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Iversen Jr., Edwin Severin

Overview:

Bayesian statistical modeling with application to problems in genetic
epidemiology and cancer research; models for epidemiological risk
assessment, including hierarchical methods for combining related
epidemiological studies; ascertainment corrections for high risk
family data; analysis of high-throughput genomic data sets.

Positions:

Associate Research Professor of Statistical Science

Statistical Science
Trinity College of Arts & Sciences

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1987

B.S. — University of Chicago

M.S. 1989

M.S. — University of Chicago

Ph.D. 1995

Ph.D. — Yale University

Grants:

BRCA 1 and BRCA2 missense mutations and breast cancer risk

Administered By
Statistical Science
AwardedBy
Mayo Clinic
Role
Principal Investigator
Start Date
September 01, 2013
End Date
June 30, 2018

Discovery of Novel Rare Variants as Ovarian Cancer Susceptibility Factors

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

Early child care and risk of obesity

Administered By
Community and Family Medicine
AwardedBy
Johns Hopkins University - School of Public Health
Role
Co Investigator
Start Date
July 01, 2015
End Date
June 30, 2017

Early child care and risk of obesity

Administered By
Community and Family Medicine
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 01, 2012
End Date
June 30, 2017

Epidemiologic factors and survival by molecular subtypes of ovarian cancer

Administered By
Statistical Science
AwardedBy
Fred Hutchinson Cancer Research Center
Role
Principal Investigator
Start Date
April 01, 2015
End Date
March 31, 2017

Epidemiologic factors and survival by molecular subtypes of ovarian cancer

Administered By
Duke Cancer Institute
AwardedBy
Fred Hutchinson Cancer Research Center
Role
Co Investigator
Start Date
April 01, 2013
End Date
March 31, 2017

Nitrosative Stress and Symptoms During Childhood Leukemia Treatment

Administered By
School of Nursing
AwardedBy
Alex's Lemonade Stand
Role
Statistician
Start Date
January 02, 2014
End Date
January 01, 2017

Discovery of Novel Rare Variants as Ovarian Cancer Susceptibility Factors

Administered By
Obstetrics and Gynecology, Gynecologic Oncology
AwardedBy
MD Anderson Cancer Center
Role
Co Investigator
Start Date
August 01, 2015
End Date
July 31, 2016

Bioinformatics and Computational Biology Training Program

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2005
End Date
June 30, 2016

Atlantic Breast and Gynecologic Clinical Validation Center

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Statistical Programmer
Start Date
September 30, 1999
End Date
June 30, 2016

Models for Consortium Level Analysis of GxE Interaction in Complex Disease

Administered By
Statistical Science
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 15, 2012
End Date
August 31, 2015

Obesity and deregulation of imprinted genes in early life

Administered By
Obstetrics and Gynecology
AwardedBy
National Institutes of Health
Role
Statistician
Start Date
July 27, 2010
End Date
April 30, 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

Epigenetic influence on early childhood self-regulation capacities and obesity

Administered By
Community and Family Medicine
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
September 30, 2011
End Date
August 31, 2014

FitFab 4 Survivors

Administered By
Community and Family Medicine
AwardedBy
National Institutes of Health
Role
Statistician
Start Date
July 01, 2011
End Date
June 30, 2014

Disparities in cervical cancer precursors and deregulation of imprinted genes

Administered By
Obstetrics and Gynecology, Gynecologic Oncology
AwardedBy
National Institutes of Health
Role
Statistician
Start Date
June 01, 2010
End Date
April 30, 2014

The Molecular Epidemiology Of Ovarian Cancer

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

Analysis of Glutathione S-transferase polymorphism, Lifestyle & Cancer Risk

Administered By
Statistical Science
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2010
End Date
March 31, 2012

Bayesian Modeling and Optimal Design for Studies of Gene-Environment Association

Administered By
Statistical Science
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 21, 2007
End Date
July 31, 2011

Ovarian Failure Among Hysterectomized Women

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 30, 2003
End Date
August 31, 2010

Phase II trial of Cetuximab & Carboplatin in Basal-like Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Biostatistician Investigator
Start Date
September 30, 1995
End Date
June 30, 2008

Carolina and Georgia Genetics Network Center

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
August 01, 1998
End Date
April 30, 2008

Carolina and Georgia Genetics Network Center

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
August 01, 1998
End Date
July 31, 2004
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Publications:

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; Aravantinos, G; Arnold, N; Arun, BK; Arver, B; Azzollini, J; Balmaña, J; Banerjee, SN; Barjhoux, L; Barkardottir, RB; Bean, Y; Beckmann, MW 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, Aravantinos, G, Arnold, N, Arun, BK, Arver, B, Azzollini, J, Balmaña, J, Banerjee, SN, Barjhoux, L, Barkardottir, RB, Bean, Y, and Beckmann, MW et al. "Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer." Nature genetics (March 27, 2017).
PMID
28346442
Source
epmc
Published In
Nature Genetics
Publish Date
2017
DOI
10.1038/ng.3826

Cohort profile for the Nurture Observational Study examining associations of multiple caregivers on infant growth in the Southeastern USA.

Childcare has been associated with obesity in children in cross-sectional and longitudinal studies, although some observed no association. Few studies have focused on care during infancy, a period when children may be especially vulnerable.The Nurture Study is an observational birth cohort designed to assess longitudinal associations of childcare and the presence of multiple caregivers on infant adiposity and weight trajectories throughout the first year of life. We examine as potential mediators feeding, physical activity, sleep and stress. We completed recruitment in 2015. Of the 860 women who enrolled during pregnancy, 799 delivered a single live infant who met our inclusion criteria. Of those, 666 mothers (77.4%) agreed to participate in the study for themselves and their infants.Among the 666 women in the study, 472 (71%) identified as black, 127 (19%) as white, 7 (1%) as Asian or Asian American, 6 (1%) as Native American and 49 (7%) as other race or more than one race; 43 (7%) identified as Hispanic/Latina. Just under half (48%) had a high school diploma or less, 61% had household incomes <$20 000/year and 59% were married or living with a partner. The mean (SD) infant gestational age was 41.28 weeks (2.29) and birth weight for gestational age z-score was -0.31 (0.93). Just under half (49%) of infants were females, 69% received some human milk and 40% were exclusively breast fed at hospital discharge. Data collection began in 2013, is currently underway, and is scheduled to conclude in late 2016.Results will help assess the magnitude of associations between childcare in infancy and subsequent obesity. Findings will also inform intervention and policy efforts to improve childcare environments and help prevent obesity in settings where many infants spend time.Clinicaltrials.gov, NCT01788644.

Authors
Benjamin Neelon, SE; Østbye, T; Bennett, GG; Kravitz, RM; Clancy, SM; Stroo, M; Iversen, E; Hoyo, C
MLA Citation
Benjamin Neelon, SE, Østbye, T, Bennett, GG, Kravitz, RM, Clancy, SM, Stroo, M, Iversen, E, and Hoyo, C. "Cohort profile for the Nurture Observational Study examining associations of multiple caregivers on infant growth in the Southeastern USA." BMJ open 7.2 (February 8, 2017): e013939-.
PMID
28179416
Source
epmc
Published In
BMJ Open
Volume
7
Issue
2
Publish Date
2017
Start Page
e013939
DOI
10.1136/bmjopen-2016-013939

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

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

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

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; 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; Jensen, A; Karlan, BY; Kelemen, LE; Kjaer, SK; Kraft, P; Le, ND 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, 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, Jensen, A, Karlan, BY, Kelemen, LE, Kjaer, SK, Kraft, P, and Le, ND 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

Association between Prepregnancy Body Mass Index and Gestational Weight Gain with Size, Tempo, and Velocity of Infant Growth: Analysis of the Newborn Epigenetic Study Cohort.

The first 1000 days of life is a critical period of infant growth that has been linked to future adult health. Understanding prenatal factors that contribute to variation in growth during this period could inform successful prevention strategies.Prenatal and maternal characteristics, including prepregnancy obesity and gestational weight gain were evaluated in relation to weight growth trajectories during the first 24 months of life using the SuperImposition by Translation and Rotation (SITAR) method, which provides estimates of infant size, timing to peak velocity, and growth velocity. The study sample included 704 mother-infant dyads from a multiethnic prebirth cohort from the Southeastern United States. The total number of weight measures was 8670 (median number per child = 14).Several prenatal and maternal characteristics were linked with infant growth parameters. The primary findings show that compared to women with a prepregnancy BMI between 18 and 24.9, women with a prepregnancy BMI ≥40 had infants that were 8% larger during the first 24 months, a delayed tempo of around 9 days, and a slower velocity. Mothers who had greater than adequate gestational weight gain had infants that were 5% larger even after controlling for prepregnancy BMI and several other covariates.The findings contribute new data on the associations between gestational weight gain and aspects of early growth using the SITAR method, and support a growing consensus in the literature that both prepregnancy BMI and gestational weight gain relate independently to risk for greater postnatal weight growth.

Authors
Fuemmeler, BF; Wang, L; Iversen, ES; Maguire, R; Murphy, SK; Hoyo, C
MLA Citation
Fuemmeler, BF, Wang, L, Iversen, ES, Maguire, R, Murphy, SK, and Hoyo, C. "Association between Prepregnancy Body Mass Index and Gestational Weight Gain with Size, Tempo, and Velocity of Infant Growth: Analysis of the Newborn Epigenetic Study Cohort." Childhood obesity (Print) 12.3 (June 2016): 210-218.
PMID
27135650
Source
epmc
Published In
Childhood Obesity
Volume
12
Issue
3
Publish Date
2016
Start Page
210
End Page
218
DOI
10.1089/chi.2015.0253

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; 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; Yatabe, Y; Goodman, MT; Lurie, G; Matsuno, RK; Thompson, PJ; Pejovic, 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, 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, Yatabe, Y, Goodman, MT, Lurie, G, Matsuno, RK, Thompson, PJ, and Pejovic, 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

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
MLA Citation
Lee, AW, Templeman, C, Stram, DA, Beesley, J, Tyrer, J, Berchuck, A, Pharoah, PP, Chenevix-Trench, G, and Pearce, CL. "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

A Cross-Cancer Genetic Association Analysis of the DNA Repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast, and Colorectal Cancer.

DNA damage is an established mediator of carcinogenesis, although genome-wide association studies (GWAS) have identified few significant loci. This cross-cancer site, pooled analysis was performed to increase the power to detect common variants of DNA repair genes associated with cancer susceptibility.We conducted a cross-cancer analysis of 60,297 single nucleotide polymorphisms, at 229 DNA repair gene regions, using data from the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. Our analysis included data from 32 GWAS and 48,734 controls and 51,537 cases across five cancer sites (breast, colon, lung, ovary, and prostate). Because of the unavailability of individual data, data were analyzed at the aggregate level. Meta-analysis was performed using the Association analysis for SubSETs (ASSET) software. To test for genetic associations that might escape individual variant testing due to small effect sizes, pathway analysis of eight DNA repair pathways was performed using hierarchical modeling.We identified three susceptibility DNA repair genes, RAD51B (P < 5.09 × 10(-6)), MSH5 (P < 5.09 × 10(-6)), and BRCA2 (P = 5.70 × 10(-6)). Hierarchical modeling identified several pleiotropic associations with cancer risk in the base excision repair, nucleotide excision repair, mismatch repair, and homologous recombination pathways.Only three susceptibility loci were identified, which had all been previously reported. In contrast, hierarchical modeling identified several pleiotropic cancer risk associations in key DNA repair pathways.Results suggest that many common variants in DNA repair genes are likely associated with cancer susceptibility through small effect sizes that do not meet stringent significance testing criteria.

Authors
Scarbrough, PM; Weber, RP; Iversen, ES; Brhane, Y; Amos, CI; Kraft, P; Hung, RJ; Sellers, TA; Witte, JS; Pharoah, P; Henderson, BE; Gruber, SB; Hunter, DJ; Garber, JE; Joshi, AD; McDonnell, K; Easton, DF; Eeles, R; Kote-Jarai, Z; Muir, K; Doherty, JA; Schildkraut, JM
MLA Citation
Scarbrough, PM, Weber, RP, Iversen, ES, Brhane, Y, Amos, CI, Kraft, P, Hung, RJ, Sellers, TA, Witte, JS, Pharoah, P, Henderson, BE, Gruber, SB, Hunter, DJ, Garber, JE, Joshi, AD, McDonnell, K, Easton, DF, Eeles, R, Kote-Jarai, Z, Muir, K, Doherty, JA, and Schildkraut, JM. "A Cross-Cancer Genetic Association Analysis of the DNA Repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast, and Colorectal Cancer." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 25.1 (January 2016): 193-200.
PMID
26637267
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
1
Publish Date
2016
Start Page
193
End Page
200
DOI
10.1158/1055-9965.epi-15-0649

DNA Methylation of Regulatory Regions of Imprinted Genes at Birth and Its Relation to Infant Temperament.

DNA methylation of the differentially methylated regions (DMRs) of imprinted genes is relevant to neurodevelopment.DNA methylation status of the DMRs of nine imprinted genes in umbilical cord blood leukocytes was analyzed in relation to infant behaviors and temperament (n = 158).MEG3 DMR levels were positively associated with internalizing (β = 0.15, P = 0.044) and surgency (β = 0.19, P = 0.018) behaviors, after adjusting for birth weight, gender, gestational age at birth, maternal age at delivery, race/ethnicity, education level, smoking status, parity, and a history of anxiety or depression. Higher methylation levels at the intergenic MEG3-IG methylation regions were associated with surgency (β = 0.28, P = 0.0003) and PEG3 was positively related to externalizing (β = 0.20, P = 0.01) and negative affectivity (β = 0.18, P = 0.02).While the small sample size limits inference, these pilot data support gene-specific associations between epigenetic differences in regulatory regions of imprinted domains at birth and later infant temperament.

Authors
Fuemmeler, BF; Lee, C-T; Soubry, A; Iversen, ES; Huang, Z; Murtha, AP; Schildkraut, JM; Jirtle, RL; Murphy, SK; Hoyo, C
MLA Citation
Fuemmeler, BF, Lee, C-T, Soubry, A, Iversen, ES, Huang, Z, Murtha, AP, Schildkraut, JM, Jirtle, RL, Murphy, SK, and Hoyo, C. "DNA Methylation of Regulatory Regions of Imprinted Genes at Birth and Its Relation to Infant Temperament." Genetics & epigenetics 8 (January 2016): 59-67.
PMID
27920589
Source
epmc
Published In
Genetics and Epigenetics
Volume
8
Publish Date
2016
Start Page
59
End Page
67

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; 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; Cybulski, C; Plisiecka-Halasa, J; Dennis, J; Dicks, E; Doherty, JA; Dörk, T; du Bois, A 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, 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, Cybulski, C, Plisiecka-Halasa, J, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, and du Bois, A 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

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; 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; Dürst, M; Eccles, D; Easton, DF; Edwards, RP; Ekici, AB et al.
MLA Citation
Kar, SP, Tyrer, JP, Li, Q, Lawrenson, K, Aben, KKH, Anton-Culver, H, Antonenkova, N, Chenevix-Trench, G, 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, Dürst, M, Eccles, D, Easton, DF, Edwards, RP, and Ekici, AB 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

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; 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; Dennis, J; Dicks, E; Doherty, JA; Dörk, T 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, 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, Dennis, J, Dicks, E, Doherty, JA, and Dörk, T 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

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
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, and Antonenkova, N. "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

Hosts of avian brood parasites have evolved egg signatures with elevated information content.

Hosts of brood-parasitic birds must distinguish their own eggs from parasitic mimics, or pay the cost of mistakenly raising a foreign chick. Egg discrimination is easier when different host females of the same species each lay visually distinctive eggs (egg 'signatures'), which helps to foil mimicry by parasites. Here, we ask whether brood parasitism is associated with lower levels of correlation between different egg traits in hosts, making individual host signatures more distinctive and informative. We used entropy as an index of the potential information content encoded by nine aspects of colour, pattern and luminance of eggs of different species in two African bird families (Cisticolidae parasitized by cuckoo finches Anomalospiza imberbis, and Ploceidae by diederik cuckoos Chrysococcyx caprius). Parasitized species showed consistently higher entropy in egg traits than did related, unparasitized species. Decomposing entropy into two variation components revealed that this was mainly driven by parasitized species having lower levels of correlation between different egg traits, rather than higher overall levels of variation in each individual egg trait. This suggests that irrespective of the constraints that might operate on individual egg traits, hosts can further improve their defensive 'signatures' by arranging suites of egg traits into unpredictable combinations.

Authors
Caves, EM; Stevens, M; Iversen, ES; Spottiswoode, CN
MLA Citation
Caves, EM, Stevens, M, Iversen, ES, and Spottiswoode, CN. "Hosts of avian brood parasites have evolved egg signatures with elevated information content." Proceedings. Biological sciences 282.1810 (July 2015).
Website
http://hdl.handle.net/10161/12478
PMID
26085586
Source
epmc
Published In
Proceedings of the Royal Society of London: Biological Sciences
Volume
282
Issue
1810
Publish Date
2015
DOI
10.1098/rspb.2015.0598

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; 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; Wilkens, LR; Dörk, T; Hillemanns, P; Dürst, M; Runnebaum, IB; Bogdanova, N et al.
MLA Citation
Lee, AW, Tyrer, JP, Doherty, JA, Stram, DA, Kupryjanczyk, J, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Spiewankiewicz, B, Myers, EJ, 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, Wilkens, LR, Dörk, T, Hillemanns, P, Dürst, M, Runnebaum, IB, and Bogdanova, N 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

Construction and analysis of the NCI-EDRN breast cancer reference set for circulating markers of disease.

Many circulating biomarkers have been reported for the diagnosis of breast cancer, but few, if any, have undergone rigorous credentialing using prospective cohorts and blinded evaluation.The NCI Early Detection Research Network (EDRN) has created a prospective, multicenter collection of plasma and serum samples from 832 subjects designed to evaluate circulating biomarkers for the detection and diagnosis of breast cancer. These samples are available to investigators who wish to evaluate their biomarkers using a set of blinded samples. The breast cancer reference set is composed of blood samples collected using a standard operating procedure at four U.S. medical centers from 2008 to 2010 from women undergoing either tissue diagnosis for breast cancer or routine screening mammography. The reference set contains samples from women with incident invasive cancer (n = 190), carcinoma in situ (n = 55), benign pathology with atypia (n = 63), benign disease with no atypia (n = 231), and women with no evidence of breast disease by screening mammography (BI-RADS 1 or 2, n = 276). Using a subset of plasma samples (n = 505) from the reference set, we analyzed 90 proteins by multiplexed immunoassays for their potential utility as diagnostic markers.We found that none of these markers is useful for distinguishing cancer from benign controls. However, elevated CA-125 does appear to be a candidate marker for estrogen receptor-negative cancers.Markers that can distinguish benign breast conditions from invasive cancer have not yet been found.Availability of prospectively collected samples should improve future validation efforts.

Authors
Marks, JR; Anderson, KS; Engstrom, P; Godwin, AK; Esserman, LJ; Longton, G; Iversen, ES; Mathew, A; Patriotis, C; Pepe, MS
MLA Citation
Marks, JR, Anderson, KS, Engstrom, P, Godwin, AK, Esserman, LJ, Longton, G, Iversen, ES, Mathew, A, Patriotis, C, and Pepe, MS. "Construction and analysis of the NCI-EDRN breast cancer reference set for circulating markers of disease." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 24.2 (February 2015): 435-441.
PMID
25471344
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
2
Publish Date
2015
Start Page
435
End Page
441
DOI
10.1158/1055-9965.epi-14-1178

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

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

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

A joint analysis of metabolomics and genetics of breast cancer.

Remodeling of cellular metabolism appears to be a consequence and possibly a cause of oncogenic transformation in human cancers. Specific aspects of altered tumor metabolism may be amenable to therapeutic intervention and could be coordinated with other targeted therapies. In breast cancer, the genetic landscape has been defined most comprehensively in efforts such as The Cancer Genome Atlas (TCGA). However, little is known about how alterations of tumor metabolism correlate with this landscape.In total 25 cancers (23 fully analyzed by TCGA) and 5 normal breast specimens were analyzed by gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry, quantitating 399 identifiable metabolites.We found strong differences correlated with hormone receptor status with 18% of the metabolites elevated in estrogen receptor negative (ER-) cancers compared to estrogen receptor positive (ER+) including many glycolytic and glycogenolytic intermediates consistent with increased Warburg effects. Glutathione (GSH) pathway components were also elevated in ER- tumors consistent with an increased requirement for handling higher levels of oxidative stress. Additionally, ER- tumors had high levels of the oncometabolite 2-hydroxyglutarate (2-HG) and the immunomodulatory tryptophan metabolite kynurenine. Kynurenine levels were correlated with the expression of tryptophan-degrading enzyme (IDO1). However, high levels of 2-HG were not associated with somatic mutations or expression levels of IDH1 or IDH2. BRCA1 mRNA levels were positively associated with coenzyme A, acetyl coenzyme A, and GSH and negatively associated with multiple lipid species, supporting the regulation of ACC1 and NRF2 by BRCA1. Different driver mutations were associated with distinct patterns of specific metabolites, such as lower levels of several lipid-glycerophosphocholines in tumors with mutated TP53. A strong metabolomic signature associated with proliferation rate was also observed; the metabolites in this signature overlap broadly with metabolites that define ER status as receptor status and proliferation rate were correlated.The addition of metabolomic profiles to the public domain TCGA dataset provides an important new tool for discovery and hypothesis testing of the genetic regulation of tumor metabolism. Particular sets of metabolites may reveal insights into the metabolic dysregulation that underlie the heterogeneity of breast cancer.

Authors
Tang, X; Lin, C-C; Spasojevic, I; Iversen, ES; Chi, J-T; Marks, JR
MLA Citation
Tang, X, Lin, C-C, Spasojevic, I, Iversen, ES, Chi, J-T, and Marks, JR. "A joint analysis of metabolomics and genetics of breast cancer." Breast cancer research : BCR 16.4 (August 5, 2014): 415-.
PMID
25091696
Source
epmc
Published In
Breast Cancer Research
Volume
16
Issue
4
Publish Date
2014
Start Page
415
DOI
10.1186/s13058-014-0415-9

Erythrocyte folate concentrations, CpG methylation at genomically imprinted domains, and birth weight in a multiethnic newborn cohort.

Epigenetic mechanisms are proposed to link maternal concentrations of methyl group donor nutrients with the risk of low birth weight. However, empirical data are lacking. We have examined the association between maternal folate and birth weight and assessed the mediating role of DNA methylation at nine differentially methylated regions (DMRs) of genomically imprinted genes in these associations. Compared with newborns of women with folate levels in the lowest quartile, birth weight was higher in newborns of mothers in the second (β = 143.2, se = 63.2, P = 0.02), third (β = 117.3, se = 64.0, P = 0.07), and fourth (β = 133.9, se = 65.2, P = 0.04) quartiles, consistent with a threshold effect. This pattern of association did not vary by race/ethnicity but was more apparent in newborns of non-obese women. DNA methylation at the PLAGL1, SGCE, DLK1/MEG3 and IGF2/H19 DMRs was associated with maternal folate levels and also birth weight, suggestive of threshold effects. MEG3 DMR methylation mediated the association between maternal folate levels and birth weight (P =0.06). While the small sample size and partial scope of examined DMRs limit our conclusions, our data suggest that, with respect to birth weight, no additional benefits may be derived from increased maternal folate concentrations, especially in non-obese women. These data also support epigenetic plasticity as a key mechanistic response to folate availability during early fetal development.

Authors
Hoyo, C; Daltveit, AK; Iversen, E; Benjamin-Neelon, SE; Fuemmeler, B; Schildkraut, J; Murtha, AP; Overcash, F; Vidal, AC; Wang, F; Huang, Z; Kurtzberg, J; Seewaldt, V; Forman, M; Jirtle, RL; Murphy, SK
MLA Citation
Hoyo, C, Daltveit, AK, Iversen, E, Benjamin-Neelon, SE, Fuemmeler, B, Schildkraut, J, Murtha, AP, Overcash, F, Vidal, AC, Wang, F, Huang, Z, Kurtzberg, J, Seewaldt, V, Forman, M, Jirtle, RL, and Murphy, SK. "Erythrocyte folate concentrations, CpG methylation at genomically imprinted domains, and birth weight in a multiethnic newborn cohort." Epigenetics 9.8 (August 2014): 1120-1130.
PMID
24874916
Source
epmc
Published In
Epigenetics : official journal of the DNA Methylation Society
Volume
9
Issue
8
Publish Date
2014
Start Page
1120
End Page
1130
DOI
10.4161/epi.29332

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; 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; Engelholm, SA; Brown, B; Flanagan, J et al.
MLA Citation
Hedditch, EL, Gao, B, Russell, AJ, Lu, Y, Emmanuel, C, Beesley, J, Johnatty, SE, Chen, X, Harnett, P, George, J, 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, Engelholm, SA, Brown, B, and Flanagan, J 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

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

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

Probing structure-function relationships in missense variants in the carboxy-terminal region of BRCA1.

Germline inactivating variants in BRCA1 lead to a significantly increased risk of breast and ovarian cancers in carriers. While the functional effect of many variants can be inferred from the DNA sequence, determining the effect of missense variants present a significant challenge. A series of biochemical and cell biological assays have been successfully used to explore the impact of these variants on the function of BRCA1, which contribute to assessing their likelihood of pathogenicity. It has been determined that variants that co-localize with structural or functional motifs are more likely to disrupt the stability and function of BRCA1. Here we assess the functional impact of 37 variants chosen to probe the functional impact of variants in phosphorylation sites and in the BRCT domains. In addition, we perform a meta-analysis of 170 unique variants tested by the transcription activation assays in the carboxy-terminal domain of BRCA1 using a recently developed computation model to provide assessment for functional impact and their likelihood of pathogenicity.

Authors
Carvalho, RS; Abreu, RBV; Velkova, A; Marsillac, S; Rodarte, RS; Suarez-Kurtz, G; Iversen, ES; Monteiro, ANA; Carvalho, MA
MLA Citation
Carvalho, RS, Abreu, RBV, Velkova, A, Marsillac, S, Rodarte, RS, Suarez-Kurtz, G, Iversen, ES, Monteiro, ANA, and Carvalho, MA. "Probing structure-function relationships in missense variants in the carboxy-terminal region of BRCA1." PloS one 9.5 (January 2014): e97766-.
PMID
24845084
Source
epmc
Published In
PloS one
Volume
9
Issue
5
Publish Date
2014
Start Page
e97766
DOI
10.1371/journal.pone.0097766

Maternal stress, preterm birth, and DNA methylation at imprint regulatory sequences in humans.

In infants exposed to maternal stress in utero, phenotypic plasticity through epigenetic events may mechanistically explain increased risk of preterm birth (PTB), which confers increased risk for neurodevelopmental disorders, cardiovascular disease, and cancers in adulthood. We examined associations between prenatal maternal stress and PTB, evaluating the role of DNA methylation at imprint regulatory regions. We enrolled women from prenatal clinics in Durham, NC. Stress was measured in 537 women at 12 weeks of gestation using the Perceived Stress Scale. DNA methylation at differentially methylated regions (DMRs) associated with H19, IGF2, MEG3, MEST, SGCE/PEG10, PEG3, NNAT, and PLAGL1 was measured from peripheral and cord blood using bisulfite pyrosequencing in a sub-sample of 79 mother-infant pairs. We examined associations between PTB and stress and evaluated differences in DNA methylation at each DMR by stress. Maternal stress was not associated with PTB (OR = 0.98; 95% CI, 0.40-2.40; P = 0.96), after adjustment for maternal body mass index (BMI), income, and raised blood pressure. However, elevated stress was associated with higher infant DNA methylation at the MEST DMR (2.8% difference, P < 0.01) after adjusting for PTB. Maternal stress may be associated with epigenetic changes at MEST, a gene relevant to maternal care and obesity. Reduced prenatal stress may support the epigenomic profile of a healthy infant.

Authors
Vidal, AC; Benjamin Neelon, SE; Liu, Y; Tuli, AM; Fuemmeler, BF; Hoyo, C; Murtha, AP; Huang, Z; Schildkraut, J; Overcash, F; Kurtzberg, J; Jirtle, RL; Iversen, ES; Murphy, SK
MLA Citation
Vidal, AC, Benjamin Neelon, SE, Liu, Y, Tuli, AM, Fuemmeler, BF, Hoyo, C, Murtha, AP, Huang, Z, Schildkraut, J, Overcash, F, Kurtzberg, J, Jirtle, RL, Iversen, ES, and Murphy, SK. "Maternal stress, preterm birth, and DNA methylation at imprint regulatory sequences in humans." Genetics & epigenetics 6 (January 2014): 37-44.
PMID
25512713
Source
epmc
Published In
Genetics and Epigenetics
Volume
6
Publish Date
2014
Start Page
37
End Page
44
DOI
10.4137/geg.s18067

Functional Annotation Signatures of Disease Susceptibility Loci Improve SNP Association Analysis

Background Genetic association studies are conducted to discover genetic loci that contribute to an inherited trait, identify the variants behind these associations and ascertain their functional role in determining the phenotype. To date, functional annotations of the genetic variants have rarely played more than an indirect role in assessing evidence for association. Here, we demonstrate how these data can be systematically integrated into an association study’s analysis plan. Results We developed a Bayesian statistical model for the prior probability of phenotype–genotype association that incorporates data from past association studies and publicly available functional annotation data regarding the susceptibility variants under study. The model takes the form of a binary regression of association status on a set of annotation variables whose coefficients were estimated through an analysis of associated SNPs in the GWAS Catalog (GC). The functional predictors examined included measures that have been demonstrated to correlate with the association status of SNPs in the GC and some whose utility in this regard is speculative: summaries of the UCSC Human Genome Browser ENCODE super–track data, dbSNP function class, sequence conservation summaries, proximity to genomic variants in the Database of Genomic Variants and known regulatory elements in the Open Regulatory Annotation database, PolyPhen–2 probabilities and RegulomeDB categories. Because we expected that only a fraction of the annotations would contribute to predicting association, we employed a penalized likelihood method to reduce the impact of non–informative predictors and evaluated the model’s ability to predict GC SNPs not used to construct the model. We show that the functional data alone are predictive of a SNP’s presence in the GC. Further, using data from a genome–wide study of ovarian cancer, we demonstrate that their use as prior data when testing for association is practical at the genome–wide scale and improves power to detect associations. Conclusions We show how diverse functional annotations can be efficiently combined to create ‘functional signatures’ that predict the a priori odds of a variant’s association to a trait and how these signatures can be integrated into a standard genome–wide–scale association analysis, resulting in improved power to detect truly associated variants.

Authors
Iversen, ES; Lipton, G; Clyde, MA; Monteiro, ANA
MLA Citation
Iversen, ES, Lipton, G, Clyde, MA, and Monteiro, ANA. "Functional Annotation Signatures of Disease Susceptibility Loci Improve SNP Association Analysis." BMC Genomics 15 (2014): 398-398.
Website
http://hdl.handle.net/10161/8882
PMID
24886216
Source
manual
Published In
BMC Genomics
Volume
15
Publish Date
2014
Start Page
398
End Page
398
DOI
10.1186/1471-2164-15-398

Functional annotation signatures of disease susceptibility loci improve SNP association analysis

Authors
Iversen, ES; Lipton, G; Clyde, MA; Monteiro, ANA
MLA Citation
Iversen, ES, Lipton, G, Clyde, MA, and Monteiro, ANA. "Functional annotation signatures of disease susceptibility loci improve SNP association analysis." BMC Genomics 15.1 (2014): 398-398.
Source
crossref
Published In
BMC Genomics
Volume
15
Issue
1
Publish Date
2014
Start Page
398
End Page
398
DOI
10.1186/1471-2164-15-398

Gene-environment interactions in cancer epidemiology: A national cancer institute think tank report

Cancer risk is determined by a complex interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified hundreds of common (minor allele frequency [MAF] > 0.05) and less common (0.01 < MAF < 0.05) genetic variants associated with cancer. The marginal effects of most of these variants have been small (odds ratios: 1.1-1.4). There remain unanswered questions on how best to incorporate the joint effects of genes and environment, including gene-environment (G × E) interactions, into epidemiologic studies of cancer. To help address these questions, and to better inform research priorities and allocation of resources, the National Cancer Institute sponsored a "Gene-Environment Think Tank" on January 10-11, 2012. The objective of the Think Tank was to facilitate discussions on (1) the state of the science, (2) the goals of G × E interaction studies in cancer epidemiology, and (3) opportunities for developing novel study designs and analysis tools. This report summarizes the Think Tank discussion, with a focus on contemporary approaches to the analysis of G × E interactions. Selecting the appropriate methods requires first identifying the relevant scientific question and rationale, with an important distinction made between analyses aiming to characterize the joint effects of putative or established genetic and environmental factors and analyses aiming to discover novel risk factors or novel interaction effects. Other discussion items include measurement error, statistical power, significance, and replication. Additional designs, exposure assessments, and analytical approaches need to be considered as we move from the current small number of success stories to a fuller understanding of the interplay of genetic and environmental factors. © 2013 WILEY PERIODICALS, INC.

Authors
Hutter, CM; Mechanic, LE; Chatterjee, N; Kraft, P; Gillanders, EM; Abnet, CC; Amos, C; Balshaw, D; Bickeböller, H; Bierut, LJ; Boffetta, P; Bondy, M; Chanock, S; Chen, HS; Cox, N; Vivo, ID; Divi, R; Dupuis, J; Ellison, G; Fallin, MD; Gauderman, WJ; Gillanders, E; Haiman, C; Hutter, C; Simonds, NI; Iversen, E; Khoury, MJ; Marchand, LL; McAllister, K; Mechanic, L; Peters, U; Prentice, R; Rebbeck, T; Reedy, J; Rothman, N; Schully, S; Seminara, D; Shaughnessy, D; Shete, S; Spiegelman, D; Stram, DO et al.
MLA Citation
Hutter, CM, Mechanic, LE, Chatterjee, N, Kraft, P, Gillanders, EM, Abnet, CC, Amos, C, Balshaw, D, Bickeböller, H, Bierut, LJ, Boffetta, P, Bondy, M, Chanock, S, Chen, HS, Cox, N, Vivo, ID, Divi, R, Dupuis, J, Ellison, G, Fallin, MD, Gauderman, WJ, Gillanders, E, Haiman, C, Hutter, C, Simonds, NI, Iversen, E, Khoury, MJ, Marchand, LL, McAllister, K, Mechanic, L, Peters, U, Prentice, R, Rebbeck, T, Reedy, J, Rothman, N, Schully, S, Seminara, D, Shaughnessy, D, Shete, S, Spiegelman, D, and Stram, DO et al. "Gene-environment interactions in cancer epidemiology: A national cancer institute think tank report." Genetic Epidemiology 37.7 (November 1, 2013): 643-657.
PMID
24123198
Source
scopus
Published In
Genetic Epidemiology
Volume
37
Issue
7
Publish Date
2013
Start Page
643
End Page
657
DOI
10.1002/gepi.21756

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

Associations between antibiotic exposure during pregnancy, birth weight and aberrant methylation at imprinted genes among offspring.

OBJECTIVES: Low birth weight (LBW) has been associated with common adult-onset chronic diseases, including obesity, cardiovascular disease, type II diabetes and some cancers. The etiology of LBW is multi-factorial. However, recent evidence suggests exposure to antibiotics may also increase the risk of LBW. The mechanisms underlying this association are unknown, although epigenetic mechanisms are hypothesized. In this study, we evaluated the association between maternal antibiotic use and LBW and examined the potential role of altered DNA methylation that controls growth regulatory imprinted genes in these associations. METHODS: Between 2009-2011, 397 pregnant women were enrolled and followed until delivery. Prenatal antibiotic use was ascertained through maternal self-report. Imprinted genes methylation levels were measured at differentially methylated regions (DMRs) using bisulfite pyrosequencing. Generalized linear models were used to examine associations among antibiotic use, birth weight and DMR methylation fractions. RESULTS: After adjusting for infant gender, race/ethnicity, maternal body mass index, delivery route, gestational weight gain, gestational age at delivery, folic acid intake, physical activity, maternal smoking and parity, antibiotic use during pregnancy was associated with 138 g lower birth weight compared with non-antibiotic use (β-coefficient=-132.99, s.e.=50.70, P=0.008). These associations were strongest in newborns of women who reported antibiotic use other than penicillins (β-coefficient=-135.57, s.e.=57.38, P=0.02). Methylation at five DMRs, IGF2 (P=0.05), H19 (P=0.15), PLAGL1 (P=0.01), MEG3 (P=0.006) and PEG3 (P=0.08), was associated with maternal antibiotic use; among these, only methylation at the PLAGL1 DMR was also associated with birth weight. CONCLUSION: We report an inverse association between in utero exposure to antibiotics and lower infant birth weight and provide the first empirical evidence supporting imprinted gene plasticity in these associations.

Authors
Vidal, AC; Murphy, SK; Murtha, AP; Schildkraut, JM; Soubry, A; Huang, Z; Neelon, SEB; Fuemmeler, B; Iversen, E; Wang, F; Kurtzberg, J; Jirtle, RL; Hoyo, C
MLA Citation
Vidal, AC, Murphy, SK, Murtha, AP, Schildkraut, JM, Soubry, A, Huang, Z, Neelon, SEB, Fuemmeler, B, Iversen, E, Wang, F, Kurtzberg, J, Jirtle, RL, and Hoyo, C. "Associations between antibiotic exposure during pregnancy, birth weight and aberrant methylation at imprinted genes among offspring." Int J Obes (Lond) 37.7 (July 2013): 907-913.
PMID
23609933
Source
pubmed
Published In
International Journal of Obesity
Volume
37
Issue
7
Publish Date
2013
Start Page
907
End Page
913
DOI
10.1038/ijo.2013.47

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

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

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

Associations between antibiotic exposure during pregnancy, birth weight and aberrant methylation at imprinted genes among offspring

Objectives: Low birth weight (LBW) has been associated with common adult-onset chronic diseases, including obesity, cardiovascular disease, type II diabetes and some cancers. The etiology of LBW is multi-factorial. However, recent evidence suggests exposure to antibiotics may also increase the risk of LBW. The mechanisms underlying this association are unknown, although epigenetic mechanisms are hypothesized. In this study, we evaluated the association between maternal antibiotic use and LBW and examined the potential role of altered DNA methylation that controls growth regulatory imprinted genes in these associations. Methods: Between 2009-2011, 397 pregnant women were enrolled and followed until delivery. Prenatal antibiotic use was ascertained through maternal self-report. Imprinted genes methylation levels were measured at differentially methylated regions (DMRs) using bisulfite pyrosequencing. Generalized linear models were used to examine associations among antibiotic use, birth weight and DMR methylation fractions. Results: After adjusting for infant gender, race/ethnicity, maternal body mass index, delivery route, gestational weight gain, gestational age at delivery, folic acid intake, physical activity, maternal smoking and parity, antibiotic use during pregnancy was associated with 138 g lower birth weight compared with non-antibiotic use (β-coefficient=-132.99, s.e.=50.70, P=0.008). These associations were strongest in newborns of women who reported antibiotic use other than penicillins (β-coefficient=-135.57, s.e.=57.38, P=0.02). Methylation at five DMRs, IGF2 (P=0.05), H19 (P=0.15), PLAGL1 (P=0.01), MEG3 (P=0.006) and PEG3 (P=0.08), was associated with maternal antibiotic use; among these, only methylation at the PLAGL1 DMR was also associated with birth weight. Conclusion: We report an inverse association between in utero exposure to antibiotics and lower infant birth weight and provide the first empirical evidence supporting imprinted gene plasticity in these associations. © 2013 Macmillan Publishers Limited.

Authors
Vidal, AC; Murphy, SK; Murtha, AP; Schildkraut, JM; Soubry, A; Huang, Z; Neelon, SEB; Fuemmeler, B; Iversen, E; Wang, F; Kurtzberg, J; Jirtle, RL; Hoyo, C
MLA Citation
Vidal, AC, Murphy, SK, Murtha, AP, Schildkraut, JM, Soubry, A, Huang, Z, Neelon, SEB, Fuemmeler, B, Iversen, E, Wang, F, Kurtzberg, J, Jirtle, RL, and Hoyo, C. "Associations between antibiotic exposure during pregnancy, birth weight and aberrant methylation at imprinted genes among offspring." International Journal of Obesity 37.7 (2013): 907-913.
Source
scival
Published In
International Journal of Obesity
Volume
37
Issue
7
Publish Date
2013
Start Page
907
End Page
913
DOI
10.1038/ijo.2013.47

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

ABO blood group and risk of epithelial ovarian cancer within the Ovarian Cancer Association Consortium.

PURPOSE: Previous studies have examined the association between ABO blood group and ovarian cancer risk, with inconclusive results. METHODS: In eight studies participating in the Ovarian Cancer Association Consortium, we determined ABO blood groups and diplotypes by genotyping 3 SNPs in the ABO locus. Odds ratios and 95 % confidence intervals were calculated in each study using logistic regression; individual study results were combined using random effects meta-analysis. RESULTS: Compared to blood group O, the A blood group was associated with a modestly increased ovarian cancer risk: (OR: 1.09; 95 % CI: 1.01-1.18; p = 0.03). In diplotype analysis, the AO, but not the AA diplotype, was associated with increased risk (AO: OR: 1.11; 95 % CI: 1.01-1.22; p = 0.03; AA: OR: 1.03; 95 % CI: 0.87-1.21; p = 0.76). Neither AB nor the B blood groups were associated with risk. Results were similar across ovarian cancer histologic subtypes. CONCLUSION: Consistent with most previous reports, the A blood type was associated modestly with increased ovarian cancer risk in this large analysis of multiple studies of ovarian cancer. Future studies investigating potential biologic mechanisms are warranted.

Authors
Poole, EM; Gates, MA; High, BA; Chanock, SJ; Cramer, DW; Cunningham, JM; Fridley, BL; Gayther, SA; Goode, EL; Iversen, ES; Lissowska, J; Palmieri Weber, RT; Pharoah, PDP; Phelan, CM; Ramus, SJ; Schildkraut, JM; Sutphen, R; Tsai, Y-Y; Tyrer, J; Vierkant, RA; Wentzensen, N; Yang, HP; Terry, KL; Tworoger, SS
MLA Citation
Poole, EM, Gates, MA, High, BA, Chanock, SJ, Cramer, DW, Cunningham, JM, Fridley, BL, Gayther, SA, Goode, EL, Iversen, ES, Lissowska, J, Palmieri Weber, RT, Pharoah, PDP, Phelan, CM, Ramus, SJ, Schildkraut, JM, Sutphen, R, Tsai, Y-Y, Tyrer, J, Vierkant, RA, Wentzensen, N, Yang, HP, Terry, KL, and Tworoger, SS. "ABO blood group and risk of epithelial ovarian cancer within the Ovarian Cancer Association Consortium." Cancer Causes Control 23.11 (November 2012): 1805-1810.
PMID
22961099
Source
pubmed
Published In
Cancer Causes & Control
Volume
23
Issue
11
Publish Date
2012
Start Page
1805
End Page
1810
DOI
10.1007/s10552-012-0059-y

Depression in pregnancy, infant birth weight and DNA methylation of imprint regulatory elements.

Depressed mood in pregnancy has been linked to low birth weight (LBW, < 2,500 g), a risk factor for adult-onset chronic diseases in offspring. We examined maternal depressed mood in relation to birth weight and evaluated the role of DNA methylation at regulatory sequences of imprinted genes in this association. We measured depressed mood among 922 pregnant women using the CES-D scale and obtained birth weight data from hospital records. Using bisulfite pyrosequencing of cord blood DNA from 508 infants, we measured methylation at differentially methylated regions (DMRs) regulating imprinted genes IGF2/H19, DLK1/MEG3, MEST, PEG3, PEG10/SGCE, NNAT and PLAGL1. Multiple regression models were used to examine the relationship between depressed mood, birth weight and DMR methylation levels. Depressed mood was associated with a more that 3-fold higher risk of LBW, after adjusting for delivery mode, parity, education, cigarette smoking, folic acid use and preterm birth. The association may be more pronounced in offspring of black women and female infants. Compared with infants of women without depressed mood, infants born to women with severe depressed mood had a 2.4% higher methylation at the MEG3 DMR. Whereas LBW infants had 1.6% lower methylation at the IGF2 DMR, high birth weight (> 4,500 g) infants had 5.9% higher methylation at the PLAGL1 DMR compared with normal birth weight infants. Our findings confirm that severe maternal depressed mood in pregnancy is associated with LBW, and that MEG3 and IGF2 plasticity may play important roles.

Authors
Liu, Y; Murphy, SK; Murtha, AP; Fuemmeler, BF; Schildkraut, J; Huang, Z; Overcash, F; Kurtzberg, J; Jirtle, R; Iversen, ES; Forman, MR; Hoyo, C
MLA Citation
Liu, Y, Murphy, SK, Murtha, AP, Fuemmeler, BF, Schildkraut, J, Huang, Z, Overcash, F, Kurtzberg, J, Jirtle, R, Iversen, ES, Forman, MR, and Hoyo, C. "Depression in pregnancy, infant birth weight and DNA methylation of imprint regulatory elements." Epigenetics 7.7 (July 2012): 735-746.
PMID
22677950
Source
pubmed
Published In
Epigenetics : official journal of the DNA Methylation Society
Volume
7
Issue
7
Publish Date
2012
Start Page
735
End Page
746
DOI
10.4161/epi.20734

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

Gender-specific methylation differences in relation to prenatal exposure to cigarette smoke.

Epigenetic alterations may mechanistically explain the developmental origins of adult disease, namely the hypothesis that many complex adult chronic diseases originate as a result of conditions encountered in utero. If true, epigenetically regulated imprinted genes, critical to normal growth and development, may partially mediate these outcomes. We determined the influence of in utero exposure to cigarette smoking on methylation at two differentially methylated regions (DMRs) regulating Insulin-like Growth Factor 2 (IGF2) and H19, and how this might relate to birth weight of infants born to 418 pregnant women. Smoking status was ascertained through self-report and medical records. Bisulfite pyrosequencing was used to measure methylation in umbilical cord blood DNAs. Least squares DNA methylation means at each DMR and birth weight were compared between infants of smokers and non-smokers, using generalized linear models. While there were no significant differences at the H19 DMR, infants born to smokers had higher methylation at the IGF2 DMR than those born to never smokers or those who quit during pregnancy (49.5%, SD=8.0 versus 46.6%, SD=5.6 and 45.8%, SD=6.3, respectively; p=0.0002). The smoking-related increase in methylation was most pronounced in male offspring (p for sex interaction=0.03), for whom approximately 20% of smoking-related low birth weight was mediated by DNA methylation at the IGF2 DMR. Our findings suggest that IGF2 DMR plasticity is an important mechanism by which in utero adjustments to environmental toxicants are conferred. Larger studies to replicate these findings are required.

Authors
Murphy, SK; Adigun, A; Huang, Z; Overcash, F; Wang, F; Jirtle, RL; Schildkraut, JM; Murtha, AP; Iversen, ES; Hoyo, C
MLA Citation
Murphy, SK, Adigun, A, Huang, Z, Overcash, F, Wang, F, Jirtle, RL, Schildkraut, JM, Murtha, AP, Iversen, ES, and Hoyo, C. "Gender-specific methylation differences in relation to prenatal exposure to cigarette smoke." Gene 494.1 (February 15, 2012): 36-43.
PMID
22202639
Source
pubmed
Published In
Gene
Volume
494
Issue
1
Publish Date
2012
Start Page
36
End Page
43
DOI
10.1016/j.gene.2011.11.062

Charting the landscape of tandem BRCT domain-mediated protein interactions

Eukaryotic cells have evolved an intricate system to resolve DNA damage to prevent its transmission to daughter cells. This system, collectively known as the DNA damage response (DDR) network, includesmany proteins that detect DNA damage, promote repair, and coordinate progression through the cell cycle. Because defects in this network can lead to cancer, this network constitutes a barrier against tumorigenesis. The modular BRCA1 carboxyl-terminal (BRCT) domain is frequently present in proteins involved in the DDR, can exist either as an individual domain or as tandem domains (tBRCT), and can bind phosphorylated peptides. We performed a systematic analysis of protein-protein interactions involving tBRCT in the DDR by combining literature curation, yeast two-hybrid screens, and tandem affinity purification coupled to mass spectrometry. We identified 23 proteins containing conserved BRCT domains and generated a human protein-protein interaction network for seven proteins with tBRCT. This study also revealed previously unknown components in DNA damage signaling, such as COMMD1 andt he target of rapamycin complex mTORC2. Additionally, integration of tBRCT domain interactions with DDR phosphoprotein studies and analysis of kinase-substrate interactions revealed signaling subnetworks that may aid in understanding the involvement of tBRCT in disease and DNA repair.

Authors
Woods, NT; Mesquita, RD; Sweet, M; Carvalho, MA; Li, X; Liu, Y; Nguyen, H; Thomas, CE; Jr, ESI; Marsillac, S; Karchin, R; Koomen, J; Monteiro, ANA
MLA Citation
Woods, NT, Mesquita, RD, Sweet, M, Carvalho, MA, Li, X, Liu, Y, Nguyen, H, Thomas, CE, Jr, ESI, Marsillac, S, Karchin, R, Koomen, J, and Monteiro, ANA. "Charting the landscape of tandem BRCT domain-mediated protein interactions." Science Signaling 5.242 (2012).
PMID
22990118
Source
scival
Published In
Science Signaling
Volume
5
Issue
242
Publish Date
2012
DOI
10.1126/scisignal.2002255

European American stratification in ovarian cancer case control data: the utility of genome-wide data for inferring ancestry.

We investigated the ability of several principal components analysis (PCA)-based strategies to detect and control for population stratification using data from a multi-center study of epithelial ovarian cancer among women of European-American ethnicity. These include a correction based on an ancestry informative markers (AIMs) panel designed to capture European ancestral variation and corrections utilizing un-thinned genome-wide SNP data; case-control samples were drawn from four geographically distinct North-American sites. The AIMs-only and genome-wide first principal components (PC1) both corresponded to the previously described North or Northwest-Southeast axis of European variation. We found that the genome-wide PCA captured this primary dimension of variation more precisely and identified additional axes of genome-wide variation of relevance to epithelial ovarian cancer. Associations evident between the genome-wide PCs and study site corroborate North American immigration history and suggest that undiscovered dimensions of variation lie within Northern Europe. The structure captured by the genome-wide PCA was also found within control individuals and did not reflect the case-control variation present in the data. The genome-wide PCA highlighted three regions of local LD, corresponding to the lactase (LCT) gene on chromosome 2, the human leukocyte antigen system (HLA) on chromosome 6 and to a common inversion polymorphism on chromosome 8. These features did not compromise the efficacy of PCs from this analysis for ancestry control. This study concludes that although AIMs panels are a cost-effective way of capturing population structure, genome-wide data should preferably be used when available.

Authors
Raska, P; Iversen, E; Chen, A; Chen, Z; Fridley, BL; Permuth-Wey, J; Tsai, Y-Y; Vierkant, RA; Goode, EL; Risch, H; Schildkraut, JM; Sellers, TA; Barnholtz-Sloan, J
MLA Citation
Raska, P, Iversen, E, Chen, A, Chen, Z, Fridley, BL, Permuth-Wey, J, Tsai, Y-Y, Vierkant, RA, Goode, EL, Risch, H, Schildkraut, JM, Sellers, TA, and Barnholtz-Sloan, J. "European American stratification in ovarian cancer case control data: the utility of genome-wide data for inferring ancestry." PLoS One 7.5 (2012): e35235-.
PMID
22590501
Source
pubmed
Published In
PloS one
Volume
7
Issue
5
Publish Date
2012
Start Page
e35235
DOI
10.1371/journal.pone.0035235

Gene set analysis of survival following ovarian cancer implicates macrolide binding and intracellular signaling genes

Background: Genome-wide association studies (GWAS) for epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy, have identified novel susceptibility loci. GWAS for survival after EOC have had more limited success. The association of each single-nucleotide polymorphism (SNP) individually may not be well suited to detect small effects of multiple SNPs, such as those operating within the same biologic pathway. Gene set analysis (GSA) overcomes this limitation by assessing overall evidence for association of a phenotype with all measured variation in a set of genes. Methods: To determine gene sets associated with EOC overall survival, we conducted GSA using data from two large GWAS (N cases = 2,813, N deaths = 1,116), with a novel Principal Component-Gamma GSA method. Analysis was completed for all cases and then separately for high-grade serous histologic subtype. Results: Analysis of the high-grade serous subjects resulted in 43 gene sets with P < 0.005 (1.7%); of these, 21 gene sets had P < 0.10 in both GWAS, including intracellular signaling pathway (P = 7.3 × 10 -5) and macrolide binding (P = 6.2 × 10 -4) gene sets. The top gene sets in analysis of all cases were meiotic mismatch repair (P = 6.3 × 10 -4) and macrolide binding (P = 1.0 × 10 -3). Of 18 gene sets with P < 0.005 (0.7%), eight had P < 0.10 in both GWAS. Conclusion: This research detected novel gene sets associated with EOC survival. Impact: Novel gene sets associated with EOC survival might lead to new insights and avenues for development of novel therapies for EOC and pharmacogenomic studies. ©2012 AACR.

Authors
Fridley, BL; Jenkins, GD; Tsai, Y-Y; Song, H; Bolton, KL; Fenstermacher, D; Tyrer, J; Ramus, SJ; Cunningham, JM; Vierkant, RA; Chen, Z; Chen, YA; Iversen, E; Menon, U; Gentry-Maharaj, A; Schildkraut, J; Sutphen, R; Gayther, SA; Hartmann, LC; Pharoah, PDP; Sellers, TA; Goode, EL
MLA Citation
Fridley, BL, Jenkins, GD, Tsai, Y-Y, Song, H, Bolton, KL, Fenstermacher, D, Tyrer, J, Ramus, SJ, Cunningham, JM, Vierkant, RA, Chen, Z, Chen, YA, Iversen, E, Menon, U, Gentry-Maharaj, A, Schildkraut, J, Sutphen, R, Gayther, SA, Hartmann, LC, Pharoah, PDP, Sellers, TA, and Goode, EL. "Gene set analysis of survival following ovarian cancer implicates macrolide binding and intracellular signaling genes." Cancer Epidemiology Biomarkers and Prevention 21.3 (2012): 529-536.
PMID
22302016
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
21
Issue
3
Publish Date
2012
Start Page
529
End Page
536
DOI
10.1158/1055-9965.EPI-11-0741

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

Germline copy number variation and ovarian cancer survival.

Copy number variants (CNVs) have been implicated in many complex diseases. We examined whether inherited CNVs were associated with overall survival among women with invasive epithelial ovarian cancer. Germline DNA from 1,056 cases (494 deceased, average of 3.7 years follow-up) was interrogated with the Illumina 610 quad genome-wide array containing, after quality control exclusions, 581,903 single nucleotide polymorphisms (SNPs) and 17,917 CNV probes. Comprehensive analysis capitalized upon the strengths of three complementary approaches to CNV classification. First, to identify small CNVs, single markers were evaluated and, where associated with survival, consecutive markers were combined. Two chromosomal regions were associated with survival using this approach (14q31.3 rs2274736 p = 1.59 × 10(-6), p = 0.001; 22q13.31 rs2285164 p = 4.01 × 10(-5), p = 0.009), but were not significant after multiple testing correction. Second, to identify large CNVs, genome-wide segmentation was conducted to characterize chromosomal gains and losses, and association with survival was evaluated by segment. Four regions were associated with survival (1q21.3 loss p = 0.005, 5p14.1 loss p = 0.004, 9p23 loss p = 0.002, and 15q22.31 gain p = 0.002); however, again, after correcting for multiple testing, no regions were statistically significant, and none were in common with the single marker approach. Finally, to evaluate associations with general amounts of copy number changes across the genome, we estimated CNV burden based on genome-wide numbers of gains and losses; no associations with survival were observed (p > 0.40). Although CNVs that were not well-covered by the Illumina 610 quad array merit investigation, these data suggest no association between inherited CNVs and survival after ovarian cancer.

Authors
Fridley, BL; Chalise, P; Tsai, Y-Y; Sun, Z; Vierkant, RA; Larson, MC; Cunningham, JM; Iversen, ES; Fenstermacher, D; Barnholtz-Sloan, J; Asmann, Y; Risch, HA; Schildkraut, JM; Phelan, CM; Sutphen, R; Sellers, TA; Goode, EL
MLA Citation
Fridley, BL, Chalise, P, Tsai, Y-Y, Sun, Z, Vierkant, RA, Larson, MC, Cunningham, JM, Iversen, ES, Fenstermacher, D, Barnholtz-Sloan, J, Asmann, Y, Risch, HA, Schildkraut, JM, Phelan, CM, Sutphen, R, Sellers, TA, and Goode, EL. "Germline copy number variation and ovarian cancer survival. (Published online)" Front Genet 3 (2012): 142-.
PMID
22891074
Source
pubmed
Published In
Frontiers in Genetics
Volume
3
Publish Date
2012
Start Page
142
DOI
10.3389/fgene.2012.00142

Effect of hysterectomy with ovarian preservation on ovarian function.

OBJECTIVE: To prospectively estimate the risk for earlier ovarian failure among women undergoing hysterectomy with ovarian preservation, as compared with women of similar age without hysterectomy. METHODS: A prospective cohort study was conducted among women aged 30 to 47 years undergoing hysterectomy without bilateral oophorectomy (n=406) and women with intact uteri (n=465). Blood samples and questionnaire data were obtained at baseline and annually for up to 5 years. Hazard ratios (HR) for ovarian failure, defined as follicle-stimulating hormone levels 40 international units/L or higher, were calculated using Cox proportional hazards models. RESULTS: Ovarian failure occurred among 60 of the women with hysterectomy and 46 of the women in the control group. Women undergoing hysterectomy were at nearly a twofold increased risk for ovarian failure as compared with women with intact uteri (HR 1.92, 95% confidence interval [CI] 1.29-2.86). The proportional hazards model further estimated that 14.8% of women with hysterectomies experienced ovarian failure after 4 years of follow-up compared with 8.0% of the women in the control group. Risk for ovarian failure was greater for women who had a unilateral oophorectomy along with their hysterectomy (HR 2.93, 95% CI 1.57-5.49), but also it was significantly increased for women who retained both ovaries (HR 1.74, 95% CI 1.14-2.65). CONCLUSION: Increased risk of earlier ovarian failure is a possible consequence of premenopausal hysterectomy. Although it is unresolved whether it is the surgery itself or the underlying condition leading to hysterectomy that is the cause of earlier ovarian failure, physicians and patients should take into account this possible sequela when considering options for treatment of benign conditions of the uterus. LEVEL OF EVIDENCE: II.

Authors
Moorman, PG; Myers, ER; Schildkraut, JM; Iversen, ES; Wang, F; Warren, N
MLA Citation
Moorman, PG, Myers, ER, Schildkraut, JM, Iversen, ES, Wang, F, and Warren, N. "Effect of hysterectomy with ovarian preservation on ovarian function." Obstet Gynecol 118.6 (December 2011): 1271-1279.
PMID
22067716
Source
pubmed
Published In
Obstetrics and Gynecology
Volume
118
Issue
6
Publish Date
2011
Start Page
1271
End Page
1279
DOI
10.1097/AOG.0b013e318236fd12

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

Methylation variation at IGF2 differentially methylated regions and maternal folic acid use before and during pregnancy.

Folic acid (FA) supplementation before and during pregnancy has been associated with decreased risk of neural tube defects although recent reports suggest it may also increase the risk of other chronic diseases. We evaluated exposure to maternal FA supplementation before and during pregnancy in relation to aberrant DNA methylation at two differentially methylated regions (DMRs) regulating Insulin-like Growth Factor 2 (IGF2) expression in infants. Aberrant methylation at these regions has been associated with IGF2 deregulation and increased susceptibility to several chronic diseases. Using a self-administered questionnaire, we assessed FA intake before and during pregnancy in 438 pregnant women. Pyrosequencing was used to measure methylation at two IGF2 DMRs in umbilical cord blood leukocytes. Mixed models were used to determine relationships between maternal FA supplementation before or during pregnancy and DNA methylation levels at birth. Average methylation at the H19 DMR was 61.2%. Compared to infants born to women reporting no FA intake before or during pregnancy, methylation levels at the H19 DMR decreased with increasing FA intake (2.8%, p=0.03, and 4.9%, p=0.04, for intake before and during pregnancy, respectively). This methylation decrease was most pronounced in male infants (p=0.01). Methylation alterations at the H19 DMR are likely an important mechanism by which FA risks and/or benefits are conferred in utero. Because stable methylation marks at DMRs regulating imprinted genes are acquired before gastrulation, they may serve as archives of early exposures with the potential to improve our understanding of developmental origins of adult disease.

Authors
Hoyo, C; Murtha, AP; Schildkraut, JM; Jirtle, RL; Demark-Wahnefried, W; Forman, MR; Iversen, ES; Kurtzberg, J; Overcash, F; Huang, Z; Murphy, SK
MLA Citation
Hoyo, C, Murtha, AP, Schildkraut, JM, Jirtle, RL, Demark-Wahnefried, W, Forman, MR, Iversen, ES, Kurtzberg, J, Overcash, F, Huang, Z, and Murphy, SK. "Methylation variation at IGF2 differentially methylated regions and maternal folic acid use before and during pregnancy." Epigenetics 6.7 (July 2011): 928-936.
PMID
21636975
Source
pubmed
Published In
Epigenetics : official journal of the DNA Methylation Society
Volume
6
Issue
7
Publish Date
2011
Start Page
928
End Page
936

LIN28B polymorphisms influence susceptibility to epithelial ovarian cancer.

Defective microRNA (miRNA) biogenesis contributes to the development and progression of epithelial ovarian cancer (EOC). In this study, we examined the hypothesis that single nucleotide polymorphisms (SNP) in miRNA biogenesis genes may influence EOC risk. In an initial investigation, 318 SNPs in 18 genes were evaluated among 1,815 EOC cases and 1,900 controls, followed up by a replicative joint meta-analysis of data from an additional 2,172 cases and 3,052 controls. Of 23 SNPs from 9 genes associated with risk (empirical P < 0.05) in the initial investigation, the meta-analysis replicated 6 SNPs from the DROSHA, FMR1, LIN28, and LIN28B genes, including rs12194974 (G>A), an SNP in a putative transcription factor binding site in the LIN28B promoter region (summary OR = 0.90, 95% CI: 0.82-0.98; P = 0.015) which has been recently implicated in age of menarche and other phenotypes. Consistent with reports that LIN28B overexpression in EOC contributes to tumorigenesis by repressing tumor suppressor let-7 expression, we provide data from luciferase reporter assays and quantitative RT-PCR to suggest that the inverse association among rs12194974 A allele carriers may be because of reduced LIN28B expression. Our findings suggest that variants in LIN28B and possibly other miRNA biogenesis genes may influence EOC susceptibility.

Authors
Permuth-Wey, J; Kim, D; Tsai, Y-Y; Lin, H-Y; Chen, YA; Barnholtz-Sloan, J; Birrer, MJ; Bloom, G; Chanock, SJ; Chen, Z; Cramer, DW; Cunningham, JM; Dagne, G; Ebbert-Syfrett, J; Fenstermacher, D; Fridley, BL; Garcia-Closas, M; Gayther, SA; Ge, W; Gentry-Maharaj, A; Gonzalez-Bosquet, J; Goode, EL; Iversen, E; Jim, H; Kong, W; McLaughlin, J; Menon, U; Monteiro, ANA; Narod, SA; Pharoah, PDP; Phelan, CM; Qu, X; Ramus, SJ; Risch, H; Schildkraut, JM; Song, H; Stockwell, H; Sutphen, R; Terry, KL et al.
MLA Citation
Permuth-Wey, J, Kim, D, Tsai, Y-Y, Lin, H-Y, Chen, YA, Barnholtz-Sloan, J, Birrer, MJ, Bloom, G, Chanock, SJ, Chen, Z, Cramer, DW, Cunningham, JM, Dagne, G, Ebbert-Syfrett, J, Fenstermacher, D, Fridley, BL, Garcia-Closas, M, Gayther, SA, Ge, W, Gentry-Maharaj, A, Gonzalez-Bosquet, J, Goode, EL, Iversen, E, Jim, H, Kong, W, McLaughlin, J, Menon, U, Monteiro, ANA, Narod, SA, Pharoah, PDP, Phelan, CM, Qu, X, Ramus, SJ, Risch, H, Schildkraut, JM, Song, H, Stockwell, H, Sutphen, R, and Terry, KL et al. "LIN28B polymorphisms influence susceptibility to epithelial ovarian cancer." Cancer Res 71.11 (June 1, 2011): 3896-3903.
PMID
21482675
Source
pubmed
Published In
Cancer Research
Volume
71
Issue
11
Publish Date
2011
Start Page
3896
End Page
3903
DOI
10.1158/0008-5472.CAN-10-4167

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

Inherited variants in mitochondrial biogenesis genes may influence epithelial ovarian cancer risk.

BACKGROUND: Mitochondria contribute to oxidative stress, a phenomenon implicated in ovarian carcinogenesis. We hypothesized that inherited variants in mitochondrial-related genes influence epithelial ovarian cancer (EOC) susceptibility. METHODS: Through a multicenter study of 1,815 Caucasian EOC cases and 1,900 controls, we investigated associations between EOC risk and 128 single nucleotide polymorphisms (SNPs) from 22 genes/regions within the mitochondrial genome (mtDNA) and 2,839 nuclear-encoded SNPs localized to 138 genes involved in mitochondrial biogenesis (BIO, n = 35), steroid hormone metabolism (HOR, n = 13), and oxidative phosphorylation (OXP, n = 90) pathways. Unconditional logistic regression was used to estimate OR and 95% CI between genotype and case status. Overall significance of each gene and pathway was evaluated by using Fisher's method to combine SNP-level evidence. At the SNP level, we investigated whether lifetime ovulation, hormone replacement therapy (HRT), and cigarette smoking were confounders or modifiers of associations. RESULTS: Interindividual variation involving BIO was most strongly associated with EOC risk (empirical P = 0.050), especially for NRF1, MTERF, PPARGC1A, ESRRA, and CAMK2D. Several SNP-level associations strengthened after adjustment for nongenetic factors, particularly for MTERF. Statistical interactions with cigarette smoking and HRT use were observed with MTERF and CAMK2D SNPs, respectively. Overall variation within mtDNA, HOR, and OXP was not statistically significant (empirical P > 0.10). CONCLUSION: We provide novel evidence to suggest that variants in mitochondrial biogenesis genes may influence EOC susceptibility. IMPACT: A deeper understanding of the complex mechanisms implicated in mitochondrial biogenesis and oxidative stress may aid in developing strategies to reduce morbidity and mortality from EOC.

Authors
Permuth-Wey, J; Chen, YA; Tsai, Y-Y; Chen, Z; Qu, X; Lancaster, JM; Stockwell, H; Dagne, G; Iversen, E; Risch, H; Barnholtz-Sloan, J; Cunningham, JM; Vierkant, RA; Fridley, BL; Sutphen, R; McLaughlin, J; Narod, SA; Goode, EL; Schildkraut, JM; Fenstermacher, D; Phelan, CM; Sellers, TA
MLA Citation
Permuth-Wey, J, Chen, YA, Tsai, Y-Y, Chen, Z, Qu, X, Lancaster, JM, Stockwell, H, Dagne, G, Iversen, E, Risch, H, Barnholtz-Sloan, J, Cunningham, JM, Vierkant, RA, Fridley, BL, Sutphen, R, McLaughlin, J, Narod, SA, Goode, EL, Schildkraut, JM, Fenstermacher, D, Phelan, CM, and Sellers, TA. "Inherited variants in mitochondrial biogenesis genes may influence epithelial ovarian cancer risk." Cancer Epidemiol Biomarkers Prev 20.6 (June 2011): 1131-1145.
PMID
21447778
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
6
Publish Date
2011
Start Page
1131
End Page
1145
DOI
10.1158/1055-9965.EPI-10-1224

A computational method to classify variants of uncertain significance using functional assay data with application to BRCA1.

BACKGROUND: Besides revealing cancer predisposition variants or the absence of any changes, genetic testing for cancer predisposition genes can also identify variants of uncertain clinical significance (VUS). Classifying VUSs is a pressing problem, as ever more patients seek genetic testing for disease syndromes and receive noninformative results from those tests. In cases such as the breast and ovarian cancer syndrome in which prophylactic options can be severe and life changing, having information on the disease relevance of the VUS that a patient harbors can be critical. METHODS: We describe a computational approach for inferring the disease relevance of VUSs in disease genes from data derived from an in vitro functional assay. It is based on a Bayesian hierarchical model that accounts for sources of experimental heterogeneity. RESULTS: The functional data correlate well with the pathogenicity of BRCA1 BRCT VUSs, thus providing evidence regarding pathogenicity when family and genetic data are absent or uninformative. CONCLUSIONS: We show the utility of the model by using it to classify 76 VUSs located in the BRCT region of BRCA1. The approach is both sensitive and specific when evaluated on variants previously classified using independent sources of data. Although the functional data are very informative, they will need to be combined with other forms of data to meet the more stringent requirements of clinical application. IMPACT: Our work will lead to improved classification of VUSs and will aid in the clinical decision making of their carriers.

Authors
Iversen, ES; Couch, FJ; Goldgar, DE; Tavtigian, SV; Monteiro, ANA
MLA Citation
Iversen, ES, Couch, FJ, Goldgar, DE, Tavtigian, SV, and Monteiro, ANA. "A computational method to classify variants of uncertain significance using functional assay data with application to BRCA1." Cancer Epidemiol Biomarkers Prev 20.6 (June 2011): 1078-1088.
PMID
21447777
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
6
Publish Date
2011
Start Page
1078
End Page
1088
DOI
10.1158/1055-9965.EPI-10-1214

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

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

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

A latent model for prioritization of SNPs for functional studies

One difficult question facing researchers is how to prioritize SNPs detected from genetic association studies for functional studies. Often a list of the top M SNPs is determined based on solely the p-value from an association analysis, where M is determined by financial/time constraints. For many studies of complex diseases, multiple analyses have been completed and integrating these multiple sets of results may be difficult. One may also wish to incorporate biological knowledge, such as whether the SNP is in the exon of a gene or a regulatory region, into the selection of markers to follow-up. In this manuscript, we propose a Bayesian latent variable model (BLVM) for incorporating "features" about a SNP to estimate a latent "quality score", with SNPs prioritized based on the posterior probability distribution of the rankings of these quality scores. We illustrate the method using data from an ovarian cancer genome-wide association study (GWAS). In addition to the application of the BLVM to the ovarian GWAS, we applied the BLVM to simulated data which mimics the setting involving the prioritization of markers across multiple GWAS for related diseases/traits. The top ranked SNP by BLVM for the ovarian GWAS, ranked 2nd and 7th based on p-values from analyses of all invasive and invasive serous cases. The top SNP based on serous case analysis p-value (which ranked 197th for invasive case analysis), was ranked 8th based on the posterior probability of being in the top 5 markers (0.13). In summary, the application of the BLVM allows for the systematic integration of multiple SNP "features" for the prioritization of loci for fine-mapping or functional studies, taking into account the uncertainty in ranking. © 2011 Fridley et al.

Authors
Fridley, BL; Iversen, E; Tsai, Y-Y; Jenkins, GD; Goode, EL; Sellers, TA
MLA Citation
Fridley, BL, Iversen, E, Tsai, Y-Y, Jenkins, GD, Goode, EL, and Sellers, TA. "A latent model for prioritization of SNPs for functional studies." PLoS ONE 6.6 (2011).
PMID
21687685
Source
scival
Published In
PloS one
Volume
6
Issue
6
Publish Date
2011
DOI
10.1371/journal.pone.0020764

Evaluation of established breast cancer risk factors as modifiers of BRCA1 or BRCA2: a multi-center case-only analysis.

The incomplete penetrance of mutations in BRCA1 and BRCA2 suggests that some combination of environmental and genetic factors modifies the risk of breast cancer in mutation carriers. This study sought to identify possible interactions between established breast cancer risk factors and BRCA1 or BRCA2 mutations using a case-only study design. Breast cancer cases that had been tested for BRCA1 and BRCA2 mutations were identified from 11 collaborating centers. Comparisons of reproductive and lifestyle risk factors were made between women with breast cancer who were positive for BRCA1 mutations (n = 283), BRCA2 mutations (n = 204), or negative for both BRCA1 and BRCA2 mutations (n = 894). Interaction risk ratios (IRRs) were calculated using multinominal logistic regression models. Compared with non-carriers, statistically significant IRRs were observed for later age at menarche among BRCA2 mutation carriers, for a greater number of pregnancies among both BRCA1 and BRCA2 mutation carriers, and for alcohol use among BRCA1 mutation carriers. Our data suggest that the risk for breast cancer among BRCA1 or BRCA2 carriers may be modified by reproductive characteristics and alcohol use. However, our results should be interpreted cautiously given the overall inconsistency in the epidemiologic literature on modifiers of BRCA1 and BRCA2.

Authors
Moorman, PG; Iversen, ES; Marcom, PK; Marks, JR; Wang, F; Kathleen Cuningham Consortium for Research into Familial Breast Cancer, ; Lee, E; Ursin, G; Rebbeck, TR; Domchek, SM; Arun, B; Susswein, L; Isaacs, C; Garber, JE; Visvanathan, K; Griffin, CA; Sutphen, R; Brzosowicz, J; Gruber, S; Finkelstein, DM; Schildkraut, JM
MLA Citation
Moorman, PG, Iversen, ES, Marcom, PK, Marks, JR, Wang, F, Kathleen Cuningham Consortium for Research into Familial Breast Cancer, , Lee, E, Ursin, G, Rebbeck, TR, Domchek, SM, Arun, B, Susswein, L, Isaacs, C, Garber, JE, Visvanathan, K, Griffin, CA, Sutphen, R, Brzosowicz, J, Gruber, S, Finkelstein, DM, and Schildkraut, JM. "Evaluation of established breast cancer risk factors as modifiers of BRCA1 or BRCA2: a multi-center case-only analysis." Breast Cancer Res Treat 124.2 (November 2010): 441-451.
PMID
20309627
Source
pubmed
Published In
Breast Cancer Research and Treatment
Volume
124
Issue
2
Publish Date
2010
Start Page
441
End Page
451
DOI
10.1007/s10549-010-0842-y

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

Bayesian model search and multilevel inference for SNP association studies

Authors
Wilson, MA; Iversen, ES; Clyde, MA; Schmidler, SC; Schildkraut, JM
MLA Citation
Wilson, MA, Iversen, ES, Clyde, MA, Schmidler, SC, and Schildkraut, JM. "Bayesian model search and multilevel inference for SNP association studies." The Annals of Applied Statistics 4.3 (September 2010): 1342-1364.
Website
http://hdl.handle.net/10161/8405
PMID
21179394
Source
crossref
Published In
The annals of applied statistics
Volume
4
Issue
3
Publish Date
2010
Start Page
1342
End Page
1364
DOI
10.1214/09-AOAS322

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

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

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

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

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

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

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

A prospective study of weight gain after premenopausal hysterectomy.

PURPOSE: Many women who have had hysterectomies have the perception that they gained weight after surgery that cannot be attributed to changes in diet or physical activity. The purpose of this analysis was to assess weight gain in premenopausal women in the first year after hysterectomy compared with a control group of women with intact uteri and ovaries. METHODS: As part of a prospective cohort study designed to assess the risk for ovarian failure after premenopausal hysterectomy, weight was measured at baseline and 1-year follow-up in 236 women undergoing hysterectomy and 392 control women. Changes in measured weight and reported weight were assessed. Unconditional logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for weight gains of >10 pounds. RESULTS: Women with hysterectomies weighed more and had a higher mean body mass index (BMI) than control women at baseline. Mean weight gain was 1.36 kg ( approximately 3 pounds) for women with hysterectomies vs. 0.61 kg ( approximately 1.3 pounds) for control women (p = 0.07). Weight gain of >10 pounds occurred in 23% of women with hysterectomies compared with 15% of control women (multivariable OR = 1.61, 95% CI 1.04 = 2.48). CONCLUSIONS: Women undergoing hysterectomies appear to be at higher risk for weight gain in the first year after surgery. Heavier women and women who have had weight fluctuations throughout adulthood may be at greater risk for postsurgical weight gain, suggesting that lifestyle interventions to maintain or lose weight may be particularly helpful for these women in the months following hysterectomy.

Authors
Moorman, PG; Schildkraut, JM; Iversen, ES; Myers, ER; Gradison, M; Warren-White, N; Wang, F
MLA Citation
Moorman, PG, Schildkraut, JM, Iversen, ES, Myers, ER, Gradison, M, Warren-White, N, and Wang, F. "A prospective study of weight gain after premenopausal hysterectomy." J Womens Health (Larchmt) 18.5 (May 2009): 699-708.
PMID
19445617
Source
pubmed
Published In
Journal of Women's Health
Volume
18
Issue
5
Publish Date
2009
Start Page
699
End Page
708
DOI
10.1089/jwh.2008.1019

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

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 tps3 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 SMPs 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 (r2 = 0.62) SMPs: rs2287498 (median per allele OB, 1.30; 95% PI, 1.07-1.57) and rsl2951053 (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 TPS3 region. © 2009 American Association for Cancer Research.

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 Berg, DD; Conti, D; Elund, CK; Anderson, R; Goodman, MT; Lurie, G; Carney, ME; Thompson, PJ; Gayther, SA; Ramus, SJ; Jacobs, I; Kjaer, SK; 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 Berg, DD, Conti, D, Elund, CK, Anderson, R, Goodman, MT, Lurie, G, Carney, ME, Thompson, PJ, Gayther, SA, Ramus, SJ, Jacobs, I, Kjaer, SK, 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 Research 69.6 (March 15, 2009): 2349-2357.
PMID
19276375
Source
scopus
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

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

A branching process model for flow cytometry and budding index measurements in cell synchrony experiments.

We present a flexible branching process model for cell population dynamics in synchrony/time-series experiments used to study important cellular processes. Its formulation is constructive, based on an accounting of the unique cohorts in the population as they arise and evolve over time, allowing it to be written in closed form. The model can attribute effects to subsets of the population, providing flexibility not available using the models historically applied to these populations. It provides a tool for in silico synchronization of the population and can be used to deconvolve population-level experimental measurements, such as temporal expression profiles. It also allows for the direct comparison of assay measurements made from multiple experiments. The model can be fit either to budding index or DNA content measurements, or both, and is easily adaptable to new forms of data. The ability to use DNA content data makes the model applicable to almost any organism. We describe the model and illustrate its utility and flexibility in a study of cell cycle progression in the yeast Saccharomyces cerevisiae.

Authors
Orlando, DA; Iversen, ES; Hartemink, AJ; Haase, SB
MLA Citation
Orlando, DA, Iversen, ES, Hartemink, AJ, and Haase, SB. "A branching process model for flow cytometry and budding index measurements in cell synchrony experiments." Ann Appl Stat 3.4 (2009): 1521-1541.
Website
http://hdl.handle.net/10161/13267
PMID
21853014
Source
pubmed
Published In
The annals of applied statistics
Volume
3
Issue
4
Publish Date
2009
Start Page
1521
End Page
1541
DOI
10.1214/09-AOAS264

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

Global control of cell-cycle transcription by coupled CDK and network oscillators.

A significant fraction of the Saccharomyces cerevisiae genome is transcribed periodically during the cell division cycle, indicating that properly timed gene expression is important for regulating cell-cycle events. Genomic analyses of the localization and expression dynamics of transcription factors suggest that a network of sequentially expressed transcription factors could control the temporal programme of transcription during the cell cycle. However, directed studies interrogating small numbers of genes indicate that their periodic transcription is governed by the activity of cyclin-dependent kinases (CDKs). To determine the extent to which the global cell-cycle transcription programme is controlled by cyclin-CDK complexes, we examined genome-wide transcription dynamics in budding yeast mutant cells that do not express S-phase and mitotic cyclins. Here we show that a significant fraction of periodic genes are aberrantly expressed in the cyclin mutant. Although cells lacking cyclins are blocked at the G1/S border, nearly 70% of periodic genes continued to be expressed periodically and on schedule. Our findings reveal that although CDKs have a function in the regulation of cell-cycle transcription, they are not solely responsible for establishing the global periodic transcription programme. We propose that periodic transcription is an emergent property of a transcription factor network that can function as a cell-cycle oscillator independently of, and in tandem with, the CDK oscillator.

Authors
Orlando, DA; Lin, CY; Bernard, A; Wang, JY; Socolar, JES; Iversen, ES; Hartemink, AJ; Haase, SB
MLA Citation
Orlando, DA, Lin, CY, Bernard, A, Wang, JY, Socolar, JES, Iversen, ES, Hartemink, AJ, and Haase, SB. "Global control of cell-cycle transcription by coupled CDK and network oscillators." Nature 453.7197 (June 12, 2008): 944-947.
PMID
18463633
Source
pubmed
Published In
Nature
Volume
453
Issue
7197
Publish Date
2008
Start Page
944
End Page
947
DOI
10.1038/nature06955

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

Association of single nucleotide polymorphisms in glycosylation genes with risk of epithelial ovarian cancer.

Studies suggest that underglycosylation of the cell membrane mucin MUC1 may be associated with epithelial ovarian cancer. We identified 26 genes involved in glycosylation and examined 93 single nucleotide polymorphisms (SNP) with a minor allele frequency of > or =0.05 in relation to incident ovarian cancer. Cases were ascertained at the Mayo Clinic, Rochester, MN (n = 396) or a 48-county region in North Carolina (Duke University; n = 534). Ovarian cancer-free controls (n = 1,037) were frequency matched to the cases on age, race, and residence. Subjects were interviewed to obtain data on risk factors and a sample of blood for DNA and genotyped using the Illumina GoldenGate assay. We excluded subjects and individual SNPs with genotype call rates of <90%. Data were analyzed using logistic regression, with adjustment for age and residence. We fitted dominant, log additive, and recessive genetic models. Among Caucasians, nine SNPs in eight genes were associated with risk at P < 0.05 under at least one genetic model before adjusting for multiple testing. A SNP in GALNT1 (rs17647532) was the only one that remained statistically significant after Bonferroni adjustment for multiple testing but was not statistically significant in Hardy-Weinberg equilibrium among controls. Haplotype analyses revealed a global association of GALNT1 with risk (P = 0.038, under a recessive genetic model), which largely reflected a decreased risk of one haplotype (0.10 frequency; odds ratio, 0.07; P = 0.01) compared with the most common haplotype (0.39 frequency). These results suggest that genetic polymorphisms in the glycoslyation process may be novel risk factors for ovarian cancer.

Authors
Sellers, TA; Huang, Y; Cunningham, J; Goode, EL; Sutphen, R; Vierkant, RA; Kelemen, LE; Fredericksen, ZS; Liebow, M; Pankratz, VS; Hartmann, LC; Myer, J; Iversen, ES; Schildkraut, JM; Phelan, C
MLA Citation
Sellers, TA, Huang, Y, Cunningham, J, Goode, EL, Sutphen, R, Vierkant, RA, Kelemen, LE, Fredericksen, ZS, Liebow, M, Pankratz, VS, Hartmann, LC, Myer, J, Iversen, ES, Schildkraut, JM, and Phelan, C. "Association of single nucleotide polymorphisms in glycosylation genes with risk of epithelial ovarian cancer." Cancer Epidemiol Biomarkers Prev 17.2 (February 2008): 397-404.
PMID
18268124
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
2
Publish Date
2008
Start Page
397
End Page
404
DOI
10.1158/1055-9965.EPI-07-0565

Multiple model evaluation absent the gold standard through model combination

We describe a method for evaluating an ensemble of predictive models given a sample of observations comprising the model predictions and the outcome event measured with error. Our formulation allows us to simultaneously estimate measurement error parameters, true outcome - the "gold standard" - and a relative weighting of the predictive scores. We describe conditions necessary to estimate the gold standard and to calibrate these estimates and detail how our approach is related to, but distinct from, standard model combination techniques. We apply our approach to data from a study to evaluate a collection of BRCA1/BRCA2 gene mutation prediction scores. In this example, genotype is measured with error by one or more genetic assays. We estimate true genotype for each individual in the data set, operating characteristics of the commonly used genotyping procedures, and a relative weighting of the scores. Finally, we compare the scores against the gold standard genotype and find that Mendelian scores are, on average, the more refined and better calibrated of those considered and that the comparison is sensitive to measurement error in the gold standard. © 2008 American Statistical Association.

Authors
Jr, ESI; Parmigiani, G; Chen, S
MLA Citation
Jr, ESI, Parmigiani, G, and Chen, S. "Multiple model evaluation absent the gold standard through model combination." Journal of the American Statistical Association 103.483 (2008): 897-909.
Source
scival
Published In
Journal of the American Statistical Association
Volume
103
Issue
483
Publish Date
2008
Start Page
897
End Page
909
DOI
10.1198/016214507000001012

Genetic evidence and integration of various data sources for classifying uncertain variants into a single model

Genetic testing often results in the finding of a variant whose clinical significance is unknown. A number of different approaches have been employed in the attempt to classify such variants. For some variants, case-control, segregation, family history, or other statistical studies can provide strong evidence of direct association with cancer risk. For most variants, other evidence is available that relates to properties of the protein or gene sequence. In this work we propose a Bayesian method for assessing the likelihood that a variant is pathogenic. We discuss the assessment of prior probability, and how to combine the various sources of data into a statistically valid integrated assessment with a posterior probability of pathogenicity. In particular, we propose the use of a two-component mixture model to integrate these various sources of data and to estimate the parameters related to sensitivity and specificity of specific kinds of evidence. Further, we discuss some of the issues involved in this process and the assumptions that underpin many of the methods used in the evaluation process. © 2008 Wiley-Liss, Inc.

Authors
Goldgar, DE; Easton, DF; Byrnes, GB; Spurdle, AB; Iversen, ES; Greenblatt, MS
MLA Citation
Goldgar, DE, Easton, DF, Byrnes, GB, Spurdle, AB, Iversen, ES, and Greenblatt, MS. "Genetic evidence and integration of various data sources for classifying uncertain variants into a single model." Human Mutation 29.11 (2008): 1265-1272.
PMID
18951437
Source
scival
Published In
Human Mutation
Volume
29
Issue
11
Publish Date
2008
Start Page
1265
End Page
1272
DOI
10.1002/humu.20897

Limited family structure and breast cancer risk [7]

Authors
Iversen, ES; Katki, HA; Chen, S; Berry, DA; Parmigiani, G
MLA Citation
Iversen, ES, Katki, HA, Chen, S, Berry, DA, and Parmigiani, G. "Limited family structure and breast cancer risk [7]." Journal of the American Medical Association 298.17 (November 7, 2007): 2007-. (Letter)
Source
scopus
Published In
JAMA : the journal of the American Medical Association
Volume
298
Issue
17
Publish Date
2007
Start Page
2007

Validity of models for predicting BRCA1 and BRCA2 mutations.

BACKGROUND: Deleterious mutations of the BRCA1 and BRCA2 genes confer susceptibility to breast and ovarian cancer. At least 7 models for estimating the probabilities of having a mutation are used widely in clinical and scientific activities; however, the merits and limitations of these models are not fully understood. OBJECTIVE: To systematically quantify the accuracy of the following publicly available models to predict mutation carrier status: BRCAPRO, family history assessment tool, Finnish, Myriad, National Cancer Institute, University of Pennsylvania, and Yale University. DESIGN: Cross-sectional validation study, using model predictions and BRCA1 or BRCA2 mutation status of patients different from those used to develop the models. SETTING: Multicenter study across Cancer Genetics Network participating centers. PATIENTS: 3 population-based samples of participants in research studies and 8 samples from genetic counseling clinics. MEASUREMENTS: Discrimination between individuals testing positive for a mutation in BRCA1 or BRCA2 from those testing negative, as measured by the c-statistic, and sensitivity and specificity of model predictions. RESULTS: The 7 models differ in their predictions. The better-performing models have a c-statistic around 80%. BRCAPRO has the largest c-statistic overall and in all but 2 patient subgroups, although the margin over other models is narrow in many strata. Outside of high-risk populations, all models have high false-negative and false-positive rates across a range of probability thresholds used to refer for mutation testing. LIMITATION: Three recently published models were not included. CONCLUSIONS: All models identify women who probably carry a deleterious mutation of BRCA1 or BRCA2 with adequate discrimination to support individualized genetic counseling, although discrimination varies across models and populations.

Authors
Parmigiani, G; Chen, S; Iversen, ES; Friebel, TM; Finkelstein, DM; Anton-Culver, H; Ziogas, A; Weber, BL; Eisen, A; Malone, KE; Daling, JR; Hsu, L; Ostrander, EA; Peterson, LE; Schildkraut, JM; Isaacs, C; Corio, C; Leondaridis, L; Tomlinson, G; Amos, CI; Strong, LC; Berry, DA; Weitzel, JN; Sand, S; Dutson, D; Kerber, R; Peshkin, BN; Euhus, DM
MLA Citation
Parmigiani, G, Chen, S, Iversen, ES, Friebel, TM, Finkelstein, DM, Anton-Culver, H, Ziogas, A, Weber, BL, Eisen, A, Malone, KE, Daling, JR, Hsu, L, Ostrander, EA, Peterson, LE, Schildkraut, JM, Isaacs, C, Corio, C, Leondaridis, L, Tomlinson, G, Amos, CI, Strong, LC, Berry, DA, Weitzel, JN, Sand, S, Dutson, D, Kerber, R, Peshkin, BN, and Euhus, DM. "Validity of models for predicting BRCA1 and BRCA2 mutations." Ann Intern Med 147.7 (October 2, 2007): 441-450.
PMID
17909205
Source
pubmed
Published In
Annals of internal medicine
Volume
147
Issue
7
Publish Date
2007
Start Page
441
End Page
450

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

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

A probabilistic model for cell cycle distributions in synchrony experiments.

Synchronized populations of cells are often used to study dynamic processes during the cell division cycle. However, the analysis of time series measurements made on synchronized populations is confounded by the fact that populations lose synchrony over time. Time series measurements are thus averages over a population distribution that is broadening over time. Moreover, direct comparison of measurements taken from multiple synchrony experiments is difficult, as the kinetics of progression during the time series are rarely comparable. Here, we present a flexible mathematical model that describes the dynamics of population distributions resulting from synchrony loss over time. The model was developed using S. cerevisiae, but we show that it can be easily adapted to predict distributions in other organisms. We demonstrate that the model reliably fits data collected from populations synchronized by multiple techniques, and can accurately predict cell cycle distributions as measured by other experimental assays. To indicate its broad applicability, we show that the model can be used to compare global periodic transcription data sets from different organisms: S. cerevisiae and S. pombe.

Authors
Orlando, DA; Lin, CY; Bernard, A; Iversen, ES; Hartemink, AJ; Haase, SB
MLA Citation
Orlando, DA, Lin, CY, Bernard, A, Iversen, ES, Hartemink, AJ, and Haase, SB. "A probabilistic model for cell cycle distributions in synchrony experiments." Cell Cycle 6.4 (February 15, 2007): 478-488.
PMID
17329975
Source
pubmed
Published In
Cell Cycle
Volume
6
Issue
4
Publish Date
2007
Start Page
478
End Page
488
DOI
10.4161/cc.6.4.3859

A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes

Mutation screening of the breast and ovarian cancer-predisposition genes BRCA1 and BRCA2 is becoming an increasingly important part of clinical practice. Classification of rare nontruncating sequence variants in these genes is problematic, because it is not known whether these subtle changes alter function sufficiently to predispose cells to cancer development. Using data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests, we assessed the clinical significance of 1,433 sequence variants of unknown significance (VUSs) in the BRCA genes. Three independent measures were employed in the assessment: co-occurrence in trans of a VUS with known deleterious mutations; detailed analysis, by logistic regression, of personal and family history of cancer in VUS-carrying probands; and, in a subset of probands, an analysis of cosegregation with disease in pedigrees. For each of these factors, a likelihood ratio was computed under the hypothesis that the VUSs were equivalent to an "average" deleterious mutation, compared with neutral, with respect to risk. The likelihood ratios derived from each component were combined to provide an overall assessment for each VUS. A total of 133 VUSs had odds of at least 100:1 in favor of neutrality with respect to risk, whereas 43 had odds of at least 20:1 in favor of being deleterious. VUSs with evidence in favor of causality were those that were predicted to affect splicing, fell at positions that are highly conserved among BRCA orthologs, and were more likely to be located in specific domains of the proteins. In addition to their utility for improved genetics counseling of patients and their families, the global assessment reported here will be invaluable for validation of functional assays, structural models, and in silico analyses. © 2007 by The American Society of Human Genetics. All rights reserved.

Authors
Easton, DF; Deffenbaugh, AM; Pruss, D; Frye, C; Wenstrup, RJ; Allen-Brady, K; Tavtigian, SV; Monteiro, ANA; Iversen, ES; Couch, FJ; Goldgar, DE
MLA Citation
Easton, DF, Deffenbaugh, AM, Pruss, D, Frye, C, Wenstrup, RJ, Allen-Brady, K, Tavtigian, SV, Monteiro, ANA, Iversen, ES, Couch, FJ, and Goldgar, DE. "A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes." American Journal of Human Genetics 81.5 (2007): 873-883.
PMID
17924331
Source
scival
Published In
The American Journal of Human Genetics
Volume
81
Issue
5
Publish Date
2007
Start Page
873
End Page
883
DOI
10.1086/521032

Validity of models for prediction of BRCA1 and BRCA2 mutations

Authors
Parmigiani, G; Chen, S; Iversen Jr, ES; Friebel, T; Finkelstein, D; Anton Culver, H; Ziogas, A; Weber, BL; Eisen, A; Malone, K; Daling, JR; Hsu, L; Ostrander, EA; Peterson, LE; Schildkraut, JM; Isaacs, C; Corio, C; Leondaridis, L; Tomlinson, G; Amos, CI; Strong, LC; Berry, DA; Weitzel, J; Sand, S; Dutson, D; Kerber, R; Peshkin, BN; Euhus, DM
MLA Citation
Parmigiani, G, Chen, S, Iversen Jr, ES, Friebel, T, Finkelstein, D, Anton Culver, H, Ziogas, A, Weber, BL, Eisen, A, Malone, K, Daling, JR, Hsu, L, Ostrander, EA, Peterson, LE, Schildkraut, JM, Isaacs, C, Corio, C, Leondaridis, L, Tomlinson, G, Amos, CI, Strong, LC, Berry, DA, Weitzel, J, Sand, S, Dutson, D, Kerber, R, Peshkin, BN, and Euhus, DM. "Validity of models for prediction of BRCA1 and BRCA2 mutations." Annals of Internal Medicine 147.5 (2007): 441-450. (Academic Article)
Source
manual
Published In
Annals of Internal Medicine
Volume
147
Issue
5
Publish Date
2007
Start Page
441
End Page
450

Limited family structure and breast cancer risk [7]

Authors
Jr, ESI; Katki, HA; Chen, S; Berry, DA; Parmigiani, G
MLA Citation
Jr, ESI, Katki, HA, Chen, S, Berry, DA, and Parmigiani, G. "Limited family structure and breast cancer risk [7]." Journal of the American Medical Association 298.17 (2007): 2007--.
PMID
17986693
Source
scival
Published In
JAMA : the journal of the American Medical Association
Volume
298
Issue
17
Publish Date
2007
Start Page
2007-

Characterization of BRCA1 and BRCA2 mutations in a large United States sample.

PURPOSE: An accurate evaluation of the penetrance of BRCA1 and BRCA2 mutations is essential to the identification and clinical management of families at high risk of breast and ovarian cancer. Existing studies have focused on Ashkenazi Jews (AJ) or on families from outside the United States. In this article, we consider the US population using the largest US-based cohort to date of both AJ and non-AJ families. METHODS: We collected 676 AJ families and 1,272 families of other ethnicities through the Cancer Genetics Network. Two hundred eighty-two AJ families were population based, whereas the remainder was collected through counseling clinics. We used a retrospective likelihood approach to correct for bias induced by oversampling of participants with a positive family history. Our approach takes full advantage of detailed family history information and the Mendelian transmission of mutated alleles in the family. RESULTS: In the US population, the estimated cumulative breast cancer risk at age 70 years was 0.46 (95% CI, 0.39 to 0.54) in BRCA1 carriers and 0.43 (95% CI, 0.36 to 0.51) in BRCA2 carriers, whereas ovarian cancer risk was 0.39 (95% CI, 0.30 to 0.50) in BRCA1 carriers and 0.22 (95% CI, 0.14 to 0.32) in BRCA2 carriers. We also reported the prospective risks of developing cancer for cancer-free carriers in 10-year age intervals. We noted a rapid decrease in the relative risk of breast cancer with age and derived its implication for genetic counseling. CONCLUSION: The penetrance of BRCA mutations in the United States is largely consistent with previous studies on Western populations given the large CIs on existing estimates. However, the absolute cumulative risks are on the lower end of the spectrum.

Authors
Chen, S; Iversen, ES; Friebel, T; Finkelstein, D; Weber, BL; Eisen, A; Peterson, LE; Schildkraut, JM; Isaacs, C; Peshkin, BN; Corio, C; Leondaridis, L; Tomlinson, G; Dutson, D; Kerber, R; Amos, CI; Strong, LC; Berry, DA; Euhus, DM; Parmigiani, G
MLA Citation
Chen, S, Iversen, ES, Friebel, T, Finkelstein, D, Weber, BL, Eisen, A, Peterson, LE, Schildkraut, JM, Isaacs, C, Peshkin, BN, Corio, C, Leondaridis, L, Tomlinson, G, Dutson, D, Kerber, R, Amos, CI, Strong, LC, Berry, DA, Euhus, DM, and Parmigiani, G. "Characterization of BRCA1 and BRCA2 mutations in a large United States sample." J Clin Oncol 24.6 (February 20, 2006): 863-871.
PMID
16484695
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
6
Publish Date
2006
Start Page
863
End Page
871
DOI
10.1200/JCO.2005.03.6772

In reply [8]

Authors
Chen, S; Jr, ESI; Parmigiani, G
MLA Citation
Chen, S, Jr, ESI, and Parmigiani, G. "In reply [8]." Journal of Clinical Oncology 24.20 (2006): 3313-3314.
Source
scival
Published In
Journal of Clinical Oncology
Volume
24
Issue
20
Publish Date
2006
Start Page
3313
End Page
3314
DOI
10.1200/JCO.2006.06.8148

Gene expression profiling and genetic markers in glioblastoma survival.

Despite the strikingly grave prognosis for older patients with glioblastomas, significant variability in patient outcome is experienced. To explore the potential for developing improved prognostic capabilities based on the elucidation of potential biological relationships, we did analyses of genes commonly mutated, amplified, or deleted in glioblastomas and DNA microarray gene expression data from tumors of glioblastoma patients of age >50 for whom survival is known. No prognostic significance was associated with genetic changes in epidermal growth factor receptor (amplified in 17 of 41 patients), TP53 (mutated in 11 of 41 patients), p16INK4A (deleted in 15 of 33 patients), or phosphatase and tensin homologue (mutated in 15 of 41 patients). Statistical analysis of the gene expression data in connection with survival involved exploration of regression models on small subsets of genes, based on computational search over multiple regression models with cross-validation to assess predictive validity. The analysis generated a set of regression models that, when weighted and combined according to posterior probabilities implied by the statistical analysis, identify patterns in expression of a small subset of genes that are associated with survival and have value in assessing survival risks. The dominant genes across such multiple regression models involve three key genes-SPARC (Osteonectin), Doublecortex, and Semaphorin3B-which play key roles in cellular migration processes. Additional analysis, based on statistical graphical association models constructed using similar computational analysis methods, reveals other genes which support the view that multiple mediators of tumor invasion may be important prognostic factor in glioblastomas in older patients.

Authors
Rich, JN; Hans, C; Jones, B; Iversen, ES; McLendon, RE; Rasheed, BKA; Dobra, A; Dressman, HK; Bigner, DD; Nevins, JR; West, M
MLA Citation
Rich, JN, Hans, C, Jones, B, Iversen, ES, McLendon, RE, Rasheed, BKA, Dobra, A, Dressman, HK, Bigner, DD, Nevins, JR, and West, M. "Gene expression profiling and genetic markers in glioblastoma survival." Cancer Res 65.10 (May 15, 2005): 4051-4058.
PMID
15899794
Source
pubmed
Published In
Cancer Research
Volume
65
Issue
10
Publish Date
2005
Start Page
4051
End Page
4058
DOI
10.1158/0008-5472.CAN-04-3936

Patterns of gene expression that characterize long-term survival in advanced stage serous ovarian cancers.

PURPOSE: A better understanding of the underlying biology of invasive serous ovarian cancer is critical for the development of early detection strategies and new therapeutics. The objective of this study was to define gene expression patterns associated with favorable survival. EXPERIMENTAL DESIGN: RNA from 65 serous ovarian cancers was analyzed using Affymetrix U133A microarrays. This included 54 stage III/IV cases (30 short-term survivors who lived <3 years and 24 long-term survivors who lived >7 years) and 11 stage I/II cases. Genes were screened on the basis of their level of and variability in expression, leaving 7,821 for use in developing a predictive model for survival. A composite predictive model was developed that combines Bayesian classification tree and multivariate discriminant models. Leave-one-out cross-validation was used to select and evaluate models. RESULTS: Patterns of genes were identified that distinguish short-term and long-term ovarian cancer survivors. The expression model developed for advanced stage disease classified all 11 early-stage ovarian cancers as long-term survivors. The MAL gene, which has been shown to confer resistance to cancer therapy, was most highly overexpressed in short-term survivors (3-fold compared with long-term survivors, and 29-fold compared with early-stage cases). These results suggest that gene expression patterns underlie differences in outcome, and an examination of the genes that provide this discrimination reveals that many are implicated in processes that define the malignant phenotype. CONCLUSIONS: Differences in survival of advanced ovarian cancers are reflected by distinct patterns of gene expression. This biological distinction is further emphasized by the finding that early-stage cancers share expression patterns with the advanced stage long-term survivors, suggesting a shared favorable biology.

Authors
Berchuck, A; Iversen, ES; Lancaster, JM; Pittman, J; Luo, J; Lee, P; Murphy, S; Dressman, HK; Febbo, PG; West, M; Nevins, JR; Marks, JR
MLA Citation
Berchuck, A, Iversen, ES, Lancaster, JM, Pittman, J, Luo, J, Lee, P, Murphy, S, Dressman, HK, Febbo, PG, West, M, Nevins, JR, and Marks, JR. "Patterns of gene expression that characterize long-term survival in advanced stage serous ovarian cancers." Clin Cancer Res 11.10 (May 15, 2005): 3686-3696.
PMID
15897565
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
10
Publish Date
2005
Start Page
3686
End Page
3696
DOI
10.1158/1078-0432.CCR-04-2398

Population-Calibrated Gene Characterization: Estimating distirubions of age at Onset Associated wtih Breat Cancer Susceptibility Genes

Authors
Iversen Jr, ES; Chen, S
MLA Citation
Iversen Jr, ES, and Chen, S. "Population-Calibrated Gene Characterization: Estimating distirubions of age at Onset Associated wtih Breat Cancer Susceptibility Genes." Journal of the American Statistical Association 100 (2005): 399-409. (Academic Article)
Source
manual
Published In
Journal of the American Statistical Association
Issue
100
Publish Date
2005
Start Page
399
End Page
409

Classification of Missense Mutations of Disease Genes.

Clinical management of individuals found to harbor a mutation at a known disease-susceptibility gene depends on accurate assessment of mutation-specific disease risk. For missense mutations (MMs)-mutations that lead to a single amino acid change in the protein coded by the gene-this poses a particularly challenging problem. Because it is not possible to predict the structural and functional changes to the protein product for a given amino acid substitution, and because functional assays are often not available, disease association must be inferred from data on individuals with the mutation. Inference is complicated by small sample sizes and by sampling mechanisms that bias toward individuals at high familial risk of disease. We propose a Bayesian hierarchical model to classify the disease association of MMs given pedigree data collected in the high-risk setting. The model's structure allows simultaneous characterization of multiple MMs. It uses a group of pedigrees identified through probands tested positive for known disease associated mutations and a group of test-negative pedigrees, both obtained from the same clinic, to calibrate classification and control for potential ascertainment bias. We apply this model to study MMs of breast-ovarian susceptibility genes BRCA1 and BRCA2, using data collected at the Duke University Medical Center in Durham, North Carolina.

Authors
Zhou, X; Iversen, ES; Parmigiani, G
MLA Citation
Zhou, X, Iversen, ES, and Parmigiani, G. "Classification of Missense Mutations of Disease Genes." J Am Stat Assoc 100 (2005): 51-60.
PMID
18418466
Source
pubmed
Published In
Journal of the American Statistical Association
Volume
100
Publish Date
2005
Start Page
51
End Page
60
DOI
10.1198/016214504000001817

Population-Calibrated Gene Characterization: Estimating Age at Onset Distributions Associated With Cancer Genes.

Phenotypic characterization of rare disease genes poses a significant statistical challenge, but the need to do so is clear. Clinical management of patients carrying a disease gene depends crucially on an accurate characterization of the genetically predisposed disease, including its likelihood of occurrence among mutation carriers, natural history, and response to treatment. We propose a formal yet practical method for controlling for bias due to ignoring ascertainment, defined as the sampling mechanism, when quantifying the association between genotype and disease using data on high-risk families. The approach is more statistically efficient than conditioning on the variables used in sampling. In it, the likelihood is adjusted by a factor that is a function of sampling weights in strata defined by those variables. It requires that these variables and the sampling probabilities in the strata they define either are known or can be estimated. The latter requires a second, population-based dataset. As an example, we derive ascertainment-corrected estimates of penetrance for the breast cancer susceptibility genes BRCA1 and BRCA2. The Bayesian analysis that we use incorporates a modified segregation model and prior data on penetrance derived from the literature. Markov chain Monte Carlo methods are used for inference.

Authors
Iversen, ES; Chen, S
MLA Citation
Iversen, ES, and Chen, S. "Population-Calibrated Gene Characterization: Estimating Age at Onset Distributions Associated With Cancer Genes." J Am Stat Assoc 100 (2005): 399-409.
PMID
18418465
Source
pubmed
Published In
Journal of the American Statistical Association
Volume
100
Publish Date
2005
Start Page
399
End Page
409
DOI
10.1198/016214505000000196

Gene expression phenotypes of atherosclerosis.

OBJECTIVE: Fulfilling the promise of personalized medicine by developing individualized diagnostic and therapeutic strategies for atherosclerosis will depend on a detailed understanding of the genes and gene variants that contribute to disease susceptibility and progression. To that end, our group has developed a nonbiased approach congruent with the multigenic concept of complex diseases by identifying gene expression patterns highly associated with disease states in human target tissues. METHODS AND RESULTS: We have analyzed a collection of human aorta samples with varying degrees of atherosclerosis to identify gene expression patterns that predict a disease state or potential susceptibility. We find gene expression signatures that relate to each of these disease measures and are reliable and robust in predicting the classification for new samples with >93% in each analysis. The genes that provide the predictive power include many previously suspected to play a role in atherosclerosis and additional genes without prior association with atherosclerosis. CONCLUSIONS: Hence, we are reporting a novel method for generating a molecular phenotype of disease and then identifying genes whose discriminatory capability strongly implicates their potential roles in human atherosclerosis.

Authors
Seo, D; Wang, T; Dressman, H; Herderick, EE; Iversen, ES; Dong, C; Vata, K; Milano, CA; Rigat, F; Pittman, J; Nevins, JR; West, M; Goldschmidt-Clermont, PJ
MLA Citation
Seo, D, Wang, T, Dressman, H, Herderick, EE, Iversen, ES, Dong, C, Vata, K, Milano, CA, Rigat, F, Pittman, J, Nevins, JR, West, M, and Goldschmidt-Clermont, PJ. "Gene expression phenotypes of atherosclerosis." Arterioscler Thromb Vasc Biol 24.10 (October 2004): 1922-1927.
PMID
15297278
Source
pubmed
Published In
Arteriosclerosis, Thrombosis, and Vascular Biology
Volume
24
Issue
10
Publish Date
2004
Start Page
1922
End Page
1927
DOI
10.1161/01.ATV.0000141358.65242.1f

Integrated modeling of clinical and gene expression information for personalized prediction of disease outcomes.

We describe a comprehensive modeling approach to combining genomic and clinical data for personalized prediction in disease outcome studies. This integrated clinicogenomic modeling framework is based on statistical classification tree models that evaluate the contributions of multiple forms of data, both clinical and genomic, to define interactions of multiple risk factors that associate with the clinical outcome and derive predictions customized to the individual patient level. Gene expression data from DNA microarrays is represented by multiple, summary measures that we term metagenes; each metagene characterizes the dominant common expression pattern within a cluster of genes. A case study of primary breast cancer recurrence demonstrates that models using multiple metagenes combined with traditional clinical risk factors improve prediction accuracy at the individual patient level, delivering predictions more accurate than those made by using a single genomic predictor or clinical data alone. The analysis also highlights issues of communicating uncertainty in prediction and identifies combinations of clinical and genomic risk factors playing predictive roles. Implicated metagenes identify gene subsets with the potential to aid biological interpretation. This framework will extend to incorporate any form of data, including emerging forms of genomic data, and provides a platform for development of models for personalized prognosis.

Authors
Pittman, J; Huang, E; Dressman, H; Horng, C-F; Cheng, SH; Tsou, M-H; Chen, C-M; Bild, A; Iversen, ES; Huang, AT; Nevins, JR; West, M
MLA Citation
Pittman, J, Huang, E, Dressman, H, Horng, C-F, Cheng, SH, Tsou, M-H, Chen, C-M, Bild, A, Iversen, ES, Huang, AT, Nevins, JR, and West, M. "Integrated modeling of clinical and gene expression information for personalized prediction of disease outcomes." Proc Natl Acad Sci U S A 101.22 (June 1, 2004): 8431-8436.
PMID
15152076
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
101
Issue
22
Publish Date
2004
Start Page
8431
End Page
8436
DOI
10.1073/pnas.0401736101

Prediction of optimal versus suboptimal cytoreduction of advanced-stage serous ovarian cancer with the use of microarrays.

OBJECTIVE: The purpose of this study was to define gene expression patterns that are associated with the optimal versus suboptimal debulking of advanced-stage serous ovarian cancers. STUDY DESIGN: RNA from 44 advanced serous ovarian cancers (19 optimal, 25 suboptimal) was evaluated with microarrays that contain >22,000 genes. Genes were screened on the basis of their association with debulking status to obtain the top 120 differentially expressed genes. These genes were then used to develop a predictive model for debulking status, which was subjected to out-of-sample cross validation. RESULTS: We found that patterns of expression of 32 genes can distinguish between optimal and suboptimal debulking with 72.7% predictive accuracy. An analysis of the data that were based on clusters of co-ordinately expressed genes resulted in only a marginal improvement in predictive accuracy (75%). CONCLUSION: These data support the hypothesis that favorable survival that is associated with optimal debulking of advanced ovarian cancers is due to, at least in part, the underlying biologic characteristics of these cancers.

Authors
Berchuck, A; Iversen, ES; Lancaster, JM; Dressman, HK; West, M; Nevins, JR; Marks, JR
MLA Citation
Berchuck, A, Iversen, ES, Lancaster, JM, Dressman, HK, West, M, Nevins, JR, and Marks, JR. "Prediction of optimal versus suboptimal cytoreduction of advanced-stage serous ovarian cancer with the use of microarrays." Am J Obstet Gynecol 190.4 (April 2004): 910-925.
PMID
15118612
Source
pubmed
Published In
American Journal of Obstetrics & Gynecology
Volume
190
Issue
4
Publish Date
2004
Start Page
910
End Page
925
DOI
10.1016/j.ajog.2004.02.005

Prediction of optimal versus suboptimal cytoreduction of advanced-stage serious ovarian cancer with the use of microarrays

Authors
Andrew, B; Iversen, ES; Lancaster, JM; Dressman, HK; West, M; Nevins, JR; Marks, JR; Miller, BE
MLA Citation
Andrew, B, Iversen, ES, Lancaster, JM, Dressman, HK, West, M, Nevins, JR, Marks, JR, and Miller, BE. "Prediction of optimal versus suboptimal cytoreduction of advanced-stage serious ovarian cancer with the use of microarrays." Women's Oncology Review 4.3 (2004): 203-204.
Source
scival
Published In
Women's Oncology Review
Volume
4
Issue
3
Publish Date
2004
Start Page
203
End Page
204
DOI
10.1080/14733400412331312585

Gene expression predictors of breast cancer outcomes.

BACKGROUND: Correlation of risk factors with genomic data promises to provide specific treatment for individual patients, and needs interpretation of complex, multivariate patterns in gene expression data, as well as assessment of their ability to improve clinical predictions. We aimed to predict nodal metastatic states and relapse for breast cancer patients. METHODS: We analysed DNA microarray data from samples of primary breast tumours, using non-linear statistical analyses to assess multiple patterns of interactions of groups of genes that have predictive value for the individual patient, with respect to lymph node metastasis and cancer recurrence. FINDINGS: We identified aggregate patterns of gene expression (metagenes) that associate with lymph node status and recurrence, and that are capable of predicting outcomes in individual patients with about 90% accuracy. The metagenes defined distinct groups of genes, suggesting different biological processes underlying these two characteristics of breast cancer. Initial external validation came from similarly accurate predictions of nodal status of a small sample in a distinct population. INTERPRETATION: Multiple aggregate measures of profiles of gene expression define valuable predictive associations with lymph node metastasis and disease recurrence for individual patients. Gene expression data have the potential to aid accurate, individualised, prognosis. Importantly, these data are assessed in terms of precise numerical predictions, with ranges of probabilities of outcome. Precise and statistically valid assessments of risks specific for patients, will ultimately be of most value to clinicians faced with treatment decisions.

Authors
Huang, E; Cheng, SH; Dressman, H; Pittman, J; Tsou, MH; Horng, CF; Bild, A; Iversen, ES; Liao, M; Chen, CM; West, M; Nevins, JR; Huang, AT
MLA Citation
Huang, E, Cheng, SH, Dressman, H, Pittman, J, Tsou, MH, Horng, CF, Bild, A, Iversen, ES, Liao, M, Chen, CM, West, M, Nevins, JR, and Huang, AT. "Gene expression predictors of breast cancer outcomes." Lancet 361.9369 (May 10, 2003): 1590-1596.
PMID
12747878
Source
pubmed
Published In
The Lancet
Volume
361
Issue
9369
Publish Date
2003
Start Page
1590
End Page
1596
DOI
10.1016/S0140-6736(03)13308-9

Gene expression predictors of breast cancer outcomes (with commentary).

Authors
Huang, ; E, ; Cheng, ; H, S; Dressman, ; H, ; Pittman, ; J, ; Tsou, ; H, M; Horng, ; F, C; Bild, ; Al, ; Iversen, ; Jr, ; S, E; Liao, ; M, ; Chen, ; M, C; West, ; M, ; Nevins, ; R, J; Juang, ; T, A
MLA Citation
Huang, , E, , Cheng, , H, S, Dressman, , H, , Pittman, , J, , Tsou, , H, M, Horng, , F, C, Bild, , Al, , Iversen, , Jr, , S, E, Liao, , M, , Chen, , M, C, West, , M, , Nevins, , R, J, Juang, , and T, A. "Gene expression predictors of breast cancer outcomes (with commentary)." The Lancet 361 (2003): 1590-1596. (Academic Article)
Source
manual
Published In
The Lancet
Issue
361
Publish Date
2003
Start Page
1590
End Page
1596

BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes

Purpose: To compare genetic test results for deleterious mutations of BRCA1 and BRCA2 with estimated probabilities of carrying such mutations; to assess sensitivity of genetic testing; and to assess the relevance of other susceptibility genes in familial breast and ovarian cancer. Patients and Methods: Data analyzed were from six high-risk genetic counseling clinics and concern individuals from families for which at least one member was tested for mutations at BRCA1 and BRCA2. Predictions of genetic predisposition to breast and ovarian cancer for 301 individuals were made using BRCAPRO, a statistical model and software using Mendelian genetics and Bayesian updating. Model predictions were compared with the results of genetic testing. Results: Among the test individuals, 126 were Ashkenazi Jewish, three were male subjects, 243 had breast cancer, 49 had ovarian cancer, 34 were unaffected, and 139 tested positive for BRCA1 mutations and 29 for BRCA2 mutations. BRCAPRO performed well: for the 150 probands with the smallest BRCAPRO carrier probabilities (average, 29.0%), the proportion testing positive was 32.7%; for the 151 probands with the largest carrier probabilities (average, 95.2%), 78.8% tested positive. Genetic testing sensitivity was estimated to be at least 85%, with false-negatives including mutations of susceptibility genes heretofore unknown. Conclusion: BRCAPRO is an accurate counseling tool for determining the probability of carrying mutations of BRCA1 and BRCA2. Genetic testing for BRCA1 and BRCA2 is highly sensitive, missing an estimated 15% of mutations. In the populations studied, breast cancer susceptibility genes other than BRCA1 and BRCA2 either do not exist, are rare, or are associated with low disease penetrance. © 2002 by American Society of Clinical Oncology.

Authors
Berry, DA; Jr, ESI; Gudbjartsson, DF; Hiller, EH; Garber, JE; Peshkin, BN; Lerman, C; Watson, P; Lynch, HT; Hilsenbeck, SG; Rubinstein, WS; Hughes, KS; Parmigiani, G
MLA Citation
Berry, DA, Jr, ESI, Gudbjartsson, DF, Hiller, EH, Garber, JE, Peshkin, BN, Lerman, C, Watson, P, Lynch, HT, Hilsenbeck, SG, Rubinstein, WS, Hughes, KS, and Parmigiani, G. "BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes." Journal of Clinical Oncology 20.11 (2002): 2701-2712.
PMID
12039933
Source
scival
Published In
Journal of Clinical Oncology
Volume
20
Issue
11
Publish Date
2002
Start Page
2701
End Page
2712
DOI
10.1200/JCO.2002.05.121

Spatially disaggregated real estate indices

A spatial-temporal Markov random-field model is used to produce indices for residential real estate from repeat home sale data. A set of regions is represented by a graph in which neighboring regions are linked. This graph, repeated consecutively a number of times, with each region linked to the same region at adjacent times, defines a spatial-temporal graph that connects regions over space and time in which each node represents a region at a particular time. An index is defined at each node to be the rate of appreciation of log sale price in a region during the preceding time interval. The indices are estimated from data consisting of repeat home sales. The Markov random-field model specifies spatial and temporal correlations between neighboring indices and relations between indices and individual repeat sales. A method is proposed for estimating various parameters in the model and for obtaining real-estate indices. Following this prescription, indices are calculated for the Dade County, Florida, residential real-estate market. Results are compared to those obtained using competing space-only models.

Authors
Jr, ESI
MLA Citation
Jr, ESI. "Spatially disaggregated real estate indices." Journal of Business and Economic Statistics 19.3 (2001): 341-357.
Source
scival
Published In
Journal of Business and Economic Statistics
Volume
19
Issue
3
Publish Date
2001
Start Page
341
End Page
357
DOI
10.1198/073500101681019990

Genetic Susceptibility and Survival: Application to Breast Cancer

Inherited mutations of the BRCA1 and BRCA2 genes are known to confer an elevated risk of both breast and ovarian cancers. The effect of carrying such a mutation on survival after developing breast or ovarian cancer is less well understood. We investigate the relationship between BRCA1 and BRCA2 carrier status and survival after breast cancer. We obtained data from the Cancer and Steroid Hormone Study, a large population-based study including more than 4,000 breast cancer cases. Patient data include extensive information about breast and ovarian cancer in relatives. We obtained follow-up information about patients via record linkage with the Surveillance, Epidemiology, and End Results registry, with maximum follow-up of 15 years. In the absence of genetic testing for each individual, presence or absence of mutation at a breast cancer susceptibility gene is captured by a pair of binary latent variables whose marginal probability depends on the patient's family history of breast and ovarian cancer. We estimate the effect of genotype on survival using a Cox proportional hazards model, treating genetic status as a latent variable and controlling for stage at diagnosis, histology, whether radiation treatment was administered, the individual's smoking history, body mass, race, and age at diagnosis. Inference is accomplished using a Markov chain Monte Carlo algorithm to draw a sample from the posterior distribution of model parameters accounting for sampling error, uncertainty in the genotype of study participants, and uncertainty in estimates of genetic parameters. An analysis that does not discriminate between BRCA1 and BRCA2 estimates the genetic effect on survival after breast cancer for women carrying a mutation at either site. We find evidence that survival of nonirradiated mutation carriers is better than that of noncarriers; we estimate the probability of improved survival to be .990. As a byproduct of this analysis, we estimate that a study based on 901 women with known mutation status would yield estimates of genetic effect on survival with comparable uncertainty to that obtained in the combined-gene analysis. An analysis assessing the separate effects of the two genes indicates that carriers of either mutation may have an improved prognosis. We estimate the probability of improved survival among nonirradiated BRCA1 carriers to be .844, and that among nonirradiated BRCA2 carriers to be .924. However, substantial uncertainty remains about the magnitude of the BRCA2 effect.

Authors
Jr, ESI; Parmigiani, G; Berry, DA; Schildkraut, JM
MLA Citation
Jr, ESI, Parmigiani, G, Berry, DA, and Schildkraut, JM. "Genetic Susceptibility and Survival: Application to Breast Cancer." Journal of the American Statistical Association 95.449 (2000): 28-42.
Source
scival
Published In
Journal of the American Statistical Association
Volume
95
Issue
449
Publish Date
2000
Start Page
28
End Page
42

Effect of BRCA1 and BRCA2 on the association between breast cancer risk and family history.

BACKGROUND: The discovery of BRCA1 and BRCA2 has led to a reassessment of the association between family history of breast/ovarian cancer and breast cancer risk after controlling for carrier status for mutations in the BRCA1 and BRCA2 genes. We examined whether family history of breast cancer remains a predictive risk factor for this disease after carrier status for BRCA1 and/or BRCA2 mutations is taken into consideration. METHODS: The data are from 4730 case subjects with breast cancer and 4688 control subjects enrolled in the Cancer and Steroid Hormone Study. The probability of being a BRCA1 and/or BRCA2 gene carrier was calculated for each woman. Among predicted noncarriers, logistic regression was used to assess the relationship (odds ratios and 95% confidence intervals [CIs]) between case or control status and family history of breast or ovarian cancer. Estimates of age-specific breast cancer risk are presented by predicted carrier status. RESULTS: Among predicted noncarriers, case subjects were 2.06 times (95% CI = 1.69-2.50) and 1.24 times (95% CI = 1.17-1.32) more likely to report a first-degree or second-degree family history of breast cancer, respectively, than were control subjects. Case subjects were 1.99 times (95% CI = 1.63-2.44), 1.66 times (95% CI = 1.18-2.38), and 2.23 times (95% CI = 0.21-24.65) more likely to report an affected mother, sister, or both, respectively, than were control subjects. A family history of ovarian cancer was not statistically significantly associated with breast cancer risk. Noncarriers were predicted to have a lifetime risk of 9% of developing breast cancer compared with a 63% risk for carriers. CONCLUSIONS: Among women with a moderate family history of breast cancer, i.e., predicted noncarriers of BRCA1 and/or BRCA2 mutations, family history remains a factor in predicting breast cancer risk. In families with breast and ovarian cancers, the aggregation of these two cancers appears to be explained by BRCA1/BRCA2 mutation-carrier probability.

Authors
Claus, EB; Schildkraut, J; Iversen, ES; Berry, D; Parmigiani, G
MLA Citation
Claus, EB, Schildkraut, J, Iversen, ES, Berry, D, and Parmigiani, G. "Effect of BRCA1 and BRCA2 on the association between breast cancer risk and family history." J Natl Cancer Inst 90.23 (December 2, 1998): 1824-1829.
PMID
9839523
Source
pubmed
Published In
Journal of the National Cancer Institute
Volume
90
Issue
23
Publish Date
1998
Start Page
1824
End Page
1829

Prognostic Significance of Estimated BRCA1 and BRCA2 mutation status in women diagnosed with breast cancer

Authors
Schildkraut, J; Iversen Jr, ES; Parmigiani, G; Berry, D
MLA Citation
Schildkraut, J, Iversen Jr, ES, Parmigiani, G, and Berry, D. "Prognostic Significance of Estimated BRCA1 and BRCA2 mutation status in women diagnosed with breast cancer." Genetic Epidemiology 14 (1997): 538-. (Academic Article)
Source
manual
Published In
Genetic Epidemiology
Issue
14
Publish Date
1997
Start Page
538

A statistical technique for validating velocity models

Authors
Iversen Jr, ES; Lees, JM
MLA Citation
Iversen Jr, ES, and Lees, JM. "A statistical technique for validating velocity models." Bulletin of the Seismological Society of America 86.60 (1996): 1853-1862. (Academic Article)
Source
manual
Published In
Bulletin of the Seismological Society of America
Volume
86
Issue
60
Publish Date
1996
Start Page
1853
End Page
1862

A statistical technique for validating velocity models

This study investigates the use of a station influence statistic to identify velocity model shortcomings in the earthquake hypocenter location problem. Two groups of microearthquake events are examined. The first is a group of 81 events from the Mount St. Helens region that occurred between November 1987 and September 1991; the second, 110 well-located events from the 1992 Joshua Tree after-shock sequence. We describe a method for validating a postulated earth model. Let λ denote the hypocenter estimates that Geiger's method obtains. Systematically remove each station observation from the location problem, and recompute the location estimate. Call this estimate λ(i) when the ith station is removed. For a single event, define a station's influence (SI) as a weighted difference between λ and λ(i). Distributional summaries of SI statistics across events are used to identify model shortcomings: Given a specified velocity model, SI distributions that are not homogeneous across stations provide evidence of model inadequacies and/or failures in the weighting scheme. We show that velocity model shortcomings detected using SI statistics for the Mount St. Helens sequence under a one-dimensional model appear to correlate with known physical anomalies; while SI distributions evaluated under a three-dimensional model are more homogeneous and reflect a modest improvement over the one-dimensional model. SI distributions provide evidence of model failure for the Joshua Tree sequence under a one-dimensional model, but no evidence of failure under a three-dimensional model. Finally, the weighting scheme's validity is verified for the Joshua Tree sequence under the three-dimensional model.

Authors
Jr, ESI; Lees, JM
MLA Citation
Jr, ESI, and Lees, JM. "A statistical technique for validating velocity models." Bulletin of the Seismological Society of America 86.6 (1996): 1853-1862.
Source
scival
Published In
Bulletin of the Seismological Society of America
Volume
86
Issue
6
Publish Date
1996
Start Page
1853
End Page
1862

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

Authors
Coetzee, SG; Shen, HC; Hazelett, DJ; Lawrenson, K; Kuchenbaecker, K; Tyrer, J; Rhie, SK; Levanon, K; Karst, A; Drapkin, R; Ramus, SJ; Couch, FJ; Offit, K; Chenevix-Trench, G; Monteiro, ANA; Antoniou, A; Freedman, M; Coetzee, GA; Pharoah, PDP; Noushmehr, H; Gayther, SA
MLA Citation
Coetzee, SG, Shen, HC, Hazelett, DJ, Lawrenson, K, Kuchenbaecker, K, Tyrer, J, Rhie, SK, Levanon, K, Karst, A, Drapkin, R, Ramus, SJ, Couch, FJ, Offit, K, Chenevix-Trench, G, Monteiro, ANA, Antoniou, A, Freedman, M, Coetzee, GA, Pharoah, PDP, Noushmehr, H, and Gayther, SA. "Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci (Published online)." Human Molecular Genetics.
Source
crossref
Published In
Human Molecular Genetics
DOI
10.1093/hmg/ddv101
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