-free survival (PFS) in the model, with hazard ratios of 0.28 and 0.29, respectively, when >or=12 pelvic lymph nodes were identified. Pelvic lymph node count had no association with OS or PFS in women with low-risk histology. CONCLUSION: Pelvic lymph node count >or=12 is an important prognostic variable in patients with FIGO stage I and II endometrial cancer who have high-risk histology. Most likely, the association of survival and lymph node count in this group is the result of improved staging among patients with higher pelvic lymph node counts.

Authors
Lutman, CV; Havrilesky, LJ; Cragun, JM; Secord, AA; Calingaert, B; Berchuck, A; Clarke-Pearson, DL; Soper, JT
MLA Citation
Lutman, CV, Havrilesky, LJ, Cragun, JM, Secord, AA, Calingaert, B, Berchuck, A, Clarke-Pearson, DL, and Soper, JT. "Pelvic lymph node count is an important prognostic variable for FIGO stage I and II endometrial carcinoma with high-risk histology." Gynecol Oncol 102.1 (July 2006): 92-97.
PMID
16406063
Source
pubmed
Published In
Gynecologic Oncology
Volume
102
Issue
1
Publish Date
2006
Start Page
92
End Page
97
DOI
10.1016/j.ygyno.2005.11.032

High expression of insulin-like growth factor binding protein-2 messenger RNA in epithelial ovarian cancers produces elevated preoperative serum levels.

The molecular etiology of epithelial ovarian cancer remains unclear. Using microarray expression analysis, we recently reported that expression of the insulin-like growth factor binding protein-2 (IGFBP-2) gene is elevated in advanced epithelial ovarian cancers. The aim of this study was to further delineate the role of IGFBP-2 in the pathoetiology of epithelial ovarian cancer and determine if elevated ovarian cancer IGFBP-2 gene expression is reflected in serum. Relative IGFBP-2 expression was measured using quantitative real-time polymerase chain reaction in 113 epithelial ovarian cancers and 6 normal ovarian surface epithelial samples. Preoperative serum IGFBP-2 levels were measured by radioimmunoassay in 84 women (42 ovarian cancers, 26 benign gynecological conditions, and 10 healthy female controls). Ovarian cancers demonstrated 38-fold higher mean IGFBP-2 expression than normal ovarian epithelium (P < 0.01). Serum IGFBP-2 levels were elevated in women with early- and advanced-stage ovarian cancer compared to controls and patients with benign gynecological conditions (P = 0.05 and P < 0.01, respectively). Epithelial ovarian cancers express high levels of IGFBP-2 relative to normal ovarian epithelium, and this is associated with elevated serum IGFBP-2 levels compared to both normal controls and patients with benign gynecological disease. Our findings provide further support that the insulin-like growth factor pathway plays a significant role in epithelial ovarian cancer pathogenesis. Further, IGFBP-2 may represent an additional serum biomarker with utility in detection and monitoring of epithelial ovarian cancer.

Authors
Lancaster, JM; Sayer, RA; Blanchette, C; Calingaert, B; Konidari, I; Gray, J; Schildkraut, J; Schomberg, DW; Marks, JR; Berchuck, A
MLA Citation
Lancaster, JM, Sayer, RA, Blanchette, C, Calingaert, B, Konidari, I, Gray, J, Schildkraut, J, Schomberg, DW, Marks, JR, and Berchuck, A. "High expression of insulin-like growth factor binding protein-2 messenger RNA in epithelial ovarian cancers produces elevated preoperative serum levels." Int J Gynecol Cancer 16.4 (July 2006): 1529-1535.
PMID
16884361
Source
pubmed
Published In
International Journal of Gynecological Cancer
Volume
16
Issue
4
Publish Date
2006
Start Page
1529
End Page
1535
DOI
10.1111/j.1525-1438.2006.00623.x

A comparison of combination docetaxel/carboplatin versus sequential docetaxel then carboplatin in patients with recurrent platinum-sensitive ovarian cancer.

5092 Background: Combination paclitaxel and platinum-based chemotherapy has been shown to improve survival in patients with recurrent platinum-sensitive ovarian cancer. However, the incidence of neurotoxicity was significantly greater with combination therapy than with other platinum-based regimens. The aim of this study was to compare the efficacy and adverse event profile of combination versus sequential weekly docetaxel and carboplatin therapy in patients with recurrent platinum-sensitive ovarian cancer. METHODS: Patients with recurrent platinum-sensitive ovarian, peritoneal, or tubal cancer were randomized to either weekly docetaxel 30 mg/m(2)/days 1 and 8 and carboplatin AUC 6/day 1 q 3 weeks (regimen A) or docetaxel 30 mg/m(2)/days 1 and 8, repeated every 3 weeks for 6 cycles followed by carboplatin AUC 6/day 1 every 3 weeks (regimen B) for 6 cycles or until disease progression. The primary endpoint was time to progression (TTP). RESULTS: At the time of this analysis, 51 patients, with a median age of 65.1 years, had been enrolled. There were 25 randomized to regimen A and 26 to regimen B from January 2004 to April 2005. There were no differences between the groups with respect to age, performance status, prior consolidation therapy, or anatomic site of cancer. The study is still open to accrual and thus far the overall response rate was 51% (2 CR, 24 PR) with stable disease in 26%. Median TTP was 12.6 months. The incidence of grade 2 or 3 neurotoxicity and grade 3 or 4 neutropenia was higher with regimen A compared to regimen B (15% vs. 3%; 44% vs. 10%), respectively. CONCLUSIONS: Combination and sequential weekly docetaxel and carboplatin have significant activity in recurrent platinum-sensitive ovarian cancer. Both regimens have a low incidence of moderate to severe neurotoxicity relative to that observed in other studies that employed paclitaxel. [Table: see text].

Authors
Alvarez Secord, A; Havrilesky, LJ; Higgins, RV; Nycum, LR; Kohler, MF; Puls, LE; Holloway, R; Soper, JT; Valea, FA; Berchuck, A
MLA Citation
Alvarez Secord, A, Havrilesky, LJ, Higgins, RV, Nycum, LR, Kohler, MF, Puls, LE, Holloway, R, Soper, JT, Valea, FA, and Berchuck, A. "A comparison of combination docetaxel/carboplatin versus sequential docetaxel then carboplatin in patients with recurrent platinum-sensitive ovarian cancer." J Clin Oncol 24.18_suppl (June 20, 2006): 5092-.
PMID
27952341
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
5092

A multi-institutional evaluation of the safety and efficacy of bevacizumab for recurrent, platinum-resistant ovarian cancer.

5019 Background: Bevacizumab has shown activity in recurrent ovarian cancer with an acceptable adverse event profile. However, the incidence of bowel perforation in a recent trial of heavily pretreated ovarian cancer patients was higher than expected from prior experience with bevacizumab. Whether the difference in the rate of bowel perforation was due to refractory disease, treatment history, disease burden, or location of tumor is uncertain. We sought to review our multi-institutional experience with bevacizumab in patients with recurrent ovarian cancer. METHODS: A retrospective review of patients with recurrent ovarian cancer treated with single agent or combination bevacizumab therapy was undertaken. Toxicity was assessed using standard criteria. Response was determined radiographically and through serial CA125 measurements. Statistical analysis to determine factors associated with toxicity and response was performed. RESULTS: Sixty-two eligible patients were identified. All had failed prior platinum-based therapy and had received a median of 5 prior chemotherapy regimens and 2 prior platinum-containing regimens. Single agent bevacizumab was administered to 12 (19%) women, while 50 (81%) received the drug in combination with a cytotoxic agent. The most common toxicities were myelosuppression (60%), proteinuria (19%) and hypertension (16%). Grade 3-5 toxicities occurred in 15 (24%) patients, including grade 3-4 hypertension in 4 (7%). Gastrointestinal perforations were identified in 4 (7%) subjects. Nine (15%) patients discontinued therapy due to toxicity. Fifty-eight patients were assessable for response. The overall response rate was 36% (4 CR, 17 PR) with stable disease in 40%. Clinical benefit (CR, PR, stable disease) was seen in 83% of patients treated with single agent therapy and 74% of those treated with bevacizumab-combination regimens. CONCLUSIONS: Bevacizumab demonstrates significant activity for recurrent, platinum-resistant ovarian cancer. Life threatening bowel perforations were noted in 7% of our subjects. The frequency of perforations in our cohort suggests that this complication is more likely to occur in heavily pretreated patients. No significant financial relationships to disclose.

Authors
Wright, JD; Alvarezsecord, A; Numnum, TM; Rocconi, RP; Powell, MA; Berchuck, A; Alvarez, RD; Trinkaus, K; Rader, JS; Mutch, DG
MLA Citation
Wright, JD, Alvarezsecord, A, Numnum, TM, Rocconi, RP, Powell, MA, Berchuck, A, Alvarez, RD, Trinkaus, K, Rader, JS, and Mutch, DG. "A multi-institutional evaluation of the safety and efficacy of bevacizumab for recurrent, platinum-resistant ovarian cancer." J Clin Oncol 24.18_suppl (June 20, 2006): 5019-.
PMID
27952209
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
5019

A comparison of combination docetaxel/carboplatin versus sequential docetaxel then carboplatin in patients with recurrent platinum-sensitive ovarian cancer.

Authors
Secord, AA; Havrilesky, LJ; Higgins, RV; Nycum, LR; Kohler, MF; Puls, LE; Holloway, R; Soper, JT; Valea, FA; Berchuck, A
MLA Citation
Secord, AA, Havrilesky, LJ, Higgins, RV, Nycum, LR, Kohler, MF, Puls, LE, Holloway, R, Soper, JT, Valea, FA, and Berchuck, A. "A comparison of combination docetaxel/carboplatin versus sequential docetaxel then carboplatin in patients with recurrent platinum-sensitive ovarian cancer." June 20, 2006.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
24
Issue
18
Publish Date
2006
Start Page
278S
End Page
278S

A multi-institutional evaluation of the safety and efficacy of bevacizumab for recurrent, platinum-resistant ovarian cancer.

Authors
WriQht, JD; Alvarezsecord, A; Numnum, TM; Rocconi, RP; Powell, MA; Berchuck, A; Alvarez, RD; Trinkaus, K; Rader, JS; Mutch, DG
MLA Citation
WriQht, JD, Alvarezsecord, A, Numnum, TM, Rocconi, RP, Powell, MA, Berchuck, A, Alvarez, RD, Trinkaus, K, Rader, JS, and Mutch, DG. "A multi-institutional evaluation of the safety and efficacy of bevacizumab for recurrent, platinum-resistant ovarian cancer." June 20, 2006.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
24
Issue
18
Publish Date
2006
Start Page
260S
End Page
260S

Maspin expression in epithelial ovarian cancer and associations with poor prognosis: a Gynecologic Oncology Group study.

OBJECTIVE: This study examined MASPIN expression in human ovarian cancer, and explored the association between MASPIN and prognosis in patients with advanced stage disease treated with first-line cisplatin, carboplatin and/or paclitaxel. METHODS: Frozen primary tumors were obtained from 68 women with previously untreated, advanced stage epithelial ovarian cancer who participated in a specimen banking protocol and a phase III treatment trial conducted by the Gynecologic Oncology Group. Immunoblot analysis was performed in lysates prepared from these tumor specimens to quantify the relative expression of MASPIN/beta-actin. RESULTS: MASPIN was expressed at detected levels in 49 (72%) cases with relative expression ranging from 0.02 to 7.7 (median = 0.2), and was not detected in 19 (28%) of the primary tumors tested. Non-detectable levels of this class II tumor suppressor gene product and inhibitor of angiogenesis were associated with suboptimally-debulked disease (P = 0.034) but not with patient age, FIGO stage, tumor grade, or histologic subtype. After adjusting for prognostic variables for disease progression or death, non-detectable MASPIN expression predicted an increased risk of disease progression (hazard ratio [HR] = 1.89; 95% confidence interval [CI]: 1.04-3.45; P = 0.038) and death (HR = 1.99; 95% CI: 1.07-3.69; P = 0.030). CONCLUSIONS: In advanced stage epithelial ovarian cancer, non-detectable MASPIN appears to be associated with suboptimally-debulked disease and be an independent predictor of an increased risk of progression and death. Further studies are needed to validate these exploratory findings, determine the molecular mechanism controlling MASPIN expression as well as down-regulation and loss in ovarian cancer, and determine if MASPIN can prevent progression of this disease.

Authors
Gynecologic Oncology Group, ; Secord, AA; Lee, PS; Darcy, KM; Havrilesky, LJ; Grace, LA; Marks, JR; Berchuck, A
MLA Citation
Gynecologic Oncology Group, , Secord, AA, Lee, PS, Darcy, KM, Havrilesky, LJ, Grace, LA, Marks, JR, and Berchuck, A. "Maspin expression in epithelial ovarian cancer and associations with poor prognosis: a Gynecologic Oncology Group study." Gynecol Oncol 101.3 (June 2006): 390-397.
PMID
16551475
Source
pubmed
Published In
Gynecologic Oncology
Volume
101
Issue
3
Publish Date
2006
Start Page
390
End Page
397
DOI
10.1016/j.ygyno.2006.02.014

Use of trastuzumab in the treatment of metastatic endometrial cancer.

Systemic therapy of metastatic endometrial cancer is relatively ineffective. Response rates to chemotherapy and hormonal therapy in published studies range from 11% to 57%, but most responses are partial and of limited duration. In this case, we present a 76-year-old woman with stage IIIA endometrial adenocarcinoma who was initially treated with surgery and pelvic radiation. She developed multiple pulmonary metastases. She was treated with weekly paclitaxel chemotherapy. Immunostaining revealed that the primary endometrial cancer overexpressed HER-2/neu. Trastuzumab was added to the regimen, and a dramatic partial response was achieved. After a second pulmonary relapse following discontinuation of prior therapy, she was again successfully treated with trastuzumab in combination with paclitaxel and then docetaxel. Therefore, trastuzumab may be a useful adjuvant to taxane-based chemotherapy in some patients with metastatic endometrial cancers that overexpress HER-2/neu.

Authors
Jewell, E; Secord, AA; Brotherton, T; Berchuck, A
MLA Citation
Jewell, E, Secord, AA, Brotherton, T, and Berchuck, A. "Use of trastuzumab in the treatment of metastatic endometrial cancer." Int J Gynecol Cancer 16.3 (May 2006): 1370-1373.
PMID
16803532
Source
pubmed
Published In
International Journal of Gynecological Cancer
Volume
16
Issue
3
Publish Date
2006
Start Page
1370
End Page
1373
DOI
10.1111/j.1525-1438.2006.00543.x

The granulin-epithelin precursor is a steroid-regulated growth factor in endometrial cancer.

OBJECTIVES: The majority of endometrial cancers arise as a result of estrogen stimulation, the molecular targets of which remain incompletely defined. We hypothesize that the granulin-epithelin precursor (GEP) may be one such target. In this study, we examined the frequency of GEP and estrogen receptor (ER) co-expression in human endometrial cancers. Once we established the co-expression of GEP with the estrogen receptor we examined the potential estrogen regulation of GEP expression, as well as the functional significance of GEP expression in vitro. METHODS: Double immunofluorescence and confocal microscopy were used to compare GEP and ER expression among 41 endometrial cancers. The effects of estradiol and tamoxifen treatment on GEP expression in two endometrial cancer cell lines, KLE and HEC-1-A, were assessed through reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis. The antiproliferative effect of GEP silencing by short hairpin (sh)RNA, was evaluated in HEC-1-A cells using an MTT assay. RESULTS: GEP co-expression with ER was observed in 63% of the cancers examined. A two- to fivefold increase in GEP expression with estradiol and/or tamoxifen treatment was observed in KLE cells. Silencing of GEP in HEC-1-A cells using shRNA resulted in a decrease in proliferation among transfected cells. CONCLUSIONS: Co-expression of GEP and ER in endometrial cancer cells, and the regulation of GEP by estrogen, suggests a role for GEP in steroid-mediated endometrial cancer cell growth. Further characterization of GEP as a steroid-mediated growth factor in these cells may broaden our understanding of endometrial cancer biology and also provide guidance in the development of novel therapeutic targets.

Authors
Jones, MB; Houwink, AP; Freeman, BK; Greenwood, TM; Lafky, JM; Lingle, WL; Berchuck, A; Maxwell, GL; Podratz, KC; Maihle, NJ
MLA Citation
Jones, MB, Houwink, AP, Freeman, BK, Greenwood, TM, Lafky, JM, Lingle, WL, Berchuck, A, Maxwell, GL, Podratz, KC, and Maihle, NJ. "The granulin-epithelin precursor is a steroid-regulated growth factor in endometrial cancer." J Soc Gynecol Investig 13.4 (May 2006): 304-311.
PMID
16697948
Source
pubmed
Published In
Journal of the Society for Gynecologic Investigation (Elsevier)
Volume
13
Issue
4
Publish Date
2006
Start Page
304
End Page
311
DOI
10.1016/j.jsgi.2006.03.003

Frequent IGF2/H19 domain epigenetic alterations and elevated IGF2 expression in epithelial ovarian cancer.

Overexpression of the imprinted insulin-like growth factor-II (IGF2) is a prominent characteristic of gynecologic malignancies. The purpose of this study was to determine whether IGF2 loss of imprinting (LOI), aberrant H19 expression, and/or epigenetic deregulation of the IGF2/H19 imprinted domain contributes to elevated IGF2 expression in serous epithelial ovarian tumors. IGF2 LOI was observed in 5 of 23 informative serous epithelial ovarian cancers, but this did not correlate with elevated expression of IGF2 H19 RNA expression levels were also found not to correlate with IGF2 transcript levels. However, we identified positive correlations between elevated IGF2 expression and hypermethylation of CCCTC transcription factor binding sites 1 and 6 at the H19 proximal imprint center (P = 0.05 and 0.02, respectively). Hypermethylation of CCCTC transcription factor sites 1 and 6 was observed more frequently in cancer DNA compared with lymphocyte DNA obtained from women without malignancy (P < 0.0001 for both sites 1 and 6). Ovarian cancers were also more likely to exhibit maternal allele-specific hypomethylation upstream of the imprinted IGF2 promoters when compared with normal lymphocyte DNA (P = 0.004). This is the same region shown previously to be hypomethylated in colon cancers with IGF2 LOI, but this was not associated with LOI in ovarian cancers. Elevated IGF2 expression is a frequent event in serous ovarian cancer and this occurs in the absence of IGF2 LOI. These data indicate that the epigenetic changes observed in these cancers at the imprint center may contribute to IGF2 overexpression in a novel mechanistic manner.

Authors
Murphy, SK; Huang, Z; Wen, Y; Spillman, MA; Whitaker, RS; Simel, LR; Nichols, TD; Marks, JR; Berchuck, A
MLA Citation
Murphy, SK, Huang, Z, Wen, Y, Spillman, MA, Whitaker, RS, Simel, LR, Nichols, TD, Marks, JR, and Berchuck, A. "Frequent IGF2/H19 domain epigenetic alterations and elevated IGF2 expression in epithelial ovarian cancer." Mol Cancer Res 4.4 (April 2006): 283-292.
PMID
16603642
Source
pubmed
Published In
Molecular cancer research : MCR
Volume
4
Issue
4
Publish Date
2006
Start Page
283
End Page
292
DOI
10.1158/1541-7786.MCR-05-0138

Intra-peritoneal cisplatin and whole abdomen hyperthermia for relapsed ovarian carcinoma.

The study was designed to determine the maximum tolerated dose (MTD) of IP cisplatin [CDDP] combined with intravenous thiosulphate and concurrent whole abdomen hyperthermia for advanced, recurrent or progressive ovarian carcinoma. Between September 1991 and November 1998, 41 patients with advanced epithelial ovarian cancer received escalating doses of IP (IP) cisplatin (six cycles given every 3-4 weeks) and whole abdomen hyperthermia with intravenous thiosulphate as second line treatment. Whole abdomen hyperthermia was administrated using a BSD-2000 annular phased array system. Forty-one patients were enrolled in the phase I/II portions of the study. Forty-four per cent (18/41) had undergone sub-optimal cytoreductive surgery and 15% (6/41) had been optimally debulked of their disease. Ninety per cent (37/41) had platinum-resistant disease and 10% (4/41) had platinum-sensitive disease. No DLTs occurred in the phase I testing and the recommended dose for this combination schedule was 180 mg m-2 of IP cisplatin with thiosulphate and whole abdomen hyperthermia. The overall response rate was 44% (10 CR, 8 PR) and the median survival for all patients from protocol entry was 30 months (range 2-107 months). Median duration and survival of those achieving a pathologic CR was 14 months (range 2-27 months) and 35 months (range 14-71 months, 95% CI 16-54 months), respectively. Salvage platinum based IP cisplatin with hyperthermia did achieve pathologic CR in selected patients and was well tolerated. These promising results suggest a role for the use of adjuvant whole abdomen hyperthermia as a means of augmenting chemosensitization.

Authors
Jones, E; Alvarez Secord, A; Prosnitz, LR; Samulski, TV; Oleson, JR; Berchuck, A; Clarke-Pearson, D; Soper, J; Dewhirst, MW; Vujaskovic, Z
MLA Citation
Jones, E, Alvarez Secord, A, Prosnitz, LR, Samulski, TV, Oleson, JR, Berchuck, A, Clarke-Pearson, D, Soper, J, Dewhirst, MW, and Vujaskovic, Z. "Intra-peritoneal cisplatin and whole abdomen hyperthermia for relapsed ovarian carcinoma." Int J Hyperthermia 22.2 (March 2006): 161-172.
PMID
16754599
Source
pubmed
Published In
International Journal of Hyperthermia (Informa)
Volume
22
Issue
2
Publish Date
2006
Start Page
161
End Page
172
DOI
10.1080/02656730500515270

Oncogenic pathway signatures in human cancers as a guide to targeted therapies.

The development of an oncogenic state is a complex process involving the accumulation of multiple independent mutations that lead to deregulation of cell signalling pathways central to the control of cell growth and cell fate. The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies. Various studies have also demonstrated the potential for using gene expression profiles for the analysis of oncogenic pathways. Here we show that gene expression signatures can be identified that reflect the activation status of several oncogenic pathways. When evaluated in several large collections of human cancers, these gene expression signatures identify patterns of pathway deregulation in tumours and clinically relevant associations with disease outcomes. Combining signature-based predictions across several pathways identifies coordinated patterns of pathway deregulation that distinguish between specific cancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosis in respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underlie the development of the oncogenic phenotype and reflect the biology and outcome of specific cancers. Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity to therapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivity to therapeutics that target components of the pathway provides an opportunity to make use of these oncogenic pathway signatures to guide the use of targeted therapeutics.

Authors
Bild, AH; Yao, G; Chang, JT; Wang, Q; Potti, A; Chasse, D; Joshi, M-B; Harpole, D; Lancaster, JM; Berchuck, A; Olson, JA; Marks, JR; Dressman, HK; West, M; Nevins, JR
MLA Citation
Bild, AH, Yao, G, Chang, JT, Wang, Q, Potti, A, Chasse, D, Joshi, M-B, Harpole, D, Lancaster, JM, Berchuck, A, Olson, JA, Marks, JR, Dressman, HK, West, M, and Nevins, JR. "Oncogenic pathway signatures in human cancers as a guide to targeted therapies." Nature 439.7074 (January 19, 2006): 353-357.
PMID
16273092
Source
pubmed
Published In
Nature
Volume
439
Issue
7074
Publish Date
2006
Start Page
353
End Page
357
DOI
10.1038/nature04296

Prediction of lymph node metastasis in patients with endometrioid endometrial cancer using expression microarray.

PURPOSE: To characterize the gene expression profiles of endometrioid endometrial cancers associated with lymph node metastasis in an effort to identify genes associated with metastatic spread. EXPERIMENTAL DESIGN: Tumors from 41 patients with endometrioid endometrial cancer grossly confined to the uterine cavity were evaluated. Positive lymph nodes were noted in 12 of 41 patients. RNA was analyzed for gene expression using the Affymetrix HG133A and HG133B GeneChip set, representing 45,000 array features covering >28,000 UniGene clusters. Data analysis was done using multidimensional scaling, binary comparison, and hierarchical clustering. Gene expression for several differentially expressed genes was examined using quantitative PCR. RESULTS: Gene expression data was obtained from 30,964 genes that were detected in at least 5% of the cases. Supervised analysis of node-positive versus node-negative cases indicated that 450 genes were significantly differentially expressed between the two classes at P < 0.005, 81 of which were differentially expressed by at least 2-fold at P < 0.005. Overexpressed genes included two cell cycle checkpoint genes, CDC2 and MAD2L1, which have previously been described in association with lymph node metastasis in other cancer types. The ZIC2 zinc finger gene was overexpressed in endometrial cancers with positive nodes versus those with negative nodes. CONCLUSION: Gene expression profiling of the primary tumors in patients with endometrioid endometrial cancers seems promising for identifying genes associated with lymph node metastasis. Future studies should address whether the status of nodal metastasis can be determined from the expression profiles of preoperative tissue specimens.

Authors
Bidus, MA; Risinger, JI; Chandramouli, GVR; Dainty, LA; Litzi, TJ; Berchuck, A; Barrett, JC; Maxwell, GL
MLA Citation
Bidus, MA, Risinger, JI, Chandramouli, GVR, Dainty, LA, Litzi, TJ, Berchuck, A, Barrett, JC, and Maxwell, GL. "Prediction of lymph node metastasis in patients with endometrioid endometrial cancer using expression microarray." Clin Cancer Res 12.1 (January 1, 2006): 83-88.
PMID
16397028
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
1
Publish Date
2006
Start Page
83
End Page
88
DOI
10.1158/1078-0432.CCR-05-0835

Analgesic drug use and risk of ovarian cancer.

BACKGROUND: Previous epidemiologic research suggests that analgesic use may reduce the risk of ovarian cancer, although results are not consistent. METHODS: In a population-based, case-control study, we analyzed data from 586 ovarian cancer cases and 627 matched controls in North Carolina for the relationship between analgesic use and ovarian cancer risk. Logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) while adjusting for potential confounders. RESULTS: Use of any nonsteroidal antiinflammatory drugs, including aspirin, within 5 years of diagnosis/interview was found to be associated with a reduction in the risk of ovarian cancer (adjusted OR = 0.72; 95% CI = 0.56-0.92). For use of acetaminophen, the OR was 0.78 (95% CI = 0.56-1.08). CONCLUSIONS: These data support an inverse relationship between the use of both nonsteroidal antiinflammatory drugs and acetaminophen and the risk of ovarian cancer.

Authors
Schildkraut, JM; Moorman, PG; Halabi, S; Calingaert, B; Marks, JR; Berchuck, A
MLA Citation
Schildkraut, JM, Moorman, PG, Halabi, S, Calingaert, B, Marks, JR, and Berchuck, A. "Analgesic drug use and risk of ovarian cancer." Epidemiology 17.1 (January 2006): 104-107.
PMID
16357602
Source
pubmed
Published In
Epidemiology
Volume
17
Issue
1
Publish Date
2006
Start Page
104
End Page
107

High throughput detection of M6P/IGF2R intronic hypermethylation and LOH in ovarian cancer.

Cell surface mannose 6-phosphate/insulin-like growth factor II receptors (M6P/IGF2R) bind and target exogenous insulin-like growth factor II (IGF2) to the prelysosomes where it is degraded. Loss of heterozygosity (LOH) for M6P/IGF2R is found in cancers, with mutational inactivation of the remaining allele. We exploited the normal allele-specific differential methylation of the M6P/IGF2R intron 2 CpG island to rapidly evaluate potential LOH in ovarian cancers, since every normal individual is informative. To this end, we developed a method for bisulfite modification of genomic DNA in 96-well format that allows for rapid methylation profiling. We identified ovarian cancers with M6P/IGF2R LOH, but unexpectedly also found frequent abnormal acquisition of methylation on the paternally inherited allele at intron 2. These results demonstrate the utility of our high-throughput method of bisulfite modification for analysis of large sample numbers. They further show that the methylation status of the intron 2 CpG island may be a useful indicator of LOH and biomarker of disease.

Authors
Huang, Z; Wen, Y; Shandilya, R; Marks, JR; Berchuck, A; Murphy, SK
MLA Citation
Huang, Z, Wen, Y, Shandilya, R, Marks, JR, Berchuck, A, and Murphy, SK. "High throughput detection of M6P/IGF2R intronic hypermethylation and LOH in ovarian cancer. (Published online)" Nucleic Acids Res 34.2 (2006): 555-563.
PMID
16432260
Source
pubmed
Published In
Nucleic Acids Research
Volume
34
Issue
2
Publish Date
2006
Start Page
555
End Page
563
DOI
10.1093/nar/gkj468

Gene expression analysis of tumor infiltrating lymphocyte markers in endometrial cancers indicates no significant increases in those cases with microsatellite instability.

Microsatellite instability (MSI) is seen in many cancers and is the result of either a germline or somatic defect in the DNA mismatch repair system. Microsatellite instability is common in endometrial cancers occurring in about 25% of cases with endometrioid histology. Tumor infiltrating lymphocytes (TIL) are more prominent in colorectal cancer cases with MSI. The presence of increased TIL is associated with increased survival in these colorectal cancers, and is suggested as one possible mechanism to explain the increased survival rates in colorectal cancer patients with MSI positive cancers. Some degree of evidence indicates that increased TIL is also predictive of increased survival in endometrial cancer. The relative levels and states of activation of TIL in endometrial cancers with and without MSI has not been explored. Our previous data indicates that global gene expression patterns from MSI and non-MSI endometrial cancers are distinct, however TIL markers were not over-represented on statistically relevant gene lists that distinguish these groups. We further examined these pre-existing microarray data by directly querying transcripts present in the T-cell gene ontology (GO) group. No significant differences were observed between MSI and microsatellite stable (MSS) groups. Finally we directly examined a set of T-cell marker transcripts previously utilized to define increased activated and cytotoxic TIL in MSI positive colorectal cancers. Whereas colorectal cancers with MSI have been previously demonstrated to contain higher ratios of CD8/CD3 message levels we observed no difference in endometrial cancers. In addition, levels of CD3 indicated no increases in TIL in MSI positive cases and 2 markers of activation, granzyme B and IL-2R were not different in MSI positive and negative cancers. These data indicate that significant differences in TIL derived transcripts do not occur between endometrioid endometrial cancers with and without microsatellite instability.

Authors
Risinger, JI; Chandramouli, GVR; Maxwell, GL; Litzi, T; Berchuck, A; Umar, A
MLA Citation
Risinger, JI, Chandramouli, GVR, Maxwell, GL, Litzi, T, Berchuck, A, and Umar, A. "Gene expression analysis of tumor infiltrating lymphocyte markers in endometrial cancers indicates no significant increases in those cases with microsatellite instability." Cancer Biomark 2.1-2 (2006): 61-68.
PMID
17192060
Source
pubmed
Published In
Cancer biomarkers : section A of Disease markers
Volume
2
Issue
1-2
Publish Date
2006
Start Page
61
End Page
68

... what about this mole?

Authors
McDaniel, ML; Berchuck, A
MLA Citation
McDaniel, ML, and Berchuck, A. ".. what about this mole?." Contemporary Ob/Gyn 51.11 (2006): 44-46.
Source
scival
Published In
Contemporary ob/gyn
Volume
51
Issue
11
Publish Date
2006
Start Page
44
End Page
46

Targeted bio weapons in the war against gynecologic cancers

Will biological warfare revolutionize the battle against gynecologic cancers? Two experts share the latest molecular tactics using "special" agents. Lethal weapons like Herceptin can throw up some roadblocks, even when they can't always destroy a tumor.

Authors
Secord, AA; Berchuck, A
MLA Citation
Secord, AA, and Berchuck, A. "Targeted bio weapons in the war against gynecologic cancers." Contemporary Ob/Gyn 51.10 (2006): 48-54.
Source
scival
Published In
Contemporary ob/gyn
Volume
51
Issue
10
Publish Date
2006
Start Page
48
End Page
54

Resection of lymph node metastases influences survival in stage IIIC endometrial cancer.

OBJECTIVE: Surgical staging of endometrial cancer identifies those patients with microscopic metastatic disease most likely to benefit from adjuvant therapy and may also confer therapeutic benefit. Our objective was to compare survival of patients who underwent resection of grossly positive lymph nodes (LN) to those with microscopically positive LN. METHODS: Patients had stage IIIC endometrial cancer with pelvic and/or aortic LN metastases and underwent surgery between 1973 and 2002. Exclusion criteria included pre-surgical radiation and second primary cancer. Survival was analyzed using Kaplan-Meier method and Cox proportional hazards model. RESULTS: Mean age of 96 patients with stage IIIC endometrial cancer was 64. There were 45 cases with microscopic LN involvement and 51 with grossly enlarged LN. Overall, 41% had disease in aortic LN, which in 18% represented isolated aortic LN metastasis. Adjuvant therapies were given to 92% of patients (85% radiotherapy, 10% chemotherapy, 10% progestins). Among those with grossly involved LN, 86% were completely resected. Five-year disease-specific survival (DSS) was 63% in 45 patients with microscopic metastatic disease compared to 50% in 44 patients with grossly positive LN completely resected and 43% in 7 with residual macroscopic disease. In multivariable analyses, gross nodal disease not debulked (HR=6.85, P=0.009), serosal/adnexal involvement (HR=2.24, P=0.036), diagnosis prior to 1989 (HR=4.33, P<0.001), older age (HR=1.09, P<0.001), and >2 positive lymph nodes (HR=3.12, P=0.007) were associated with lower DSS. CONCLUSION: Grossly involved LN can often be completely resected in patients with stage IIIC endometrial cancer. These retrospective data provide evidence suggestive of a therapeutic benefit for lymphadenectomy in endometrial cancer.

Authors
Havrilesky, LJ; Cragun, JM; Calingaert, B; Synan, I; Secord, AA; Soper, JT; Clarke-Pearson, DL; Berchuck, A
MLA Citation
Havrilesky, LJ, Cragun, JM, Calingaert, B, Synan, I, Secord, AA, Soper, JT, Clarke-Pearson, DL, and Berchuck, A. "Resection of lymph node metastases influences survival in stage IIIC endometrial cancer." Gynecol Oncol 99.3 (December 2005): 689-695.
PMID
16126261
Source
pubmed
Published In
Gynecologic Oncology
Volume
99
Issue
3
Publish Date
2005
Start Page
689
End Page
695
DOI
10.1016/j.ygyno.2005.07.014

Oncogenic pathway signatures in human cancers as a guide to targeted therapies.

Authors
Bild, AH; Yao, G; Chang, JT; Wang, QL; Potti, A; Harpole, D; Lancaster, J; Berchuck, A; Olson, JA; Marks, J; Dressman, HK; West, M; Nevins, JR
MLA Citation
Bild, AH, Yao, G, Chang, JT, Wang, QL, Potti, A, Harpole, D, Lancaster, J, Berchuck, A, Olson, JA, Marks, J, Dressman, HK, West, M, and Nevins, JR. "Oncogenic pathway signatures in human cancers as a guide to targeted therapies." November 2005.
Source
wos-lite
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
14
Issue
11
Publish Date
2005
Start Page
2743S
End Page
2743S

Anthropometric measurements and epithelial ovarian cancer risk in African-American and White women.

Previous studies of anthropometric factors and ovarian cancer risk have been inconsistent and none have evaluated the association among African-American women. Data from a population-based, case-control study of 593 cases and 628 controls were used to evaluate ovarian cancer risk in relation to weight, height, body mass index (BMI) and waist-to-hip ratio (WHR). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed and established risk factors were adjusted for using logistic regression models, stratified by race. Among all races, weight at age 18, WHR, weight and BMI one year prior to interview were associated with elevated ovarian cancer risk. When stratified by race, the association between WHR and ovarian was similar among Whites and among African Americans. However, African-American women in the fourth quartile of height had an elevated risk of ovarian cancer (OR = 3.2; 95% CI = 1.3-7.8), but this risk was not apparent in Whites (OR = 1.0; 95% CI = 0.7-1.4). These findings support the hypothesis that obesity is an important risk factor of ovarian cancer among African-Americans and Whites and also suggest that height may be a risk factor specific to African-Americans.

Authors
Hoyo, C; Berchuck, A; Halabi, S; Bentley, RC; Moorman, P; Calingaert, B; Schildkraut, JM
MLA Citation
Hoyo, C, Berchuck, A, Halabi, S, Bentley, RC, Moorman, P, Calingaert, B, and Schildkraut, JM. "Anthropometric measurements and epithelial ovarian cancer risk in African-American and White women." Cancer Causes Control 16.8 (October 2005): 955-963.
PMID
16132804
Source
pubmed
Published In
Cancer Causes & Control
Volume
16
Issue
8
Publish Date
2005
Start Page
955
End Page
963
DOI
10.1007/s10552-005-3205-y

Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon.

PURPOSE: Epithelial ovarian cancers are thought to arise from flattened epithelial cells that cover the ovarian surface or that line inclusion cysts. During malignant transformation, different histotypes arise that resemble epithelial cells from normal fallopian tube, endometrium, and intestine. This study compares gene expression in serous, endometrioid, clear cell, and mucinous ovarian cancers with that in the normal tissues that they resemble. EXPERIMENTAL DESIGN: Expression of 63,000 probe sets was measured in 50 ovarian cancers, in 5 pools of normal ovarian epithelial brushings, and in mucosal scrapings from 4 normal fallopian tube, 5 endometrium, and 4 colon specimens. Using rank-sum analysis, genes whose expressions best differentiated the ovarian cancer histotypes and normal ovarian epithelium were used to determine whether a correlation based on gene expression existed between ovarian cancer histotypes and the normal tissues they resemble. RESULTS: When compared with normal ovarian epithelial brushings, alterations in serous tumors correlated with those in normal fallopian tube (P = 0.0042) but not in other normal tissues. Similarly, mucinous cancers correlated with those in normal colonic mucosa (P = 0.0003), and both endometrioid and clear cell histotypes correlated with changes in normal endometrium (P = 0.0172 and 0.0002, respectively). Mucinous cancers displayed the greatest number of alterations in gene expression when compared with normal ovarian epithelial cells. CONCLUSION: Studies at a molecular level show distinct expression profiles of different histologies of ovarian cancer and support the long-held belief that histotypes of ovarian cancers come to resemble normal fallopian tube, endometrial, and colonic epithelium. Several potential molecular markers for mucinous ovarian cancers have been identified.

Authors
Marquez, RT; Baggerly, KA; Patterson, AP; Liu, J; Broaddus, R; Frumovitz, M; Atkinson, EN; Smith, DI; Hartmann, L; Fishman, D; Berchuck, A; Whitaker, R; Gershenson, DM; Mills, GB; Bast, RC; Lu, KH
MLA Citation
Marquez, RT, Baggerly, KA, Patterson, AP, Liu, J, Broaddus, R, Frumovitz, M, Atkinson, EN, Smith, DI, Hartmann, L, Fishman, D, Berchuck, A, Whitaker, R, Gershenson, DM, Mills, GB, Bast, RC, and Lu, KH. "Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon." Clin Cancer Res 11.17 (September 1, 2005): 6116-6126.
PMID
16144910
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
17
Publish Date
2005
Start Page
6116
End Page
6126
DOI
10.1158/1078-0432.CCR-04-2509

Menopausal hormones and risk of ovarian cancer.

OBJECTIVE: The objective of this study was to determine if use of menopausal hormones was associated with ovarian cancer and if risk varied by type of hormone used. STUDY DESIGN: Data from a population-based, case-control study of ovarian cancer in North Carolina (364 cases, 370 controls, all postmenopausal) were analyzed to evaluate the relationship between menopausal hormones and ovarian cancer. Logistic regression analyses were used to calculate odds ratios (OR) and 95% CIs associated with various patterns of hormone use. RESULTS: Ovarian cancer cases were more likely than controls to report long-term use (>or=10 years) of unopposed estrogens (OR 2.2; 95% CI 1.2-4.1). No relationship was observed for estrogen always used with progestin. CONCLUSION: Hormone replacement therapy used according to current recommendations should not increase risk of ovarian cancer; however, clinicians should be aware of possible increased risk among women with a long history of estrogen replacement therapy.

Authors
Moorman, PG; Schildkraut, JM; Calingaert, B; Halabi, S; Berchuck, A
MLA Citation
Moorman, PG, Schildkraut, JM, Calingaert, B, Halabi, S, and Berchuck, A. "Menopausal hormones and risk of ovarian cancer." Am J Obstet Gynecol 193.1 (July 2005): 76-82.
PMID
16021062
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
193
Issue
1
Publish Date
2005
Start Page
76
End Page
82
DOI
10.1016/j.ajog.2004.11.013

Gene expression profiling of microsatellite unstable and microsatellite stable endometrial cancers indicates distinct pathways of aberrant signaling.

Microsatellite instability (MSI) is a molecular phenotype present in approximately 25% of endometrial cancers. We examined the global gene expression profiles of early-stage endometrioid endometrial cancers with and without the MSI phenotype to test the hypothesis that MSI phenotype may determine a unique molecular signature among otherwise similar cancers. Unsupervised principal component analysis of the expression data from these cases indicated two distinct groupings of cancers based on MSI phenotype. A relatively small number of array features (392) at high statistical value (P < 0.001) were identified that drive the instability signature in these cancers; 109 of these transcripts differed by at least 2-fold. These data identify distinct gene expression profiles for MSI and microsatellite stable (MSS) cancers, which suggest that cancers with MSI develop in part by different mechanisms from their similar stable counterparts. In particular, we found evidence that two members of the secreted frizzled related protein family (SFRP1 and SFRP4) were more frequently down-regulated in MSI cancers as compared with MSS cancers. Down-regulation was accompanied by promoter hypermethylation for SFRP1. SFRP1 was hypermethylated in 8 of 12 MSI cancers whereas only 3 of 16 MSS cancers were methylated. The WNT target fibroblast growth factor 18 was found to be up-regulated in MSI cancers. These data classify histologically similar endometrioid endometrial cancers into two distinct groupings with implications affecting therapy and prevention.

Authors
Risinger, JI; Maxwell, GL; Chandramouli, GVR; Aprelikova, O; Litzi, T; Umar, A; Berchuck, A; Barrett, JC
MLA Citation
Risinger, JI, Maxwell, GL, Chandramouli, GVR, Aprelikova, O, Litzi, T, Umar, A, Berchuck, A, and Barrett, JC. "Gene expression profiling of microsatellite unstable and microsatellite stable endometrial cancers indicates distinct pathways of aberrant signaling." Cancer Res 65.12 (June 15, 2005): 5031-5037.
PMID
15958545
Source
pubmed
Published In
Cancer Research
Volume
65
Issue
12
Publish Date
2005
Start Page
5031
End Page
5037
DOI
10.1158/0008-5472.CAN-04-0850

Retrospective analysis of selective lymphadenectomy in apparent early-stage endometrial cancer.

PURPOSE: Selective lymphadenectomy is widely accepted in the management of endometrial cancer. Purported benefits are individualization of adjuvant therapy based on extent of disease and resection of occult metastases. Our goal was to assess effects of the extent of selective lymphadenectomy on outcomes in women with apparent stage I endometrial cancer at laparotomy. PATIENTS AND METHODS: Patients with endometrial cancer who received primary surgical treatment between 1973 and 2002 were identified through an institutional tumor registry. Inclusion criteria were clinical stage I/IIA disease and procedure including hysterectomy and selective lymphadenectomy (pelvic or pelvic + aortic). Exclusion criteria included presurgical radiation, grossly positive lymph nodes, or extrauterine metastases at laparotomy. Recurrence and survival were analyzed using Kaplan-Meier analysis and Cox proportional hazards model. RESULTS: Among 509 patients, the median number of lymph nodes removed was 15 (median pelvic, 11; median aortic, three). Pelvic and aortic node metastases were found in 24 (5%) of 509 patients and 11 (3%) of 373 patients, respectively. Patients with poorly differentiated cancers having more than 11 pelvic nodes removed had improved overall survival (hazard ratio [HR], 0.25; P < .0001) and progression-free survival (HR, 0.26; P < .0001) compared with patients having poorly differentiated cancers with 11 or fewer nodes removed. Number of nodes removed was not predictive of survival among patients with cancers of grade 1 to 2. Performance of aortic selective lymphadenectomy was not associated with survival. Three (27%) of 11 patients with microscopic aortic nodal metastasis are alive without recurrence. CONCLUSION: These data add to the literature documenting the possible therapeutic benefit of selective lymphadenectomy in management of patients with apparent early-stage endometrial cancer.

Authors
Cragun, JM; Havrilesky, LJ; Calingaert, B; Synan, I; Secord, AA; Soper, JT; Clarke-Pearson, DL; Berchuck, A
MLA Citation
Cragun, JM, Havrilesky, LJ, Calingaert, B, Synan, I, Secord, AA, Soper, JT, Clarke-Pearson, DL, and Berchuck, A. "Retrospective analysis of selective lymphadenectomy in apparent early-stage endometrial cancer." J Clin Oncol 23.16 (June 1, 2005): 3668-3675.
PMID
15738538
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
3668
End Page
3675
DOI
10.1200/JCO.2005.04.144

Microarray analysis of endometrial carcinomas and mixed mullerian tumors reveals distinct gene expression profiles associated with different histologic types of uterine cancer.

Previous studies using cDNA microarray have indicated that distinct gene expression profiles characterize endometrioid and papillary serous carcinomas of the endometrium. Molecular studies have observed that mixed mullerian tumors, characterized by both carcinomatous and sarcomatous components, share features that are characteristic of endometrial carcinomas. The objective of this analysis was to more precisely define gene expression patterns that distinguish endometrioid and papillary serous histologies of endometrial carcinoma and mixed mullerian tumors of the uterus. One hundred nineteen pathologically confirmed uterine cancer samples were studied (66 endometrioid, 24 papillary serous, and 29 mixed mullerian tumors). Gene expressions were analyzed using the Affymetrix Human Genome Arrays U133A and U133B Genechip set. Unsupervised analysis revealed distinct global gene expression patterns of endometrioid, papillary serous, mixed mullerian tumors, and normal tissues as grossly separated clusters. Two-sample t tests comparing endometrioid and papillary serous, endometrioid and mixed mullerian tumor, and papillary serous and mixed mullerian tumor pairs identified 1,055, 5,212, and 1,208 differentially expressed genes at P < 0.001, respectively. These data revealed that distinct patterns of gene expression characterize various histologic types of uterine cancer. Gene expression profiles for select genes were confirmed using quantitative PCR. An understanding of the molecular heterogeneity of various histologic types of endometrial cancer has the potential to lead to better individualization of treatment in the future.

Authors
Maxwell, GL; Chandramouli, GVR; Dainty, L; Litzi, TJ; Berchuck, A; Barrett, JC; Risinger, JI
MLA Citation
Maxwell, GL, Chandramouli, GVR, Dainty, L, Litzi, TJ, Berchuck, A, Barrett, JC, and Risinger, JI. "Microarray analysis of endometrial carcinomas and mixed mullerian tumors reveals distinct gene expression profiles associated with different histologic types of uterine cancer." Clin Cancer Res 11.11 (June 1, 2005): 4056-4066.
PMID
15930340
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
11
Publish Date
2005
Start Page
4056
End Page
4066
DOI
10.1158/1078-0432.CCR-04-2001

Gene expression profiles that predict response to platinum and identify patterns of pathway deregulation in advanced ovarian cancer.

Authors
Lancaster, JM; Bild, A; Pittman, J; Sayer, R; Whitaker, RS; Marks, J; Mike, W; Dressman, H; Nevins, J; Berchuck, A
MLA Citation
Lancaster, JM, Bild, A, Pittman, J, Sayer, R, Whitaker, RS, Marks, J, Mike, W, Dressman, H, Nevins, J, and Berchuck, A. "Gene expression profiles that predict response to platinum and identify patterns of pathway deregulation in advanced ovarian cancer." June 1, 2005.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
462S
End Page
462S

Characterization of the insulin-like growth factor pathway in endometrial cancers.

Authors
Cragaun, JM; Elahi, A; Boulware, D; Beam, C; Sayer, R; Maxwell, GL; Sutphen, R; Berchuck, A; Lancaster, JM
MLA Citation
Cragaun, JM, Elahi, A, Boulware, D, Beam, C, Sayer, R, Maxwell, GL, Sutphen, R, Berchuck, A, and Lancaster, JM. "Characterization of the insulin-like growth factor pathway in endometrial cancers." June 1, 2005.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
474S
End Page
474S

Expression analysis of genes involved in ovarian cancer metastasis.

Authors
Martino, MA; Elahi, A; Sutphen, R; Klippel, C; Boren, T; Dressman, HK; Berchuck, A; Lancaster, JM
MLA Citation
Martino, MA, Elahi, A, Sutphen, R, Klippel, C, Boren, T, Dressman, HK, Berchuck, A, and Lancaster, JM. "Expression analysis of genes involved in ovarian cancer metastasis." June 1, 2005.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
464S
End Page
464S

Expression analysis of genes involved in ovarian cancer metastasis.

5038 Background: Epithelial ovarian cancer is the most lethal gynecologic malignancy. Patients with early stage ovarian cancer have an excellent prognosis, in contrast to patients with advanced stage disease, who have a 5-year survival of less than 30%. Although the transition from early to advanced stage disease is a critical determinant of survival, little is known about the molecular genetics that underlie metastasis. The purpose of this study was to evaluate the role of 5 genes previously implicated in human carcinogenesis (FABP4, P53, CCL19, FHL2, POLYDOM), in ovarian cancer metastasis.Expression levels of the FABP4, P53, CCL19, FHL2, and POLYDOM genes were measured using quantitative real time polymerase chain reaction (QRTPCR) in 39 ovarian cancer samples collected from primary and metastatic sites from 14 patients undergoing primary surgical cytoreduction for advanced stage (IIIC/IV) serous epithelial ovarian cancer. Twenty-five samples were resected from the left and/or right ovary and 14 samples from the omentum. All samples were subject to QRTPCR analysis in triplicate and mean values reported. Mean expression values were subject to statistical analysis by student's t-test. This study was IRB approved and informed consent obtained.Higher expression was identified in omental metastases compared to primary ovarian specimens in the CCL19 (7.8-fold), FABP4 (5.2-fold), POLYDOM (2.4-fold), and P53 (1.1-fold) genes. In contrast, FHL-2 gene expression was 1.25-fold higher in primary ovarian samples than matched omental metastasis.We have evaluated expression of 5 genes that may contribute to omental metastasis from epithelial ovarian cancer. All 5 genes have functions that are biologically consistent with a role in cancer progression and metastasis. Defining the molecular genetic changes associated with ovarian cancer metastasis identifies targets for novel therapeutic interventions that may improve survival for patients with advanced stage disease. No significant financial relationships to disclose.

Authors
Martino, MA; Elahi, A; Sutphen, R; Klippel, C; Boren, T; Dressman, HK; Berchuck, A; Lancaster, JM
MLA Citation
Martino, MA, Elahi, A, Sutphen, R, Klippel, C, Boren, T, Dressman, HK, Berchuck, A, and Lancaster, JM. "Expression analysis of genes involved in ovarian cancer metastasis." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23.16_suppl (June 2005): 5038-.
PMID
27946293
Source
epmc
Published In
Journal of Clinical Oncology
Volume
23
Issue
16_suppl
Publish Date
2005
Start Page
5038

Phase I/II trial of intravenous Doxil and whole abdomen hyperthermia in patients with refractory ovarian cancer.

OBJECTIVE: A phase I/II study of Doxil combined with whole abdomen hyperthermia was conducted in patients with refractory ovarian cancer. Liposomal doxorubicin combined with hyperthermia has been shown to increase both liposomal delivery and drug extravasation into tumour xenografts resulting in enhanced cytotoxic effects. PATIENTS AND METHODS: Thirty patients with either recurrent or persistent epithelial ovarian cancer were enrolled. All patients had either measurable or assessable disease. Patients received intravenous (IV) Doxil at a dose of 40 mg m-2 as a 1-h infusion followed by whole abdomen hyperthermia. The phase I portion of the study was performed to determine the maximal tolerated dose (MTD) of hyperthermia. Quality of life (QoL) was performed at baseline, prior to each cycle and every 3 months. Plasma pharmacokinetic studies were performed with the first cycle. RESULTS: Ten patients participated in the phase I portion of the study which demonstrated that the MTD of hyperthermia was 60 min after either average vaginal and rectal temperatures of 40 degrees C had been achieved or after 30 min of power application, whichever was shorter. All 30 patients were either paclitaxel and/or platinum resistant initially or developed resistant disease. The median number of prior chemotherapeutic regimens was three (range 2-8) and six patients had been previously treated with Doxil. There were three partial responses for a response rate of 10% (95% CI: [2%, 27%]) and eight patients (27%; 95% CI: [12%, 46%]) had disease stabilization. The median time to progression or death was 3.4 months (95% CI: [2.6, 5.2]) and the median survival was 10.8 months (95% CI: [8.8, 17.4]). Twelve patients (40%) experienced palmar-plantar erythrodysesthesia (PPE), but only four (13%) experienced grade 3-4 PPE toxicity. Doxil systemic exposure was higher in those with grade 3-4 PPE compared to those with no PPE. None of the patients had grade 3-4 thermal toxicity due to hyperthermia. QoL was not decreased in patients responding to therapy. CONCLUSIONS: Therapy with intravenous Doxil and whole abdomen hyperthermia for patients with platinum/paclitaxel resistant ovarian cancer is feasible and does not negatively impact quality of life.

Authors
Alvarez Secord, A; Jones, EL; Hahn, CA; Petros, WP; Yu, D; Havrilesky, LJ; Soper, JT; Berchuck, A; Spasojevic, I; Clarke-Pearson, DL; Prosnitz, LR; Dewhirst, MW
MLA Citation
Alvarez Secord, A, Jones, EL, Hahn, CA, Petros, WP, Yu, D, Havrilesky, LJ, Soper, JT, Berchuck, A, Spasojevic, I, Clarke-Pearson, DL, Prosnitz, LR, and Dewhirst, MW. "Phase I/II trial of intravenous Doxil and whole abdomen hyperthermia in patients with refractory ovarian cancer." Int J Hyperthermia 21.4 (June 2005): 333-347.
PMID
16019859
Source
pubmed
Published In
International Journal of Hyperthermia (Informa)
Volume
21
Issue
4
Publish Date
2005
Start Page
333
End Page
347
DOI
10.1080/02656730500110155

BRAF polymorphisms and the risk of ovarian cancer of low malignant potential.

OBJECTIVE: The object of this study was to test the hypothesis that BRAF is a low-risk susceptibility gene for low malignant potential (LMP) ovarian cancer. A recent study of the relationship between BRAF polymorphisms and malignant melanoma identified strong linkage disequilibrium across the BRAF gene with one of the three most common haplotypes (haplotype C) having a population attributable risk of approximately 1.6%. We therefore hypothesized that the same BRAF haplotype may confer an increased risk of serous ovarian tumors of low malignant potential. METHODS: We genotyped 383 cases of LMP ovarian cancer, including 234 of serous histology, and 987 controls for seven SNPs, representative of the most common BRAF gene haplotypes, using MALDI-TOF mass spectrometry. RESULTS: Haplotype information was obtained for 369 LMP ovarian cancer cases and 983 healthy controls. None of the haplotypes were found to be associated with risk of LMP ovarian cancer (OR for haplotype C 0.81, 95% CI = 0.54-1.22), or with the risk of serous LMP ovarian cancer (OR for haplotype C 0.90, 95% CI = 0.56-1.45). CONCLUSION: We found no evidence to suggest that BRAF is a low-risk LMP ovarian cancer susceptibility gene.

Authors
Kelemen, L; James, M; Spurdle, A; Campbell, I; Chang-Claude, J; Peel, D; Anton-Culver, H; Berchuck, A; Schildkraut, J; Whittemore, A; McGurie, V; DiCioccio, RA; Duffy, D; Chenevix-Trench, G
MLA Citation
Kelemen, L, James, M, Spurdle, A, Campbell, I, Chang-Claude, J, Peel, D, Anton-Culver, H, Berchuck, A, Schildkraut, J, Whittemore, A, McGurie, V, DiCioccio, RA, Duffy, D, and Chenevix-Trench, G. "BRAF polymorphisms and the risk of ovarian cancer of low malignant potential." Gynecol Oncol 97.3 (June 2005): 807-812.
PMID
15904951
Source
pubmed
Published In
Gynecologic Oncology
Volume
97
Issue
3
Publish Date
2005
Start Page
807
End Page
812
DOI
10.1016/j.ygyno.2005.03.007

Antidepressant medication use for and risk of ovarian cancer (vol 105, pg 725, 2005)

Authors
Moorman, PG; Berchuck, A; Calingaert, B; Halabi, S; Schildkraut, AM
MLA Citation
Moorman, PG, Berchuck, A, Calingaert, B, Halabi, S, and Schildkraut, AM. "Antidepressant medication use for and risk of ovarian cancer (vol 105, pg 725, 2005)." OBSTETRICS AND GYNECOLOGY 105.6 (June 2005): 1495-1495.
Source
wos-lite
Published In
Obstetrics & Gynecology (Elsevier)
Volume
105
Issue
6
Publish Date
2005
Start Page
1495
End Page
1495