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Walsh, Kyle

Overview:

Dr. Walsh’s research program focuses on genetic and epigenetic factors contributing to cancer predisposition in children and adults, with a special interest in brain tumors. This research is informed by both epidemiology and anthropological genetics, with computational work stressing statistical methodologies for “gene hunting” (e.g. GWAS, fine-mapping, admixture mapping, whole-genome sequencing). The laboratory engages in functional genomics research, investigating the biological impact of genetic variants linked to cancer risk, with a particular focus on regulation of telomere maintenance in pre-malignant cells. 

Positions:

Associate Professor of Neurosurgery

Neurosurgery
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2011

Ph.D. — Yale University School of Medicine

Publications:

Genomic analysis of the origins and evolution of multicentric diffuse lower-grade gliomas

Authors
Hayes, J; Yu, Y; Jalbert, LE; Mazor, T; Jones, LE; Wood, MD; Walsh, KM; Bengtsson, H; Hong, C; Oberndorfer, S; Roetzer, T; Smirnov, IV; Clarke, JL; Aghi, MK; Chang, SM; Nelson, SJ; Woehrer, A; Phillips, JJ; Solomon, DA; Costello, JF
MLA Citation
Hayes, J, Yu, Y, Jalbert, LE, Mazor, T, Jones, LE, Wood, MD, Walsh, KM, Bengtsson, H, Hong, C, Oberndorfer, S, Roetzer, T, Smirnov, IV, Clarke, JL, Aghi, MK, Chang, SM, Nelson, SJ, Woehrer, A, Phillips, JJ, Solomon, DA, and Costello, JF. "Genomic analysis of the origins and evolution of multicentric diffuse lower-grade gliomas." Neuro-Oncology (October 25, 2017).
Source
crossref
Published In
Neuro-Oncology
Publish Date
2017
DOI
10.1093/neuonc/nox205

Buccal mucosa micronuclei counts in relation to exposure to low dose-rate radiation from the Chornobyl nuclear accident and other medical and occupational radiation exposures.

Ionizing radiation is a well-known carcinogen. Chromosome aberrations, and in particular micronuclei represent an early biological predictor of cancer risk. There are well-documented associations of micronuclei with ionizing radiation dose in some radiation-exposed groups, although not all. That associations are not seen in all radiation-exposed groups may be because cells with micronuclei will not generally pass through mitosis, so that radiation-induced micronuclei decay, generally within a few years after exposure.Buccal samples from a group of 111 male workers in Ukraine exposed to ionizing radiation during the cleanup activities at the Chornobyl nuclear power plant were studied. Samples were taken between 12 and 18 years after their last radiation exposure from the Chornobyl cleanup. The frequency of binucleated micronuclei was analyzed in relation to estimated bone marrow dose from the cleanup activities along with a number of environmental/occupational risk factors using Poisson regression adjusted for overdispersion.Among the 105 persons without a previous cancer diagnosis, the mean Chornobyl-related dose was 59.5 mSv (range 0-748.4 mSv). There was a borderline significant increase in micronuclei frequency among those reporting work as an industrial radiographer compared with all others, with a relative risk of 6.19 (95% CI 0.90, 31.08, 2-sided p = 0.0729), although this was based on a single person. There was a borderline significant positive radiation dose response for micronuclei frequency with increase in micronuclei per 1000 scored cells per Gy of 3.03 (95% CI -0.78, 7.65, 2-sided p = 0.1170), and a borderline significant reduction of excess relative MN prevalence with increasing time since last exposure (p = 0.0949). There was a significant (p = 0.0388) reduction in MN prevalence associated with bone X-ray exposure, but no significant trend (p = 0.3845) of MN prevalence with numbers of bone X-ray procedures.There are indications of increasing trends of micronuclei prevalence with Chornobyl-cleanup-associated dose, and indications of reduction in radiation-associated excess prevalence of micronuclei with time after exposure. There are also indications of substantially increased micronuclei associated with work as an industrial radiographer. This analysis adds to the understanding of the long-term effects of low-dose radiation exposures on relevant cellular structures and methods appropriate for long-term radiation biodosimetry.

Authors
Bazyka, D; Finch, SC; Ilienko, IM; Lyaskivska, O; Dyagil, I; Trotsiuk, N; Gudzenko, N; Chumak, VV; Walsh, KM; Wiemels, J; Little, MP; Zablotska, LB
MLA Citation
Bazyka, D, Finch, SC, Ilienko, IM, Lyaskivska, O, Dyagil, I, Trotsiuk, N, Gudzenko, N, Chumak, VV, Walsh, KM, Wiemels, J, Little, MP, and Zablotska, LB. "Buccal mucosa micronuclei counts in relation to exposure to low dose-rate radiation from the Chornobyl nuclear accident and other medical and occupational radiation exposures." Environmental health : a global access science source 16.1 (June 23, 2017): 70-.
PMID
28645274
Source
epmc
Published In
Environmental Health
Volume
16
Issue
1
Publish Date
2017
Start Page
70
DOI
10.1186/s12940-017-0273-x

Perinatal factors associated with clinical presentation of osteosarcoma in children and adolescents.

Osteosarcoma typically develops during puberty with tumors arising at sites of rapid bone growth, suggesting a role for growth-regulating pathways in tumor etiology. Birthweight is one measure of perinatal growth that has been investigated as an osteosarcoma risk factor. Whether birthweight affects clinical features of osteosarcoma remains unexplored.Six hundred seventy patients with osteosarcoma, aged 0-19 years, were identified through the California Cancer Registry. We analyzed birth certificate data from the California Department of Public Health vital statistics unit for these patients and 2,860 controls, matched by sex, birth-year, and race/ethnicity. We examined the impact of birthweight on the risk, timing, and clinical presentation of pediatric osteosarcoma including tumor location, size, extension, differentiation, presence of metastasis, and age at onset. Regression models were adjusted for race, sex, gestational age, socioeconomic status, and tumor site.Higher birthweight was associated with more advanced tumor stage (P = 0.017), a trend toward greater tumor extension into surrounding tissues (P = 0.083), and with occurrence of tumors in sites other than the long bones of the arms/legs (P = 9.7 × 10-3 ). Higher birthweight was also associated with an increased likelihood of metastases present at diagnosis (P = 0.047), with each 200 g increase in birthweight associated with a 1.11-fold increase in the odds of having metastatic disease (95% confidence interval: 1.01-1.22).The association between higher birthweight and more aggressive osteosarcoma, frequently occurring at sites other than the long bones, suggests that growth pathways active during gestation may play an important role in future osteosarcoma progression, especially at anatomic sites with diminished rates of osteoblastic proliferation.

Authors
Endicott, AA; Morimoto, LM; Kline, CN; Wiemels, JL; Metayer, C; Walsh, KM
MLA Citation
Endicott, AA, Morimoto, LM, Kline, CN, Wiemels, JL, Metayer, C, and Walsh, KM. "Perinatal factors associated with clinical presentation of osteosarcoma in children and adolescents." Pediatric blood & cancer 64.6 (June 2017).
PMID
27860191
Source
epmc
Published In
Pediatric Blood & Cancer
Volume
64
Issue
6
Publish Date
2017
DOI
10.1002/pbc.26349

Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT

Authors
Pekmezci, M; Rice, T; Molinaro, AM; Walsh, KM; Decker, PA; Hansen, H; Sicotte, H; Kollmeyer, TM; McCoy, LS; Sarkar, G; Perry, A; Giannini, C; Tihan, T; Berger, MS; Wiemels, JL; Bracci, PM; Eckel-Passow, JE; Lachance, DH; Clarke, J; Taylor, JW; Luks, T; Wiencke, JK; Jenkins, RB; Wrensch, MR
MLA Citation
Pekmezci, M, Rice, T, Molinaro, AM, Walsh, KM, Decker, PA, Hansen, H, Sicotte, H, Kollmeyer, TM, McCoy, LS, Sarkar, G, Perry, A, Giannini, C, Tihan, T, Berger, MS, Wiemels, JL, Bracci, PM, Eckel-Passow, JE, Lachance, DH, Clarke, J, Taylor, JW, Luks, T, Wiencke, JK, Jenkins, RB, and Wrensch, MR. "Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT ." Acta Neuropathologica 133.6 (June 2017): 1001-1016.
Source
crossref
Published In
Acta Neuropathologica
Volume
133
Issue
6
Publish Date
2017
Start Page
1001
End Page
1016
DOI
10.1007/s00401-017-1690-1

Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.

The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.Genomewide association studies (GWAS) published up to January 15, 2015.GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Authors
Telomeres Mendelian Randomization Collaboration, ; Haycock, PC; Burgess, S; Nounu, A; Zheng, J; Okoli, GN; Bowden, J; Wade, KH; Timpson, NJ; Evans, DM; Willeit, P; Aviv, A; Gaunt, TR; Hemani, G; Mangino, M; Ellis, HP; Kurian, KM; Pooley, KA; Eeles, RA; Lee, JE; Fang, S; Chen, WV; Law, MH; Bowdler, LM; Iles, MM; Yang, Q; Worrall, BB; Markus, HS; Hung, RJ; Amos, CI; Spurdle, AB; Thompson, DJ; O'Mara, TA; Wolpin, B; Amundadottir, L; Stolzenberg-Solomon, R; Trichopoulou, A; Onland-Moret, NC et al.
MLA Citation
Telomeres Mendelian Randomization Collaboration, , Haycock, PC, Burgess, S, Nounu, A, Zheng, J, Okoli, GN, Bowden, J, Wade, KH, Timpson, NJ, Evans, DM, Willeit, P, Aviv, A, Gaunt, TR, Hemani, G, Mangino, M, Ellis, HP, Kurian, KM, Pooley, KA, Eeles, RA, Lee, JE, Fang, S, Chen, WV, Law, MH, Bowdler, LM, Iles, MM, Yang, Q, Worrall, BB, Markus, HS, Hung, RJ, Amos, CI, Spurdle, AB, Thompson, DJ, O'Mara, TA, Wolpin, B, Amundadottir, L, Stolzenberg-Solomon, R, Trichopoulou, A, and Onland-Moret, NC et al. "Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study." JAMA oncology 3.5 (May 2017): 636-651.
PMID
28241208
Source
epmc
Published In
JAMA oncology
Volume
3
Issue
5
Publish Date
2017
Start Page
636
End Page
651
DOI
10.1001/jamaoncol.2016.5945

Correlates of Prenatal and Early-Life Tobacco Smoke Exposure and Frequency of Common Gene Deletions in Childhood Acute Lymphoblastic Leukemia.

Tobacco smoke exposure has been associated with risk of childhood acute lymphoblastic leukemia (ALL). Understanding the relationship between tobacco exposures and specific mutations may yield etiologic insights. We carried out a case-only analysis to explore whether prenatal and early-life tobacco smoke exposure influences the formation of leukemogenic genomic deletions. Somatic copy number of 8 genes frequently deleted in ALL (CDKN2A, ETV6, IKZF1, PAX5, RB1, BTG1, PAR1 region, and EBF1) was assessed in 559 pretreatment tumor samples from the California Childhood Leukemia Study. Parent and child's passive tobacco exposure was assessed using interview-assisted questionnaires as well as DNA methylation in aryl-hydrocarbon receptor repressor (AHRR), a sentinel epigenetic biomarker of exposure to maternal smoking during pregnancy. Multivariable Poisson regressions were used to test the association between the smoking exposures and total number of deletions. Deletion burden varied by subtype, with a lower frequency in high-hyperdiploid and higher frequency in ETV6-RUNX1 fusion ALL. The total number of deletions per case was positively associated with tobacco smoke exposure, in particular for maternal ever-smoking (ratio of means, RM, 1.31; 95% CI, 1.08-1.59), maternal smoking during pregnancy (RM, 1.48; 95% CI, 1.12-1.94), and during breastfeeding (RM, 2.11; 95% CI, 1.48-3.02). The magnitude of association with maternal ever-smoking was stronger in male children compared with females (Pinteraction = 0.04). The total number of deletions was also associated with DNA methylation at the AHRR epigenetic biomarker (RM, 1.32; 95% CI, 1.02-1.69). Our results suggest that prenatal and early-life tobacco smoke exposure increase the frequency of somatic deletions in children who develop ALL. Cancer Res; 77(7); 1674-83. ©2017 AACR.

Authors
de Smith, AJ; Kaur, M; Gonseth, S; Endicott, A; Selvin, S; Zhang, L; Roy, R; Shao, X; Hansen, HM; Kang, AY; Walsh, KM; Dahl, GV; McKean-Cowdin, R; Metayer, C; Wiemels, JL
MLA Citation
de Smith, AJ, Kaur, M, Gonseth, S, Endicott, A, Selvin, S, Zhang, L, Roy, R, Shao, X, Hansen, HM, Kang, AY, Walsh, KM, Dahl, GV, McKean-Cowdin, R, Metayer, C, and Wiemels, JL. "Correlates of Prenatal and Early-Life Tobacco Smoke Exposure and Frequency of Common Gene Deletions in Childhood Acute Lymphoblastic Leukemia." Cancer research 77.7 (April 2017): 1674-1683.
PMID
28202519
Source
epmc
Published In
Cancer Research
Volume
77
Issue
7
Publish Date
2017
Start Page
1674
End Page
1683
DOI
10.1158/0008-5472.can-16-2571

In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia.

It is widely suspected, yet controversial, that infection plays an etiologic role in the development of acute lymphoblastic leukemia (ALL), the most common childhood cancer and a disease with a confirmed prenatal origin in most cases. We investigated infections at diagnosis and then assessed the timing of infection at birth in children with ALL and age, gender, and ethnicity matched controls to identify potential causal initiating infections. Comprehensive untargeted virome and bacterial analyses of pretreatment bone marrow specimens (n = 127 ALL in comparison with 38 acute myeloid leukemia cases in a comparison group) revealed prevalent cytomegalovirus (CMV) infection at diagnosis in childhood ALL, demonstrating active viral transcription in leukemia blasts as well as intact virions in serum. Screening of newborn blood samples revealed a significantly higher prevalence of in utero CMV infection in ALL cases (n = 268) than healthy controls (n = 270) (odds ratio [OR], 3.71, confidence interval [CI], 1.56-7.92, P = .0016). Risk was more pronounced in Hispanics (OR=5.90, CI=1.89-25.96) than in non-Hispanic whites (OR=2.10 CI= 0.69-7.13). This is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children. Further investigation of CMV as an etiologic agent for ALL is warranted.

Authors
Francis, SS; Wallace, AD; Wendt, GA; Li, L; Liu, F; Riley, LW; Kogan, S; Walsh, KM; de Smith, AJ; Dahl, GV; Ma, X; Delwart, E; Metayer, C; Wiemels, JL
MLA Citation
Francis, SS, Wallace, AD, Wendt, GA, Li, L, Liu, F, Riley, LW, Kogan, S, Walsh, KM, de Smith, AJ, Dahl, GV, Ma, X, Delwart, E, Metayer, C, and Wiemels, JL. "In utero cytomegalovirus infection and development of childhood acute lymphoblastic leukemia." Blood 129.12 (March 2017): 1680-1684.
PMID
27979823
Source
epmc
Published In
Blood
Volume
129
Issue
12
Publish Date
2017
Start Page
1680
End Page
1684
DOI
10.1182/blood-2016-07-723148

Epidemiology of Brain Tumors

Authors
Walsh, KM; Wrensch, MR
MLA Citation
Walsh, KM, and Wrensch, MR. "Epidemiology of Brain Tumors." Youmans and Winn Neurological Surgery. Elsevier, November 30, 2016. (Chapter)
Source
manual
Publish Date
2016

Mutant IDH1 Expression Drives TERT Promoter Reactivation as Part of the Cellular Transformation Process.

Mutations in the isocitrate dehydrogenase gene IDH1 are common in low-grade glioma, where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation, and gliomagenesis. IDH1 mutations also cosegregate with mutations in the ATRX gene and the TERT promoter, suggesting that IDH mutation may drive the creation or selection of telomere-stabilizing events as part of immortalization/transformation process. To determine whether and how this may occur, we investigated the phenotype of pRb-/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H-mutant (IDH1mut) genes as they progressed through their lifespan. IDH1mut expression promoted 2HG production and altered histone methylation within 20 population doublings (PD) but had no effect on telomerase expression or telomere length. Accordingly, cells expressing either IDH1WT or IDH1mut entered a telomere-induced crisis at PD 70. In contrast, only IDH1mut cells emerged from crisis, grew indefinitely in culture, and formed colonies in soft agar and tumors in vivo Clonal populations of postcrisis IDH1mut cells displayed shared genetic alterations, but no mutations in ATRX or the TERT promoter were detected. Instead, these cells reactivated telomerase and stabilized their telomeres in association with increased histone lysine methylation (H3K4me3) and c-Myc/Max binding at the TERT promoter. Overall, these results show that although IDH1mut does not create or select for ATRX or TERT promoter mutations, it can indirectly reactivate TERT, and in doing so contribute to astrocytic immortalization and transformation. Cancer Res; 76(22); 6680-9. ©2016 AACR.

Authors
Ohba, S; Mukherjee, J; Johannessen, T-C; Mancini, A; Chow, TT; Wood, M; Jones, L; Mazor, T; Marshall, RE; Viswanath, P; Walsh, KM; Perry, A; Bell, RJA; Phillips, JJ; Costello, JF; Ronen, SM; Pieper, RO
MLA Citation
Ohba, S, Mukherjee, J, Johannessen, T-C, Mancini, A, Chow, TT, Wood, M, Jones, L, Mazor, T, Marshall, RE, Viswanath, P, Walsh, KM, Perry, A, Bell, RJA, Phillips, JJ, Costello, JF, Ronen, SM, and Pieper, RO. "Mutant IDH1 Expression Drives TERT Promoter Reactivation as Part of the Cellular Transformation Process." Cancer research 76.22 (November 2016): 6680-6689.
PMID
27758882
Source
epmc
Published In
Cancer Research
Volume
76
Issue
22
Publish Date
2016
Start Page
6680
End Page
6689
DOI
10.1158/0008-5472.can-16-0696

Genetic contribution to variation in DNA methylation at maternal smoking-sensitive loci in exposed neonates.

Epigenome-wide DNA methylation association studies have identified highly replicable genomic loci sensitive to maternal smoking during gestation. The role of inter-individual genetic variation in influencing DNA methylation, leading to the possibility of confounding or bias of such associations, has not been assessed. We investigated whether the DNA methylation levels at the top 10 CpG sites previously associated with exposure to maternal smoking during gestation were associated with individual genetic variation at the genome-wide level. Genome-wide association tests between DNA methylation at the top 10 candidate CpG and genome-wide SNPs were performed in 736 case and control participants of the California Childhood Leukemia Study. Three of the strongest maternal-smoking sensitive CpG sites in newborns were significantly associated with SNPs located proximal to each gene: cg18146737 in the GFI1 gene with rs141819830 (P = 8.2×10-44), cg05575921 in the AHRR gene with rs148405299 (P = 5.3×10-10), and cg12803068 in the MYO1G gene with rs61087368 (P = 1.3×10-18). For the GFI1 CpG cg18146737, the underlying genetic variation at rs141819830 confounded the association between maternal smoking and DNA methylation in our data (the regression coefficient changed from -0.02 [P = 0.139] to -0.03 [P = 0.015] after including the genotype). Our results suggest that further studies using DNA methylation at cg18146737, cg05575921, or cg12803068 that aim to assess exposure to maternal smoking during gestation should include genotype at the corresponding SNP. New methods are required for adequate and routine inclusion of genotypic influence on DNA methylation in epigenome-wide association studies to control for potential confounding.

Authors
Gonseth, S; de Smith, AJ; Roy, R; Zhou, M; Lee, S-T; Shao, X; Ohja, J; Wrensch, MR; Walsh, KM; Metayer, C; Wiemels, JL
MLA Citation
Gonseth, S, de Smith, AJ, Roy, R, Zhou, M, Lee, S-T, Shao, X, Ohja, J, Wrensch, MR, Walsh, KM, Metayer, C, and Wiemels, JL. "Genetic contribution to variation in DNA methylation at maternal smoking-sensitive loci in exposed neonates." Epigenetics 11.9 (September 2016): 664-673.
PMID
27403598
Source
epmc
Published In
Epigenetics : official journal of the DNA Methylation Society
Volume
11
Issue
9
Publish Date
2016
Start Page
664
End Page
673
DOI
10.1080/15592294.2016.1209614

Genetic Variation Associated with Longer Telomere Length Increases Risk of Chronic Lymphocytic Leukemia

Authors
Ojha, J; Codd, V; Nelson, CP; Samani, NJ; Smirnov, IV; Madsen, NR; Hansen, HM; de Smith, AJ; Bracci, PM; Wiencke, JK; Wrensch, MR; Wiemels, JL; Walsh, KM
MLA Citation
Ojha, J, Codd, V, Nelson, CP, Samani, NJ, Smirnov, IV, Madsen, NR, Hansen, HM, de Smith, AJ, Bracci, PM, Wiencke, JK, Wrensch, MR, Wiemels, JL, and Walsh, KM. "Genetic Variation Associated with Longer Telomere Length Increases Risk of Chronic Lymphocytic Leukemia." Cancer Epidemiology Biomarkers & Prevention 25.7 (July 1, 2016): 1043-1049.
Source
crossref
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
25
Issue
7
Publish Date
2016
Start Page
1043
End Page
1049
DOI
10.1158/1055-9965.EPI-15-1329

Epidemiology

More than 250 000 new cases of primary malignant brain tumors are diagnosed annually worldwide, 77% of which are gliomas. A small proportion of gliomas are caused by the inheritance of rare high-penetrance genetic variants or high-dose radiation. Since 2009, inherited genetic variants in 10 regions near eight different genes have been consistently associated with glioma risk via genome-wide association studies. Most of these variants increase glioma risk by 20–40%, but two have higher relative risks. One on chromosome 8 increases risk of IDH-mutated gliomas sixfold and another that affects TP53 function confers a 2.5-fold increased risk of glioma. Functions of some of the other risk variants are known or suspected, but future research will determine functions of other risk loci. Recent progress also has been made in defining subgroups of glioma based on acquired alterations within tumors. Allergy history has been consistently associated with reduced glioma risk, though the mechanisms have not yet been clarified. Future studies will need to be large enough so that environmental and constitutive genetic risk factors can be examined within molecularly defined, etiologically homogeneous subgroups.

Authors
Walsh, KM; Ohgaki, H; Wrensch, MR
MLA Citation
Walsh, KM, Ohgaki, H, and Wrensch, MR. "Epidemiology." Gliomas. Ed. MS Berger and M Weller. Elsevier, June 3, 2016. 3-18. (Chapter)
Source
manual
Volume
134
Publish Date
2016
Start Page
3
End Page
18

Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers.

Aberrant telomere lengthening is an important feature of cancer cells in adults and children. In addition to somatic mutations, germline polymorphisms in telomere maintenance genes impact telomere length. Whether these telomere-associated polymorphisms affect risk of childhood malignancies remains largely unexplored. We collected genome-wide data from three groups with pediatric malignancies [neuroblastoma (N = 1516), acute lymphoblastic leukemia (ALL) (N = 958) and osteosarcoma (N = 660)] and three control populations (N = 6892). Using case-control comparisons, we analyzed eight single nucleotide polymorphisms (SNPs) in genes definitively associated with interindividual variation in leukocyte telomere length (LTL) in prior genome-wide association studies: ACYP2, TERC, NAF1, TERT, OBFC1, CTC1, ZNF208 and RTEL1 Six of these SNPs were associated (P < 0.05) with neuroblastoma risk, one with leukemia risk and one with osteosarcoma risk. The allele associated with longer LTL increased cancer risk for all these significantly associated SNPs. Using a weighted linear combination of the eight LTL-associated SNPs, we observed that neuroblastoma patients were predisposed to longer LTL than controls, with each standard deviation increase in genotypically estimated LTL associated with a 1.15-fold increased odds of neuroblastoma (95%CI = 1.09-1.22; P = 7.9×10(-7)). This effect was more pronounced in adolescent-onset neuroblastoma patients (OR = 1.46; 95%CI = 1.03-2.08). A one standard deviation increase in genotypically estimated LTL was more weakly associated with osteosarcoma risk (OR = 1.10; 95%CI = 1.01-1.19; P = 0.017) and leukemia risk (OR = 1.07; 95%CI = 1.00-1.14; P = 0.044), specifically for leukemia patients who relapsed (OR = 1.19; 95%CI = 1.01-1.40; P = 0.043). These results indicate that genetic predisposition to longer LTL is a newly identified risk factor for neuroblastoma and potentially for other cancers of childhood.

Authors
Walsh, KM; Whitehead, TP; de Smith, AJ; Smirnov, IV; Park, M; Endicott, AA; Francis, SS; Codd, V; ENGAGE Consortium Telomere Group, ; Samani, NJ; Metayer, C; Wiemels, JL
MLA Citation
Walsh, KM, Whitehead, TP, de Smith, AJ, Smirnov, IV, Park, M, Endicott, AA, Francis, SS, Codd, V, ENGAGE Consortium Telomere Group, , Samani, NJ, Metayer, C, and Wiemels, JL. "Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers." Carcinogenesis 37.6 (June 2016): 576-582.
PMID
27207662
Source
epmc
Published In
Carcinogenesis
Volume
37
Issue
6
Publish Date
2016
Start Page
576
End Page
582
DOI
10.1093/carcin/bgw037

Telomere length connects melanoma and glioma predispositions.

Authors
Endicott, AA; Taylor, JW; Walsh, KM
MLA Citation
Endicott, AA, Taylor, JW, and Walsh, KM. "Telomere length connects melanoma and glioma predispositions." Aging 8.3 (March 29, 2016): 423-424.
PMID
27029497
Source
epmc
Published In
Aging
Volume
8
Issue
3
Publish Date
2016
Start Page
423
End Page
424

Gene by Environment Investigation of Incident Lung Cancer Risk in African-Americans.

Genome-wide association studies have identified polymorphisms linked to both smoking exposure and risk of lung cancer. The degree to which lung cancer risk is driven by increased smoking, genetics, or gene-environment interactions is not well understood.We analyzed associations between 28 single nucleotide polymorphisms (SNPs) previously associated with smoking quantity and lung cancer in 7156 African-American females in the Women's Health Initiative (WHI), then analyzed main effects of top nominally significant SNPs and interactions between SNPs, cigarettes per day (CPD) and pack-years for lung cancer in an independent, multi-center case-control study of African-American females and males (1078 lung cancer cases and 822 controls).Nine nominally significant SNPs for CPD in WHI were associated with incident lung cancer (corrected p-values from 0.027 to 6.09 × 10(-5)). CPD was found to be a nominally significant effect modifier between SNP and lung cancer for six SNPs, including CHRNA5 rs2036527[A](betaSNP*CPD = - 0.017, p = 0.0061, corrected p = 0.054), which was associated with CPD in a previous genome-wide meta-analysis of African-Americans.These results suggest that chromosome 15q25.1 variants are robustly associated with CPD and lung cancer in African-Americans and that the allelic dose effect of these polymorphisms on lung cancer risk is most pronounced in lighter smokers.

Authors
David, SP; Wang, A; Kapphahn, K; Hedlin, H; Desai, M; Henderson, M; Yang, L; Walsh, KM; Schwartz, AG; Wiencke, JK; Spitz, MR; Wenzlaff, AS; Wrensch, MR; Eaton, CB; Furberg, H; Mark Brown, W; Goldstein, BA; Assimes, T; Tang, H; Kooperberg, CL; Quesenberry, CP; Tindle, H; Patel, MI; Amos, CI; Bergen, AW; Swan, GE; Stefanick, ML
MLA Citation
David, SP, Wang, A, Kapphahn, K, Hedlin, H, Desai, M, Henderson, M, Yang, L, Walsh, KM, Schwartz, AG, Wiencke, JK, Spitz, MR, Wenzlaff, AS, Wrensch, MR, Eaton, CB, Furberg, H, Mark Brown, W, Goldstein, BA, Assimes, T, Tang, H, Kooperberg, CL, Quesenberry, CP, Tindle, H, Patel, MI, Amos, CI, Bergen, AW, Swan, GE, and Stefanick, ML. "Gene by Environment Investigation of Incident Lung Cancer Risk in African-Americans." EBioMedicine 4 (February 2016): 153-161.
Website
http://hdl.handle.net/10161/15151
PMID
26981579
Source
epmc
Published In
EBioMedicine
Volume
4
Publish Date
2016
Start Page
153
End Page
161
DOI
10.1016/j.ebiom.2016.01.002

Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk.

Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82x10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48x10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83x10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis.

Authors
Walsh, KM; Codd, V; Rice, T; Nelson, CP; Smirnov, IV; McCoy, LS; Hansen, HM; Elhauge, E; Ojha, J; Francis, SS; Madsen, NR; Bracci, PM; Pico, AR; Molinaro, AM; Tihan, T; Berger, MS; Chang, SM; Prados, MD; Jenkins, RB; Wiemels, JL; ENGAGE Consortium Telomere Group, ; Samani, NJ; Wiencke, JK; Wrensch, MR
MLA Citation
Walsh, KM, Codd, V, Rice, T, Nelson, CP, Smirnov, IV, McCoy, LS, Hansen, HM, Elhauge, E, Ojha, J, Francis, SS, Madsen, NR, Bracci, PM, Pico, AR, Molinaro, AM, Tihan, T, Berger, MS, Chang, SM, Prados, MD, Jenkins, RB, Wiemels, JL, ENGAGE Consortium Telomere Group, , Samani, NJ, Wiencke, JK, and Wrensch, MR. "Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk." Oncotarget 6.40 (December 4, 2015): 42468-42477.
PMID
26646793
Source
epmc
Published In
Oncotarget
Volume
6
Issue
40
Publish Date
2015
Start Page
42468
End Page
42477
DOI
10.18632/oncotarget.6468

A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution.

Genome-wide association studies (GWAS) have identified SNPs in six genes that are associated with childhood acute lymphoblastic leukemia (ALL). A lead SNP was found to occur on chromosome 9p21.3, a region that is deleted in 30% of childhood ALLs, suggesting the presence of causal polymorphisms linked to ALL risk. We used SNP genotyping and imputation-based fine-mapping of a multiethnic ALL case-control population (Ncases = 1,464, Ncontrols = 3,279) to identify variants of large effect within 9p21.3. We identified a CDKN2A missense variant (rs3731249) with 2% allele frequency in controls that confers three-fold increased risk of ALL in children of European ancestry (OR, 2.99; P = 1.51 × 10(-9)) and Hispanic children (OR, 2.77; P = 3.78 × 10(-4)). Moreover, of 17 patients whose tumors displayed allelic imbalance at CDKN2A, 14 preferentially retained the risk allele and lost the protective allele (PBinomial = 0.006), suggesting that the risk allele provides a selective advantage during tumor growth. Notably, the CDKN2A variant was not significantly associated with melanoma, glioblastoma, or pancreatic cancer risk, implying that this polymorphism specifically confers ALL risk but not general cancer risk. Taken together, our findings demonstrate that coding polymorphisms of large effect can underlie GWAS "hits" and that inherited polymorphisms may undergo directional selection during clonal expansion of tumors.

Authors
Walsh, KM; de Smith, AJ; Hansen, HM; Smirnov, IV; Gonseth, S; Endicott, AA; Xiao, J; Rice, T; Fu, CH; McCoy, LS; Lachance, DH; Eckel-Passow, JE; Wiencke, JK; Jenkins, RB; Wrensch, MR; Ma, X; Metayer, C; Wiemels, JL
MLA Citation
Walsh, KM, de Smith, AJ, Hansen, HM, Smirnov, IV, Gonseth, S, Endicott, AA, Xiao, J, Rice, T, Fu, CH, McCoy, LS, Lachance, DH, Eckel-Passow, JE, Wiencke, JK, Jenkins, RB, Wrensch, MR, Ma, X, Metayer, C, and Wiemels, JL. "A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution." Cancer research 75.22 (November 2, 2015): 4884-4894.
PMID
26527286
Source
epmc
Published In
Cancer Research
Volume
75
Issue
22
Publish Date
2015
Start Page
4884
End Page
4894
DOI
10.1158/0008-5472.can-15-1105

Telomere maintenance and the etiology of adult glioma.

A growing body of epidemiologic and tumor genomic research has identified an important role for telomere maintenance in glioma susceptibility, initiation, and prognosis. Telomere length has long been investigated in relation to cancer, but whether longer or shorter telomere length might be associated with glioma risk has remained elusive. Recent data address this question and are reviewed here. Common inherited variants near the telomerase-component genes TERC and TERT are associated both with longer telomere length and increased risk of glioma. Exome sequencing of glioma patients from families with multiple affected members has identified rare inherited mutations in POT1 (protection of telomeres protein 1) as high-penetrance glioma risk factors. These heritable POT1 mutations are also associated with increased telomere length in leukocytes. Tumor sequencing studies further indicate that acquired somatic mutations of TERT and ATRX are among the most frequent alterations found in adult gliomas. These mutations facilitate telomere lengthening, thus bypassing a critical mechanism of apoptosis. Although future research is needed, mounting evidence suggests that glioma is, at least in part, a disease of telomere dysregulation. Specifically, several inherited and acquired variants underlying gliomagenesis affect telomere pathways and are also associated with increased telomere length.

Authors
Walsh, KM; Wiencke, JK; Lachance, DH; Wiemels, JL; Molinaro, AM; Eckel-Passow, JE; Jenkins, RB; Wrensch, MR
MLA Citation
Walsh, KM, Wiencke, JK, Lachance, DH, Wiemels, JL, Molinaro, AM, Eckel-Passow, JE, Jenkins, RB, and Wrensch, MR. "Telomere maintenance and the etiology of adult glioma." Neuro-oncology 17.11 (November 2015): 1445-1452. (Review)
PMID
26014050
Source
epmc
Published In
Neuro-Oncology
Volume
17
Issue
11
Publish Date
2015
Start Page
1445
End Page
1452
DOI
10.1093/neuonc/nov082

A functional polymorphism in the CEBPE gene promoter influences acute lymphoblastic leukemia risk through interaction with the hematopoietic transcription factor ikaros

Authors
Wiemels, JL; de Smith, AJ; Xiao, J; Lee, S-T; Muench, MO; Fomin, ME; Zhou, M; Hansen, HM; Termuhlen, A; Metayer, C; Walsh, KM
MLA Citation
Wiemels, JL, de Smith, AJ, Xiao, J, Lee, S-T, Muench, MO, Fomin, ME, Zhou, M, Hansen, HM, Termuhlen, A, Metayer, C, and Walsh, KM. "A functional polymorphism in the CEBPE gene promoter influences acute lymphoblastic leukemia risk through interaction with the hematopoietic transcription factor ikaros." Leukemia (September 16, 2015).
Source
crossref
Published In
Leukemia
Publish Date
2015
DOI
10.1038/leu.2015.251

Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors.

The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants.We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants.Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants.Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. (Funded by the National Institutes of Health and others.).

Authors
Eckel-Passow, JE; Lachance, DH; Molinaro, AM; Walsh, KM; Decker, PA; Sicotte, H; Pekmezci, M; Rice, T; Kosel, ML; Smirnov, IV; Sarkar, G; Caron, AA; Kollmeyer, TM; Praska, CE; Chada, AR; Halder, C; Hansen, HM; McCoy, LS; Bracci, PM; Marshall, R; Zheng, S; Reis, GF; Pico, AR; O'Neill, BP; Buckner, JC; Giannini, C; Huse, JT; Perry, A; Tihan, T; Berger, MS; Chang, SM; Prados, MD; Wiemels, J; Wiencke, JK; Wrensch, MR; Jenkins, RB
MLA Citation
Eckel-Passow, JE, Lachance, DH, Molinaro, AM, Walsh, KM, Decker, PA, Sicotte, H, Pekmezci, M, Rice, T, Kosel, ML, Smirnov, IV, Sarkar, G, Caron, AA, Kollmeyer, TM, Praska, CE, Chada, AR, Halder, C, Hansen, HM, McCoy, LS, Bracci, PM, Marshall, R, Zheng, S, Reis, GF, Pico, AR, O'Neill, BP, Buckner, JC, Giannini, C, Huse, JT, Perry, A, Tihan, T, Berger, MS, Chang, SM, Prados, MD, Wiemels, J, Wiencke, JK, Wrensch, MR, and Jenkins, RB. "Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors." The New England journal of medicine 372.26 (June 10, 2015): 2499-2508.
PMID
26061753
Source
epmc
Published In
The New England journal of medicine
Volume
372
Issue
26
Publish Date
2015
Start Page
2499
End Page
2508
DOI
10.1056/nejmoa1407279

Cancer. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer.

Reactivation of telomerase reverse transcriptase (TERT) expression enables cells to overcome replicative senescence and escape apoptosis, which are fundamental steps in the initiation of human cancer. Multiple cancer types, including up to 83% of glioblastomas (GBMs), harbor highly recurrent TERT promoter mutations of unknown function but specific to two nucleotide positions. We identified the functional consequence of these mutations in GBMs to be recruitment of the multimeric GA-binding protein (GABP) transcription factor specifically to the mutant promoter. Allelic recruitment of GABP is consistently observed across four cancer types, highlighting a shared mechanism underlying TERT reactivation. Tandem flanking native E26 transformation-specific motifs critically cooperate with these mutations to activate TERT, probably by facilitating GABP heterotetramer binding. GABP thus directly links TERT promoter mutations to aberrant expression in multiple cancers.

Authors
Bell, RJA; Rube, HT; Kreig, A; Mancini, A; Fouse, SD; Nagarajan, RP; Choi, S; Hong, C; He, D; Pekmezci, M; Wiencke, JK; Wrensch, MR; Chang, SM; Walsh, KM; Myong, S; Song, JS; Costello, JF
MLA Citation
Bell, RJA, Rube, HT, Kreig, A, Mancini, A, Fouse, SD, Nagarajan, RP, Choi, S, Hong, C, He, D, Pekmezci, M, Wiencke, JK, Wrensch, MR, Chang, SM, Walsh, KM, Myong, S, Song, JS, and Costello, JF. "Cancer. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer." Science (New York, N.Y.) 348.6238 (May 14, 2015): 1036-1039.
PMID
25977370
Source
epmc
Published In
Science
Volume
348
Issue
6238
Publish Date
2015
Start Page
1036
End Page
1039
DOI
10.1126/science.aab0015

CDKN2A loss is associated with shortened overall survival in lower-grade (World Health Organization Grades II-III) astrocytomas.

Lower-grade (World Health Organization Grades II and III) gliomas vary widely in clinical behavior and are classified as astrocytic, oligodendroglial, or mixed. Anaplasia depends greatly on mitotic activity, with CDKN2A loss considered as the most common mechanism for cell cycle dysregulation. We investigated whether loss of the CDKN2A gene is associated with overall survival across pathologically and genetically defined glioma subtypes. After adjustment for IDH mutation, sex, and age, CDKN2A deletion was strongly associated with poorer overall survival in astrocytomas but not in oligodendrogliomas or oligoastrocytomas. Molecular classification of astrocytomas by IDH mutation, TP53 mutation, and /or ATRX loss of expression revealed that CDKN2A loss in IDH/TP53 mutated tumors was strongly associated with worse overall survival. CDKN2A loss in IDH mutated tumors with ATRX loss was only weakly associated with worse overall survival. These findings suggest that CDKN2A testing may provide further clinical aid in lower-grade glioma substratification beyond IDH mutation and 1p19q codeletion status, particularly in IDH/TP53 mutated astrocytomas.

Authors
Reis, GF; Pekmezci, M; Hansen, HM; Rice, T; Marshall, RE; Molinaro, AM; Phillips, JJ; Vogel, H; Wiencke, JK; Wrensch, MR; Walsh, KM; Perry, A
MLA Citation
Reis, GF, Pekmezci, M, Hansen, HM, Rice, T, Marshall, RE, Molinaro, AM, Phillips, JJ, Vogel, H, Wiencke, JK, Wrensch, MR, Walsh, KM, and Perry, A. "CDKN2A loss is associated with shortened overall survival in lower-grade (World Health Organization Grades II-III) astrocytomas." Journal of neuropathology and experimental neurology 74.5 (May 2015): 442-452.
PMID
25853694
Source
epmc
Published In
Journal of Neuropathology and Experimental Neurology
Volume
74
Issue
5
Publish Date
2015
Start Page
442
End Page
452
DOI
10.1097/nen.0000000000000188

Association of genetic variation in IKZF1, ARID5B, and CEBPE and surrogates for early-life infections with the risk of acute lymphoblastic leukemia in Hispanic children.

Genome-wide association studies focusing on European-ancestry populations have identified ALL risk loci on IKZF1, ARID5B, and CEBPE. To capture the impacts of these genes on ALL risk in the California Hispanic population, we comprehensively assessed the variation within the genes and further assessed the joint effects between the genetic variation and surrogates for early-life infections (the presence of older siblings, daycare attendance, and ear infections).Genotypic data for 323 Hispanic ALL cases and 454 controls from the California Childhood Leukemia Study were generated using Illumina OmniExpress v1 platform. Logistic regression assuming a log-additive model estimated odds ratios (OR) associated with each SNP, adjusted for age, sex, and the first five principal components. In addition, we examined potential interactions between six ALL risk alleles and surrogates for early-life infections using logistic regression models that included an interaction term.Significant associations between genotypes at IKZF1, ARID5B, and CEBPE and ALL risk were identified: rs7780012, OR 0.50, 95% confidence interval (CI) 0.35-0.71 (p = 0.004); rs7089424, OR 2.12, 95% CI 1.70-2.65 (p = 1.16 × 10(-9)); rs4982731, OR 1.69, 95% CI 1.37-2.08 (p = 2.35 × 10(-6)), respectively. Evidence for multiplicative interactions between genetic variants and surrogates for early-life infections with ALL risk was not observed.Consistent with findings in non-Hispanic White population, our study showed that variants within IKZF1, ARID5B, and CEBPE were associated with increased ALL risk, and the effects for ARID5B and CEBPE were most prominent in the high-hyperdiploid ALL subtype in the California Hispanic population. Results implicate the ARID5B, CEBPE, and IKZF1 genes in the pathogenesis of childhood ALL.

Authors
Hsu, L-I; Chokkalingam, AP; Briggs, FBS; Walsh, K; Crouse, V; Fu, C; Metayer, C; Wiemels, JL; Barcellos, LF; Buffler, PA
MLA Citation
Hsu, L-I, Chokkalingam, AP, Briggs, FBS, Walsh, K, Crouse, V, Fu, C, Metayer, C, Wiemels, JL, Barcellos, LF, and Buffler, PA. "Association of genetic variation in IKZF1, ARID5B, and CEBPE and surrogates for early-life infections with the risk of acute lymphoblastic leukemia in Hispanic children." Cancer causes & control : CCC 26.4 (April 2015): 609-619.
PMID
25761407
Source
epmc
Published In
Cancer Causes & Control
Volume
26
Issue
4
Publish Date
2015
Start Page
609
End Page
619
DOI
10.1007/s10552-015-0550-3

Response to "the epidemiology of glioma in adults: a 'state of the science' review".

Authors
Ostrom, QT; Bauchet, L; Davis, FG; Deltour, I; Fisher, JL; Langer, CE; Pekmezci, M; Schwartzbaum, JA; Turner, MC; Walsh, KM; Wrensch, MR; Barnholtz-Sloan, JS
MLA Citation
Ostrom, QT, Bauchet, L, Davis, FG, Deltour, I, Fisher, JL, Langer, CE, Pekmezci, M, Schwartzbaum, JA, Turner, MC, Walsh, KM, Wrensch, MR, and Barnholtz-Sloan, JS. "Response to "the epidemiology of glioma in adults: a 'state of the science' review"." Neuro-oncology 17.4 (April 2015): 624-626. (Letter)
PMID
25762697
Source
epmc
Published In
Neuro-Oncology
Volume
17
Issue
4
Publish Date
2015
Start Page
624
End Page
626
DOI
10.1093/neuonc/nov022

Germline mutations in shelterin complex genes are associated with familial glioma.

Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma.

Authors
Bainbridge, MN; Armstrong, GN; Gramatges, MM; Bertuch, AA; Jhangiani, SN; Doddapaneni, H; Lewis, L; Tombrello, J; Tsavachidis, S; Liu, Y; Jalali, A; Plon, SE; Lau, CC; Parsons, DW; Claus, EB; Barnholtz-Sloan, J; Il'yasova, D; Schildkraut, J; Ali-Osman, F; Sadetzki, S; Johansen, C; Houlston, RS; Jenkins, RB; Lachance, D; Olson, SH; Bernstein, JL; Merrell, RT; Wrensch, MR; Walsh, KM; Davis, FG; Lai, R; Shete, S; Aldape, K; Amos, CI; Thompson, PA; Muzny, DM; Gibbs, RA; Melin, BS; Bondy, ML et al.
MLA Citation
Bainbridge, MN, Armstrong, GN, Gramatges, MM, Bertuch, AA, Jhangiani, SN, Doddapaneni, H, Lewis, L, Tombrello, J, Tsavachidis, S, Liu, Y, Jalali, A, Plon, SE, Lau, CC, Parsons, DW, Claus, EB, Barnholtz-Sloan, J, Il'yasova, D, Schildkraut, J, Ali-Osman, F, Sadetzki, S, Johansen, C, Houlston, RS, Jenkins, RB, Lachance, D, Olson, SH, Bernstein, JL, Merrell, RT, Wrensch, MR, Walsh, KM, Davis, FG, Lai, R, Shete, S, Aldape, K, Amos, CI, Thompson, PA, Muzny, DM, Gibbs, RA, Melin, BS, and Bondy, ML et al. "Germline mutations in shelterin complex genes are associated with familial glioma." Journal of the National Cancer Institute 107.1 (January 2015): 384-.
PMID
25482530
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
107
Issue
1
Publish Date
2015
Start Page
384
DOI
10.1093/jnci/dju384

Survival and low-grade glioma: the emergence of genetic information.

Significant gaps exist in our understanding of the causes and clinical management of glioma. One of the biggest gaps is how best to manage low-grade (World Health Organization [WHO] Grade II) glioma. Low-grade glioma (LGG) is a uniformly fatal disease of young adults (mean age 41 years), with survival averaging approximately 7 years. Although LGG patients have better survival than patients with high-grade (WHO Grade III or IV) glioma, all LGGs eventually progress to high-grade glioma and death. Data from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute suggest that for the majority of LGG patients, overall survival has not significantly improved over the past 3 decades, highlighting the need for intensified study of this tumor. Recently published research suggests that historically used clinical variables are not sufficient (and are likely inferior) prognostic and predictive indicators relative to information provided by recently discovered tumor markers (e.g., 1p/19q deletion and IDH1 or IDH2 mutation status), tumor expression profiles (e.g., the proneural profile) and/or constitutive genotype (e.g., rs55705857 on 8q24.21). Discovery of such tumor and constitutive variation may identify variables needed to improve randomization in clinical trials as well as identify patients more sensitive to current treatments and targets for improved treatment in the future. This article reports on survival trends for patients diagnosed with LGG within the United States from 1973 through 2011 and reviews the emerging role of tumor and constitutive genetics in refining risk stratification, defining targeted therapy, and improving survival for this group of relatively young patients.

Authors
Claus, EB; Walsh, KM; Wiencke, JK; Molinaro, AM; Wiemels, JL; Schildkraut, JM; Bondy, ML; Berger, M; Jenkins, R; Wrensch, M
MLA Citation
Claus, EB, Walsh, KM, Wiencke, JK, Molinaro, AM, Wiemels, JL, Schildkraut, JM, Bondy, ML, Berger, M, Jenkins, R, and Wrensch, M. "Survival and low-grade glioma: the emergence of genetic information." Neurosurgical focus 38.1 (January 2015): E6-.
PMID
25552286
Source
epmc
Published In
Neurosurgical focus
Volume
38
Issue
1
Publish Date
2015
Start Page
E6
DOI
10.3171/2014.10.focus12367

Somatic Mutation Allelic Ratio Test Using ddPCR (SMART-ddPCR): An Accurate Method for Assessment of Preferential Allelic Imbalance in Tumor DNA.

The extent to which heritable genetic variants can affect tumor development has yet to be fully elucidated. Tumor selection of single nucleotide polymorphism (SNP) risk alleles, a phenomenon called preferential allelic imbalance (PAI), has been demonstrated in some cancer types. We developed a novel application of digital PCR termed Somatic Mutation Allelic Ratio Test using Droplet Digital PCR (SMART-ddPCR) for accurate assessment of tumor PAI, and have applied this method to test the hypothesis that heritable SNPs associated with childhood acute lymphoblastic leukemia (ALL) may demonstrate tumor PAI. These SNPs are located at CDKN2A (rs3731217) and IKZF1 (rs4132601), genes frequently lost in ALL, and at CEBPE (rs2239633), ARID5B (rs7089424), PIP4K2A (rs10764338), and GATA3 (rs3824662), genes located on chromosomes gained in high-hyperdiploid ALL. We established thresholds of AI using constitutional DNA from SNP heterozygotes, and subsequently measured allelic copy number in tumor DNA from 19-142 heterozygote samples per SNP locus. We did not find significant tumor PAI at these loci, though CDKN2A and IKZF1 SNPs showed a trend towards preferential selection of the risk allele (p = 0.17 and p = 0.23, respectively). Using a genomic copy number control ddPCR assay, we investigated somatic copy number alterations (SCNA) underlying AI at CDKN2A and IKZF1, revealing a complex range of alterations including homozygous and hemizygous deletions and copy-neutral loss of heterozygosity, with varying degrees of clonality. Copy number estimates from ddPCR showed high agreement with those from multiplex ligation-dependent probe amplification (MLPA) assays. We demonstrate that SMART-ddPCR is a highly accurate method for investigation of tumor PAI and for assessment of the somatic alterations underlying AI. Furthermore, analysis of publicly available data from The Cancer Genome Atlas identified 16 recurrent SCNA loci that contain heritable cancer risk SNPs associated with a matching tumor type, and which represent candidate PAI regions warranting further investigation.

Authors
de Smith, AJ; Walsh, KM; Hansen, HM; Endicott, AA; Wiencke, JK; Metayer, C; Wiemels, JL
MLA Citation
de Smith, AJ, Walsh, KM, Hansen, HM, Endicott, AA, Wiencke, JK, Metayer, C, and Wiemels, JL. "Somatic Mutation Allelic Ratio Test Using ddPCR (SMART-ddPCR): An Accurate Method for Assessment of Preferential Allelic Imbalance in Tumor DNA." PloS one 10.11 (January 2015): e0143343-.
PMID
26575185
Source
epmc
Published In
PloS one
Volume
10
Issue
11
Publish Date
2015
Start Page
e0143343
DOI
10.1371/journal.pone.0143343

Familial gliomas: cases in two pairs of brothers.

The majority of gliomas are sporadic in origin. Familial gliomas have been reported, though they are exceptionally rare. Several familial cancer syndromes are associated with autosomal dominant glioma risk, typically with incomplete penetrance. When two siblings are affected in the absence of a known dominantly inherited cancer syndrome, an autosomal recessive condition may be suspected (e.g. constitutional mismatch repair syndrome). We present two separate sets of siblings, one set with low grade gliomas, and the other with high grade gliomas. Histology for all tumors were either oligodendroglioma or had features of oligodendroglioma. Interestingly, there is a nearly identical histopathology and anatomical localization noted in these clinical presentations. For one family, genetic testing and family inquiry have resulted in no identifiable genetic pattern of disease. High-penetrance familial mutations and common low-penetrance susceptibility loci (e.g. single-nucleotide polymorphism (SNPs)) may contribute to familial glioma risk. We present two instances of familial glioma without an identifiable genetic cause. These cases implicate a potential heritable etiology for glioma families in which Mendelian disorders have not been identified. Further investigation should focus on identifying the potential genetic links involved with cases such as the ones presented here.

Authors
Osorio, JA; Hervey-Jumper, SL; Walsh, KM; Clarke, JL; Butowski, NA; Prados, MD; Berger, MS
MLA Citation
Osorio, JA, Hervey-Jumper, SL, Walsh, KM, Clarke, JL, Butowski, NA, Prados, MD, and Berger, MS. "Familial gliomas: cases in two pairs of brothers." Journal of neuro-oncology 121.1 (January 2015): 135-140.
PMID
25208478
Source
epmc
Published In
Journal of Neuro-Oncology
Volume
121
Issue
1
Publish Date
2015
Start Page
135
End Page
140
DOI
10.1007/s11060-014-1611-2

Epidemiology

Neuro-Oncology: The Essentials, Third Edition, is a comprehensive introduction to the fundamental science and core clinical concepts behind the successful multidisciplinary management of patients with brain and spine tumors.

Authors
Walsh, KM; Claus, EB; Wrensch, MR
MLA Citation
Walsh, KM, Claus, EB, and Wrensch, MR. "Epidemiology." Neuro-Oncology: The Essentials. Ed. M Berstein and MS Berger. Thieme, August 1, 2014. (Chapter)
Source
manual
Publish Date
2014

The epidemiology of glioma in adults: a "state of the science" review.

Gliomas are the most common primary intracranial tumor, representing 81% of malignant brain tumors. Although relatively rare, they cause significant mortality and morbidity. Glioblastoma, the most common glioma histology (∼45% of all gliomas), has a 5-year relative survival of ∼5%. A small portion of these tumors are caused by Mendelian disorders, including neurofibromatosis, tuberous sclerosis, and Li-Fraumeni syndrome. Genomic analyses of glioma have also produced new evidence about risk and prognosis. Recently discovered biomarkers that indicate improved survival include O⁶-methylguanine-DNA methyltransferase methylation, isocitrate dehydrogenase mutation, and a glioma cytosine-phosphate-guanine island methylator phenotype. Genome-wide association studies have identified heritable risk alleles within 7 genes that are associated with increased risk of glioma. Many risk factors have been examined as potential contributors to glioma risk. Most significantly, these include an increase in risk by exposure to ionizing radiation and a decrease in risk by history of allergies or atopic disease(s). The potential influence of occupational exposures and cellular phones has also been examined, with inconclusive results. We provide a “state of the science” review of current research into causes and risk factors for gliomas in adults.

Authors
Ostrom, QT; Bauchet, L; Davis, FG; Deltour, I; Fisher, JL; Langer, CE; Pekmezci, M; Schwartzbaum, JA; Turner, MC; Walsh, KM; Wrensch, MR; Barnholtz-Sloan, JS
MLA Citation
Ostrom, QT, Bauchet, L, Davis, FG, Deltour, I, Fisher, JL, Langer, CE, Pekmezci, M, Schwartzbaum, JA, Turner, MC, Walsh, KM, Wrensch, MR, and Barnholtz-Sloan, JS. "The epidemiology of glioma in adults: a "state of the science" review." Neuro-oncology 16.7 (July 2014): 896-913. (Review)
PMID
24842956
Source
epmc
Published In
Neuro-Oncology
Volume
16
Issue
7
Publish Date
2014
Start Page
896
End Page
913
DOI
10.1093/neuonc/nou087

Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk.

Glioma, the most common central nervous system cancer in adults, has poor prognosis. Here we identify a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10(-9)) in a meta-analysis of genome-wide association studies (GWAS) of high-grade glioma and replication data (1,644 cases and 7,736 controls). This region has previously been associated with mean leukocyte telomere length (LTL). We therefore examined the relationship between LTL and both this new risk locus and other previously established risk loci for glioma using data from a recent GWAS of LTL (n = 37,684 individuals). Alleles associated with glioma risk near TERC and TERT were strongly associated with longer LTL (P = 5.5 × 10(-20) and 4.4 × 10(-19), respectively). In contrast, risk-associated alleles near RTEL1 were inconsistently associated with LTL, suggesting the presence of distinct causal alleles. No other risk loci for glioma were associated with LTL. The identification of risk alleles for glioma near TERC and TERT that also associate with telomere length implicates telomerase in gliomagenesis.

Authors
Walsh, KM; Codd, V; Smirnov, IV; Rice, T; Decker, PA; Hansen, HM; Kollmeyer, T; Kosel, ML; Molinaro, AM; McCoy, LS; Bracci, PM; Cabriga, BS; Pekmezci, M; Zheng, S; Wiemels, JL; Pico, AR; Tihan, T; Berger, MS; Chang, SM; Prados, MD; Lachance, DH; O'Neill, BP; Sicotte, H; Eckel-Passow, JE; ENGAGE Consortium Telomere Group, ; van der Harst, P; Wiencke, JK; Samani, NJ; Jenkins, RB; Wrensch, MR
MLA Citation
Walsh, KM, Codd, V, Smirnov, IV, Rice, T, Decker, PA, Hansen, HM, Kollmeyer, T, Kosel, ML, Molinaro, AM, McCoy, LS, Bracci, PM, Cabriga, BS, Pekmezci, M, Zheng, S, Wiemels, JL, Pico, AR, Tihan, T, Berger, MS, Chang, SM, Prados, MD, Lachance, DH, O'Neill, BP, Sicotte, H, Eckel-Passow, JE, ENGAGE Consortium Telomere Group, , van der Harst, P, Wiencke, JK, Samani, NJ, Jenkins, RB, and Wrensch, MR. "Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk." Nature genetics 46.7 (July 2014): 731-735.
PMID
24908248
Source
epmc
Published In
Nature Genetics
Volume
46
Issue
7
Publish Date
2014
Start Page
731
End Page
735
DOI
10.1038/ng.3004

Genomic ancestry and somatic alterations correlate with age at diagnosis in Hispanic children with B-cell acute lymphoblastic leukemia.

Hispanic children have a higher incidence of acute lymphoblastic leukemia (ALL) than non-Hispanic whites but tend to be diagnosed at older ages. In genome-wide association studies, Native American ancestry and polymorphisms in six genes have been associated with ALL risk. In multivariable regression models, we investigated whether genomic ancestry, inherited risk SNPs, or acquired somatic alterations were associated with differences in age at diagnosis in Hispanic children with B-cell ALL. Genome-wide array data were used to estimate each participant's percent membership in the three Hispanic ancestral populations: Native American, African, and European. Each 20% increase in European ancestry was associated with a six month younger age at diagnosis (95% CI = 0.36-11.6 months, P = 0.037). Correspondingly, each 20% increase in Native American ancestry was associated with a six-month older age at diagnosis (P = 0.037). Both the TEL-AML1 translocation and high-hyperdiploidy were associated with younger age at diagnosis (24.4 months, P = 2.0 x 10(-4) and 12.4 months, P = 0.011, respectively), while CDKN2A and IKZF1 deletions were associated with older age at diagnosis (19.7 months, P = 7.0 x 10(-4) and 18.1 months, P = 0.012, respectively). No associations with age at diagnosis were observed for RAS mutation, PAX5 deletion or for known heritable risk alleles in IKZF1, CDKN2A, PIP4K2A, GATA3, ARID5B, or CEBPE. Because younger age at diagnosis is associated with improved treatment outcomes for children with ALL, the effect of European ancestry on ALL survival may be mediated by its effect on age at diagnosis, or by proxy, its association with more treatable molecular subtypes of ALL.

Authors
Walsh, KM; de Smith, AJ; Welch, TC; Smirnov, I; Cunningham, MJ; Ma, X; Chokkalingam, AP; Dahl, GV; Roberts, W; Barcellos, LF; Buffler, PA; Metayer, C; Wiemels, JL
MLA Citation
Walsh, KM, de Smith, AJ, Welch, TC, Smirnov, I, Cunningham, MJ, Ma, X, Chokkalingam, AP, Dahl, GV, Roberts, W, Barcellos, LF, Buffler, PA, Metayer, C, and Wiemels, JL. "Genomic ancestry and somatic alterations correlate with age at diagnosis in Hispanic children with B-cell acute lymphoblastic leukemia." American journal of hematology 89.7 (July 2014): 721-725.
PMID
24753091
Source
epmc
Published In
American Journal of Hematology
Volume
89
Issue
7
Publish Date
2014
Start Page
721
End Page
725
DOI
10.1002/ajh.23727

The role of KIR genes and their cognate HLA class I ligands in childhood acute lymphoblastic leukemia.

Killer cell immunoglobulin-like receptors (KIRs), via interaction with their cognate HLA class I ligands, play a crucial role in the development and activity of natural killer cells. Following recent reports of KIR gene associations in childhood acute lymphoblastic leukemia (ALL), we present a more in-depth investigation of KIR genes and their cognate HLA ligands on childhood ALL risk. Genotyping of 16 KIR genes, along with HLA class I groups C1/C2 and Bw4 supertype ligands, was carried out in 212 childhood ALL cases and 231 healthy controls. Frequencies of KIR genes, KIR haplotypes, and combinations of KIR-HLA ligands were tested for disease association using logistic regression analyses. KIR A/A genotype frequency was significantly increased in cases (33.5%) compared with controls (24.2%) (odds ratio [OR] = 1.57; 95% confidence interval [CI], 1.04-2.39). Stratifying analysis by ethnicity, a significant difference in KIR genotype frequency was demonstrated in Hispanic cases (34.2%) compared with controls (21.9%) (OR = 1.86; 95% CI, 1.05-3.31). Homozygosity for the HLA-Bw4 allele was strongly associated with increased ALL risk exclusively in non-Hispanic white children (OR = 3.93; 95% CI, 1.44-12.64). Our findings suggest a role for KIR genes and their HLA ligands in childhood ALL etiology that may vary among ethnic groups.

Authors
de Smith, AJ; Walsh, KM; Ladner, MB; Zhang, S; Xiao, C; Cohen, F; Moore, TB; Chokkalingam, AP; Metayer, C; Buffler, PA; Trachtenberg, EA; Wiemels, JL
MLA Citation
de Smith, AJ, Walsh, KM, Ladner, MB, Zhang, S, Xiao, C, Cohen, F, Moore, TB, Chokkalingam, AP, Metayer, C, Buffler, PA, Trachtenberg, EA, and Wiemels, JL. "The role of KIR genes and their cognate HLA class I ligands in childhood acute lymphoblastic leukemia." Blood 123.16 (April 2014): 2497-2503.
PMID
24518758
Source
epmc
Published In
Blood
Volume
123
Issue
16
Publish Date
2014
Start Page
2497
End Page
2503
DOI
10.1182/blood-2013-11-540625

Associations between genome-wide Native American ancestry, known risk alleles and B-cell ALL risk in Hispanic children.

Authors
Walsh, KM; Chokkalingam, AP; Hsu, L-I; Metayer, C; de Smith, AJ; Jacobs, DI; Dahl, GV; Loh, ML; Smirnov, IV; Bartley, K; Ma, X; Wiencke, JK; Barcellos, LF; Wiemels, JL; Buffler, PA
MLA Citation
Walsh, KM, Chokkalingam, AP, Hsu, L-I, Metayer, C, de Smith, AJ, Jacobs, DI, Dahl, GV, Loh, ML, Smirnov, IV, Bartley, K, Ma, X, Wiencke, JK, Barcellos, LF, Wiemels, JL, and Buffler, PA. "Associations between genome-wide Native American ancestry, known risk alleles and B-cell ALL risk in Hispanic children." Leukemia 27.12 (December 2013): 2416-2419. (Letter)
PMID
23615557
Source
epmc
Published In
Leukemia
Volume
27
Issue
12
Publish Date
2013
Start Page
2416
End Page
2419
DOI
10.1038/leu.2013.130

Central Nervous System Tumors

Unlike traditional textbooks on medical genetics and dysmorphology, this is a clinical reference that covers many of the common diseases seen in everyday medical practice.

Authors
Walsh, KM; Berger, MS; Wrensch, MR
MLA Citation
Walsh, KM, Berger, MS, and Wrensch, MR. "Central Nervous System Tumors." Clinical Genomics: Practical Applications for Adult Patient Care. Ed. MF Murray, MW Babyatsky, and MA Giovanni. McGraw Hill Professional, November 7, 2013. 187-192. (Chapter)
Source
manual
Volume
1
Publish Date
2013
Start Page
187
End Page
192

GATA3 risk alleles are associated with ancestral components in Hispanic children with ALL.

Authors
Walsh, KM; de Smith, AJ; Chokkalingam, AP; Metayer, C; Roberts, W; Barcellos, LF; Wiemels, JL; Buffler, PA
MLA Citation
Walsh, KM, de Smith, AJ, Chokkalingam, AP, Metayer, C, Roberts, W, Barcellos, LF, Wiemels, JL, and Buffler, PA. "GATA3 risk alleles are associated with ancestral components in Hispanic children with ALL." Blood 122.19 (November 2013): 3385-3387. (Letter)
PMID
24203929
Source
epmc
Published In
Blood
Volume
122
Issue
19
Publish Date
2013
Start Page
3385
End Page
3387
DOI
10.1182/blood-2013-08-524124

Genetic variants in telomerase-related genes are associated with an older age at diagnosis in glioma patients: evidence for distinct pathways of gliomagenesis.

Genome-wide association studies have implicated single nucleotide polymorphisms (SNPs) in 7 genes as glioma risk factors, including 2 (TERT, RTEL1) involved in telomerase structure/function. We examined associations of these 7 established glioma risk loci with age at diagnosis among patients with glioma.SNP genotype data were available for 2286 Caucasian glioma patients from the University of California, San Francisco (n = 1434) and the Mayo Clinic (n = 852). Regression analyses were performed to test for associations between "number of risk alleles" and "age at diagnosis," adjusted for sex and study site and stratified by tumor grade/histology where appropriate.Four SNPs were significantly associated with age at diagnosis. Carrying a greater number of risk alleles at rs55705857 (CCDC26) and at rs498872 (PHLDB1) was associated with younger age at diagnosis (P = 1.4 × 10(-22) and P = 9.5 × 10(-7), respectively). These SNPs are stronger risk factors for oligodendroglial tumors, which tend to occur in younger patients, and their association with age at diagnosis varied across tumor subtypes. In contrast, carrying more risk alleles at rs2736100 (TERT) and at rs6010620 (RTEL1) was associated with older age at diagnosis (P = 6.2 × 10(-4) and P = 2.5 × 10(-4), respectively). These SNPs are risk factors for all glioma grades/histologies, and their association with age at diagnosis was consistent across tumor subgroups.Carrying a greater number of risk alleles might be expected to decrease age at diagnosis. However, glioma susceptibility conferred by variation in telomerase-related genes did not follow this pattern. This supports the hypothesis that telomerase-related mechanisms of telomere maintenance are more associated with gliomas that develop later in life than those utilizing telomerase-independent mechanisms (ie, alternative lengthening of telomeres).

Authors
Walsh, KM; Rice, T; Decker, PA; Kosel, ML; Kollmeyer, T; Hansen, HM; Zheng, S; McCoy, LS; Bracci, PM; Anderson, E; Hsuang, G; Wiemels, JL; Pico, AR; Smirnov, I; Molinaro, AM; Tihan, T; Berger, MS; Chang, SM; Prados, MD; Lachance, DH; Sicotte, H; Eckel-Passow, JE; Wiencke, JK; Jenkins, RB; Wrensch, MR
MLA Citation
Walsh, KM, Rice, T, Decker, PA, Kosel, ML, Kollmeyer, T, Hansen, HM, Zheng, S, McCoy, LS, Bracci, PM, Anderson, E, Hsuang, G, Wiemels, JL, Pico, AR, Smirnov, I, Molinaro, AM, Tihan, T, Berger, MS, Chang, SM, Prados, MD, Lachance, DH, Sicotte, H, Eckel-Passow, JE, Wiencke, JK, Jenkins, RB, and Wrensch, MR. "Genetic variants in telomerase-related genes are associated with an older age at diagnosis in glioma patients: evidence for distinct pathways of gliomagenesis." Neuro-oncology 15.8 (August 2013): 1041-1047.
PMID
23733245
Source
epmc
Published In
Neuro-Oncology
Volume
15
Issue
8
Publish Date
2013
Start Page
1041
End Page
1047
DOI
10.1093/neuonc/not051

Novel childhood ALL susceptibility locus BMI1-PIP4K2A is specifically associated with the hyperdiploid subtype.

Authors
Walsh, KM; de Smith, AJ; Chokkalingam, AP; Metayer, C; Dahl, GV; Hsu, L-I; Barcellos, LF; Wiemels, JL; Buffler, PA
MLA Citation
Walsh, KM, de Smith, AJ, Chokkalingam, AP, Metayer, C, Dahl, GV, Hsu, L-I, Barcellos, LF, Wiemels, JL, and Buffler, PA. "Novel childhood ALL susceptibility locus BMI1-PIP4K2A is specifically associated with the hyperdiploid subtype." Blood 121.23 (June 2013): 4808-4809. (Letter)
PMID
23744494
Source
epmc
Published In
Blood
Volume
121
Issue
23
Publish Date
2013
Start Page
4808
End Page
4809
DOI
10.1182/blood-2013-04-495390

Inherited variant on chromosome 11q23 increases susceptibility to IDH-mutated but not IDH-normal gliomas regardless of grade or histology.

Recent discoveries of inherited glioma risk loci and acquired IDH mutations are providing new insights into glioma etiology. IDH mutations are common in lower grade gliomas and secondary glioblastomas and uncommon in primary glioblastomas. Because the inherited variant in 11q23 has been associated with risk of lower grade glioma and not with glioblastomas, we hypothesized that this variant increases susceptibility to IDH-mutated gliomas, but not to IDH-wild-type gliomas.We tested this hypothesis in patients with glioma and controls from the San Francisco Adult Glioma Study, the Mayo Clinic, and Illumina controls (1102 total patients, 5299 total controls). Case-control additive associations of 11q23 risk alleles (rs498872, T allele) were calculated using logistic regression, stratified by tumor IDH status (mutated or wild-type) and by histology and grade. We also adjusted for the recently discovered 8q24 glioma risk locus rs55705857 G allele.The 11q23 glioma risk locus was associated with increased risk of IDH-mutated gliomas of all histologies and grades (odds ratio [OR] = 1.50; 95% confidence interval [CI] = 1.29-1.74; P = 1.3X10(-7)) but not with IDH-wild-type gliomas of any histology or grade (OR = 0.91; 95% CI = 0.81-1.03; P = 0.14). The associations were independent of the rs55705857 G allele.A variant at the 11q23 locus increases risk for IDH-mutated but not IDH-wild-type gliomas, regardless of grade or histology.

Authors
Rice, T; Zheng, S; Decker, PA; Walsh, KM; Bracci, P; Xiao, Y; McCoy, LS; Smirnov, I; Patoka, JS; Hansen, HM; Hsuang, G; Wiemels, JL; Tihan, T; Pico, AR; Prados, MD; Chang, SM; Berger, MS; Caron, A; Fink, S; Kollmeyer, T; Rynearson, A; Voss, J; Kosel, ML; Fridley, BL; Lachance, DH; Eckel-Passow, JE; Sicotte, H; O'Neill, BP; Giannini, C; Wiencke, JK; Jenkins, RB; Wrensch, MR
MLA Citation
Rice, T, Zheng, S, Decker, PA, Walsh, KM, Bracci, P, Xiao, Y, McCoy, LS, Smirnov, I, Patoka, JS, Hansen, HM, Hsuang, G, Wiemels, JL, Tihan, T, Pico, AR, Prados, MD, Chang, SM, Berger, MS, Caron, A, Fink, S, Kollmeyer, T, Rynearson, A, Voss, J, Kosel, ML, Fridley, BL, Lachance, DH, Eckel-Passow, JE, Sicotte, H, O'Neill, BP, Giannini, C, Wiencke, JK, Jenkins, RB, and Wrensch, MR. "Inherited variant on chromosome 11q23 increases susceptibility to IDH-mutated but not IDH-normal gliomas regardless of grade or histology." Neuro-oncology 15.5 (May 2013): 535-541.
PMID
23361564
Source
epmc
Published In
Neuro-Oncology
Volume
15
Issue
5
Publish Date
2013
Start Page
535
End Page
541
DOI
10.1093/neuonc/nos324

Analysis of 60 reported glioma risk SNPs replicates published GWAS findings but fails to replicate associations from published candidate-gene studies.

Genomewide association studies (GWAS) and candidate-gene studies have implicated single-nucleotide polymorphisms (SNPs) in at least 45 different genes as putative glioma risk factors. Attempts to validate these associations have yielded variable results and few genetic risk factors have been consistently replicated. We conducted a case-control study of Caucasian glioma cases and controls from the University of California San Francisco (810 cases, 512 controls) and the Mayo Clinic (852 cases, 789 controls) in an attempt to replicate previously reported genetic risk factors for glioma. Sixty SNPs selected from the literature (eight from GWAS and 52 from candidate-gene studies) were successfully genotyped on an Illumina custom genotyping panel. Eight SNPs in/near seven different genes (TERT, EGFR, CCDC26, CDKN2A, PHLDB1, RTEL1, TP53) were significantly associated with glioma risk in the combined dataset (P < 0.05), with all associations in the same direction as in previous reports. Several SNP associations showed considerable differences across histologic subtype. All eight successfully replicated associations were first identified by GWAS, although none of the putative risk SNPs from candidate-gene studies was associated in the full case-control sample (all P values > 0.05). Although several confirmed associations are located near genes long known to be involved in gliomagenesis (e.g., EGFR, CDKN2A, TP53), these associations were first discovered by the GWAS approach and are in noncoding regions. These results highlight that the deficiencies of the candidate-gene approach lay in selecting both appropriate genes and relevant SNPs within these genes.

Authors
Walsh, KM; Anderson, E; Hansen, HM; Decker, PA; Kosel, ML; Kollmeyer, T; Rice, T; Zheng, S; Xiao, Y; Chang, JS; McCoy, LS; Bracci, PM; Wiemels, JL; Pico, AR; Smirnov, I; Lachance, DH; Sicotte, H; Eckel-Passow, JE; Wiencke, JK; Jenkins, RB; Wrensch, MR
MLA Citation
Walsh, KM, Anderson, E, Hansen, HM, Decker, PA, Kosel, ML, Kollmeyer, T, Rice, T, Zheng, S, Xiao, Y, Chang, JS, McCoy, LS, Bracci, PM, Wiemels, JL, Pico, AR, Smirnov, I, Lachance, DH, Sicotte, H, Eckel-Passow, JE, Wiencke, JK, Jenkins, RB, and Wrensch, MR. "Analysis of 60 reported glioma risk SNPs replicates published GWAS findings but fails to replicate associations from published candidate-gene studies." Genetic epidemiology 37.2 (February 2013): 222-228.
PMID
23280628
Source
epmc
Published In
Genetic Epidemiology
Volume
37
Issue
2
Publish Date
2013
Start Page
222
End Page
228
DOI
10.1002/gepi.21707

Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 regions identifies functional and histology-specific lung cancer susceptibility loci in African-Americans.

Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31, and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans and refined previous association signals by using the reduced linkage disequilibrium observed in African-Americans.1,308 African-American cases and 1,241 African-American controls from 3 centers were genotyped for 760 single-nucleotide polymorphisms (SNP) spanning 3 regions, and additional SNP imputation was carried out. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate.The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution [rs16969968: OR, 1.57; 95% confidence interval (CI), 1.25-1.97; P, 1.1 × 10(-4)) and variants in the 5'-UTR. Associations on 6p22.1-p21.31 were histology specific and included a missense variant in BAT2 associated with squamous cell carcinoma (rs2736158: OR, 0.64; 95% CI, 0.48-0.85; P, 1.82 × 10(-3)). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR, 0.82; 95% CI, 0.73-0.93; P, 1.1 × 10(-3)). This association was stronger among cases with adenocarcinoma (OR, 0.75; 95% CI, 0.65-0.86; P, 8.1 × 10(-5)).Polymorphisms in 5p15.33, 6p22.1-p21.31, and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous cell carcinoma.Results implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies.

Authors
Walsh, KM; Gorlov, IP; Hansen, HM; Wu, X; Spitz, MR; Zhang, H; Lu, EY; Wenzlaff, AS; Sison, JD; Wei, C; Lloyd, SM; Chen, W; Frazier, ML; Seldin, MF; Bierut, LJ; Bracci, PM; Wrensch, MR; Schwartz, AG; Wiencke, JK; Amos, CI
MLA Citation
Walsh, KM, Gorlov, IP, Hansen, HM, Wu, X, Spitz, MR, Zhang, H, Lu, EY, Wenzlaff, AS, Sison, JD, Wei, C, Lloyd, SM, Chen, W, Frazier, ML, Seldin, MF, Bierut, LJ, Bracci, PM, Wrensch, MR, Schwartz, AG, Wiencke, JK, and Amos, CI. "Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 regions identifies functional and histology-specific lung cancer susceptibility loci in African-Americans." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 22.2 (February 2013): 251-260.
PMID
23221128
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
22
Issue
2
Publish Date
2013
Start Page
251
End Page
260
DOI
10.1158/1055-9965.epi-12-1007-t

Genome-wide association study identifies a maternal copy-number deletion in PSG11 enriched among preeclampsia patients

Authors
Zhao, L; Triche, EW; Walsh, KM; Bracken, MB; Saftlas, AF; Hoh, J; Dewan, AT
MLA Citation
Zhao, L, Triche, EW, Walsh, KM, Bracken, MB, Saftlas, AF, Hoh, J, and Dewan, AT. "Genome-wide association study identifies a maternal copy-number deletion in PSG11 enriched among preeclampsia patients." BMC Pregnancy and Childbirth 12.1 (December 2012).
Source
crossref
Published In
BMC Pregnancy and Childbirth
Volume
12
Issue
1
Publish Date
2012
DOI
10.1186/1471-2393-12-61

Association study of nicotinic acetylcholine receptor genes identifies a novel lung cancer susceptibility locus near CHRNA1 in African-Americans.

Studies in European and East Asian populations have identified lung cancer susceptibility loci in nicotinic acetylcholine receptor (nAChR) genes on chromosome 15q25.1 which also appear to influence smoking behaviors. We sought to determine if genetic variation in nAChR genes influences lung cancer susceptibly in African-Americans, and evaluated the association of these cancer susceptibility loci with smoking behavior. A total of 1308 African-Americans with lung cancer and 1241 African-American controls from three centers were genotyped for 378 single nucleotide polymorphisms (SNPs) spanning the sixteen human nAChR genes. Associations between SNPs and the risk of lung cancer were estimated using logistic regression, adjusted for relevant covariates. Seven SNPs in three nAChR genes were significantly associated with lung cancer at a strict Bonferroni-corrected level, including a novel association on chromosome 2 near the promoter of CHRNA1 (rs3755486: OR = 1.40, 95% CI = 1.18-1.67, P = 1.0 x 10-4). Association analysis of an additional 305 imputed SNPs on 2q31.1 supported this association. Publicly available expression data demonstrated that the rs3755486 risk allele correlates with increased CHRNA1 gene expression. Additional SNP associations were observed on 15q25.1 in genes previously associated with lung cancer, including a missense variant in CHRNA5 (rs16969968: OR = 1.60, 95% CI = 1.27-2.01, P = 5.9 x 10-5). Risk alleles on 15q25.1 also correlated with an increased number of cigarettes smoked per day among the controls. These findings identify a novel lung cancer risk locus on 2q31.1 which correlates with CHRNA1 expression and replicate previous associations on 15q25.1 in African-Americans.

Authors
Walsh, KM; Amos, CI; Wenzlaff, AS; Gorlov, IP; Sison, JD; Wu, X; Spitz, MR; Hansen, HM; Lu, EY; Wei, C; Zhang, H; Chen, W; Lloyd, SM; Frazier, ML; Bracci, PM; Seldin, MF; Wrensch, MR; Schwartz, AG; Wiencke, JK
MLA Citation
Walsh, KM, Amos, CI, Wenzlaff, AS, Gorlov, IP, Sison, JD, Wu, X, Spitz, MR, Hansen, HM, Lu, EY, Wei, C, Zhang, H, Chen, W, Lloyd, SM, Frazier, ML, Bracci, PM, Seldin, MF, Wrensch, MR, Schwartz, AG, and Wiencke, JK. "Association study of nicotinic acetylcholine receptor genes identifies a novel lung cancer susceptibility locus near CHRNA1 in African-Americans." Oncotarget 3.11 (November 2012): 1428-1438.
PMID
23232035
Source
epmc
Published In
Oncotarget
Volume
3
Issue
11
Publish Date
2012
Start Page
1428
End Page
1438

Whole-exome sequencing of a pedigree segregating asthma.

Despite the success of genome-wide association studies for asthma, few, if any, definitively causal variants have been identified and there is still a substantial portion of the heritability of the disease yet to be discovered. Some of this "missing heritability" may be accounted for by family-specific coding variants found to be segregating with asthma.To identify family-specific variants segregating with asthma, we recruited one family from a previous study of asthma as reporting multiple asthmatic and non-asthmatic children. We performed whole-exome sequencing on all four children and both parents and identified coding variants segregating with asthma that were not found in other variant databases.Ten novel variants were identified that were found in the two affected offspring and affected mother, but absent in the unaffected father and two unaffected offspring. Of these ten, variants in three genes (PDE4DIP, CBLB, and KALRN) were deemed of particular interest based on their functional prediction scores and previously reported function or asthma association. We did not identify any common risk variants segregating with asthma, however, we did observe an increase in the number of novel, nonsynonymous variants in asthma candidate genes in the asthmatic children compared to the non-asthmatic children.This is the first report applying exome sequencing to identify asthma susceptibility variants. Despite having sequenced only one family segregating asthma, we have identified several potentially functional variants in interesting asthma candidate genes. This will provide the basis for future work in which more families will be sequenced to identify variants across families that cluster within genes.

Authors
DeWan, AT; Egan, KB; Hellenbrand, K; Sorrentino, K; Pizzoferrato, N; Walsh, KM; Bracken, MB
MLA Citation
DeWan, AT, Egan, KB, Hellenbrand, K, Sorrentino, K, Pizzoferrato, N, Walsh, KM, and Bracken, MB. "Whole-exome sequencing of a pedigree segregating asthma." BMC medical genetics 13 (October 9, 2012): 95-.
PMID
23046476
Source
epmc
Published In
BMC Medical Genetics
Volume
13
Publish Date
2012
Start Page
95
DOI
10.1186/1471-2350-13-95

A low-frequency variant at 8q24.21 is strongly associated with risk of oligodendroglial tumors and astrocytomas with IDH1 or IDH2 mutation.

Variants at 8q24.21 have been shown to be associated with glioma development. By means of tag SNP genotyping and imputation, pooled next-generation sequencing using long-range PCR and subsequent validation SNP genotyping, we identified seven low-frequency SNPs at 8q24.21 that were strongly associated with glioma risk (P=1×10(-25) to 1×10(-14)). The most strongly associated SNP, rs55705857, remained highly significant after individual adjustment for the other top six SNPs and two previously published SNPs. After stratifying by histological and tumor genetic subtype, the most significant associations of rs55705857 were with oligodendroglial tumors and gliomas with mutant IDH1 or IDH2 (odds ratio (OR)=5.1, P=1.1×10(-31) and OR=4.8, P=6.6×10(-22), respectively). Strong associations were observed for astrocytomas with mutated IDH1 or IDH2 (grades 2-4) (OR=5.16-6.66, P=4.7×10(-12) to 2.2×10(-8)) but not for astrocytomas with wild-type IDH1 and IDH2 (smallest P=0.26). The conserved sequence block that includes rs55705857 is consistently modeled as a microRNA.

Authors
Jenkins, RB; Xiao, Y; Sicotte, H; Decker, PA; Kollmeyer, TM; Hansen, HM; Kosel, ML; Zheng, S; Walsh, KM; Rice, T; Bracci, P; McCoy, LS; Smirnov, I; Patoka, JS; Hsuang, G; Wiemels, JL; Tihan, T; Pico, AR; Prados, MD; Chang, SM; Berger, MS; Caron, AA; Fink, SR; Halder, C; Rynearson, AL; Fridley, BL; Buckner, JC; O'Neill, BP; Giannini, C; Lachance, DH; Wiencke, JK; Eckel-Passow, JE; Wrensch, MR
MLA Citation
Jenkins, RB, Xiao, Y, Sicotte, H, Decker, PA, Kollmeyer, TM, Hansen, HM, Kosel, ML, Zheng, S, Walsh, KM, Rice, T, Bracci, P, McCoy, LS, Smirnov, I, Patoka, JS, Hsuang, G, Wiemels, JL, Tihan, T, Pico, AR, Prados, MD, Chang, SM, Berger, MS, Caron, AA, Fink, SR, Halder, C, Rynearson, AL, Fridley, BL, Buckner, JC, O'Neill, BP, Giannini, C, Lachance, DH, Wiencke, JK, Eckel-Passow, JE, and Wrensch, MR. "A low-frequency variant at 8q24.21 is strongly associated with risk of oligodendroglial tumors and astrocytomas with IDH1 or IDH2 mutation." Nature genetics 44.10 (October 2012): 1122-1125.
PMID
22922872
Source
epmc
Published In
Nature Genetics
Volume
44
Issue
10
Publish Date
2012
Start Page
1122
End Page
1125
DOI
10.1038/ng.2388

Decreased use of non-steroidal anti-inflammatory drugs for the treatment of juvenile idiopathic arthritis in the era of modern aggressive treatment.

We examined whether the use of non-steroidal anti-inflammatory drugs has decreased for the treatment of juvenile idiopathic arthritis in a cohort treated with aggressive modern therapy as well as potential factors influencing their use. We randomly sampled 100 of 377 patients with juvenile idiopathic arthritis treated by pediatric rheumatologists at our center between 2003 and 2008. We used electronic health records and detailed chart review to examine the trends of non-steroidal anti-inflammatory drug use and factors impacting use, including disease subtype, disease activity, adverse effects, and other medication use. Data were analyzed longitudinally using a non-linear mixed effects regression model. Ninety-two percent used non-steroidal anti-inflammatory drugs at some point and 70% at anti-inflammatory doses. At patients' last visit within the study time frame, 52% were using non-steroidal anti-inflammatory drugs and only 28% at anti-inflammatory doses, decreased from 79 and 56%, respectively, at their first visit. In 2003, 53% used an anti-inflammatory dose compared to 35% in 2008. Active joint count was significantly associated with non-steroidal anti-inflammatory drug use at anti-inflammatory doses, while methotrexate and biologic modifiers use, later calendar year, the presence of uveitis, and positive anti-nuclear antibody status were significant negative predictors. The use of non-steroidal anti-inflammatory drugs decreased significantly over time, with decreasing numbers of active joints, and when methotrexate or biologic modifiers were used. The number of patients currently using non-steroidal anti-inflammatory drugs is less than reported in series from the 1990s.

Authors
Kochar, R; Walsh, KM; Jain, A; Spalding, SJ; Hashkes, PJ
MLA Citation
Kochar, R, Walsh, KM, Jain, A, Spalding, SJ, and Hashkes, PJ. "Decreased use of non-steroidal anti-inflammatory drugs for the treatment of juvenile idiopathic arthritis in the era of modern aggressive treatment." Rheumatology international 32.10 (October 2012): 3055-3060.
PMID
21909947
Source
epmc
Published In
Rheumatology International
Volume
32
Issue
10
Publish Date
2012
Start Page
3055
End Page
3060
DOI
10.1007/s00296-011-2084-7

Cigarette smoking associated with lung adenocarcinoma in situ in a large case-control study (SFBALCS).

Adenocarcinoma in situ (AIS), formerly bronchioloalveolar carcinoma, is an uncommon subtype of lung adenocarcinoma and accounts for approximately 3% to 4% of lung cancers. Compared with other lung cancer histologies, AIS patients are less likely to be smokers, yet associations with other lung cancer risk factors and differences by sex have not been determined.A total of 338 AIS patients and frequency-matched controls from the parent study (cases = 6039, controls = 2073) were included in these analyses. Odds ratios and 95% confidence intervals as estimates of the relative risk were obtained from multivariable unconditional logistic regression analyses.Risk of AIS was associated with ever smoking (OR = 2.7, 95% confidence intervals: 2.1, 3.6), increased 20% to 30% for each 10-year increase in pack-years of smoking and decreased with increased years since quitting (p for trend <0.0001). There was no evidence that risk differed by sex but there was some suggestion that risk may differ by exposure to asbestos and by second-hand tobacco smoke exposure in whites.There is an association between AIS and smoking, which is smaller in magnitude than the association between other subtypes of non-small-cell lung cancer and smoking. Our findings suggesting that effects may differ by exposure to asbestos and second-hand tobacco smoke should be interpreted conservatively and warrant validation and further evaluation in larger studies of AIS.

Authors
Bracci, PM; Sison, J; Hansen, H; Walsh, KM; Quesenberry, CP; Raz, DJ; Wrensch, M; Wiencke, JK
MLA Citation
Bracci, PM, Sison, J, Hansen, H, Walsh, KM, Quesenberry, CP, Raz, DJ, Wrensch, M, and Wiencke, JK. "Cigarette smoking associated with lung adenocarcinoma in situ in a large case-control study (SFBALCS)." Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 7.9 (September 2012): 1352-1360.
PMID
22814813
Source
epmc
Published In
Journal of Thoracic Oncology
Volume
7
Issue
9
Publish Date
2012
Start Page
1352
End Page
1360
DOI
10.1097/jto.0b013e31825aba47

Cigarette smoking and risk of meningioma: the effect of gender.

A number of studies have reported on the association between smoking and meningioma risk, with inconsistent findings. We examined the effect of gender on the association between cigarette smoking and risk of intracranial meningioma in a large population-based, case-control study.The data include 1,433 intracranial meningioma cases aged 29 to 79 years diagnosed among residents of the states of Connecticut, Massachusetts, North Carolina, the San Francisco Bay Area and eight Texas counties between May 1, 2006 and April 28, 2011 as well as 1,349 controls that were frequency matched on age, sex, and geography. The data are analyzed separately and in a meta-analysis with six previously reported studies.Female cases who reported having ever smoked were at significantly decreased risk of intracranial meningioma (OR, 0.8; 95% CI, 0.7-0.9) in contrast to male cases who were at increased risk (OR, 1.3; 95% CI, 1.0-1.7). Similar findings were noted for current and past smokers. Smoking-induced risk for females did not vary by menopausal status. For males, increased duration of use (P = 0.04) as well as increasing number of pack-years (P = 0.02) was associated with elevated risk. A meta-analysis including 2,614 cases and 1,179,686 controls resulted in an OR for ever smoking of 0.82 (95% CI, 0.68-0.98) for women and 1.39 (95% CI, 1.08-1.79) for men.The association of cigarette smoking and meningioma case status varies significantly by gender with women at reduced risk and men at greater risk.Whether the observed differences are associated with a hormonal etiology will require additional investigation.

Authors
Claus, EB; Walsh, KM; Calvocoressi, L; Bondy, ML; Schildkraut, JM; Wrensch, M; Wiemels, JL
MLA Citation
Claus, EB, Walsh, KM, Calvocoressi, L, Bondy, ML, Schildkraut, JM, Wrensch, M, and Wiemels, JL. "Cigarette smoking and risk of meningioma: the effect of gender." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 21.6 (June 2012): 943-950.
PMID
22473761
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
21
Issue
6
Publish Date
2012
Start Page
943
End Page
950
DOI
10.1158/1055-9965.epi-11-1059

Genetic signatures of exceptional longevity in humans.

Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different "genetic signatures" of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity.

Authors
Sebastiani, P; Solovieff, N; Dewan, AT; Walsh, KM; Puca, A; Hartley, SW; Melista, E; Andersen, S; Dworkis, DA; Wilk, JB; Myers, RH; Steinberg, MH; Montano, M; Baldwin, CT; Hoh, J; Perls, TT
MLA Citation
Sebastiani, P, Solovieff, N, Dewan, AT, Walsh, KM, Puca, A, Hartley, SW, Melista, E, Andersen, S, Dworkis, DA, Wilk, JB, Myers, RH, Steinberg, MH, Montano, M, Baldwin, CT, Hoh, J, and Perls, TT. "Genetic signatures of exceptional longevity in humans." PloS one 7.1 (January 18, 2012): e29848-.
PMID
22279548
Source
epmc
Published In
PloS one
Volume
7
Issue
1
Publish Date
2012
Start Page
e29848
DOI
10.1371/journal.pone.0029848

Leveraging Ethnic Group Incidence Variation to Investigate Genetic Susceptibility to Glioma: A Novel Candidate SNP Approach

Authors
Jacobs, DI; Walsh, KM; Wrensch, M; Wiencke, J; Jenkins, R; Houlston, RS; Bondy, M; Simon, M; Sanson, M; Gousias, K; Schramm, J; Labussière, M; Di Stefano, AL; Wichmann, H-E; Müller-Nurasyid, M; Schreiber, S; Franke, A; Moebus, S; Eisele, L; Dewan, AT; Dubrow, R
MLA Citation
Jacobs, DI, Walsh, KM, Wrensch, M, Wiencke, J, Jenkins, R, Houlston, RS, Bondy, M, Simon, M, Sanson, M, Gousias, K, Schramm, J, Labussière, M, Di Stefano, AL, Wichmann, H-E, Müller-Nurasyid, M, Schreiber, S, Franke, A, Moebus, S, Eisele, L, Dewan, AT, and Dubrow, R. "Leveraging Ethnic Group Incidence Variation to Investigate Genetic Susceptibility to Glioma: A Novel Candidate SNP Approach." Frontiers in Genetics 3 (2012).
Source
crossref
Published In
Frontiers in Genetics
Volume
3
Publish Date
2012
DOI
10.3389/fgene.2012.00203

Copy number variation in the dosage-sensitive 16p11.2 interval accounts for only a small proportion of autism incidence: a systematic review and meta-analysis.

PURPOSE: Autism is one of the most heritable complex disorders, but the genetic etiology of autism spectrum disorders is unexplained in ∼ 90% of cases. Highly penetrant microdeletions and microduplications of 16p11.2 contribute to the pathogenesis of autism spectrum disorder, but the extent to which these variants account for the total burden of idiopathic autism spectrum disorders has not been systematically investigated. METHODS: A systematic literature review and meta-analysis were performed to determine the prevalence of these variants among individuals diagnosed with autism spectrum disorders. A planned subgroup analysis was conducted to assess prevalence differences between sporadic and familial autism spectrum disorder cases. RESULTS: In the combined analysis of 3613 idiopathic autism spectrum disorder cases from seven studies, the meta-analytic prevalence of these microdeletions and microduplications was 0.76% (95% CI, 0.51-1.12%). When stratified by copy number variant-type, the prevalence of microdeletions was 0.50% (95% CI, 0.31-0.82%) and the prevalence of microduplications was 0.28% (95% CI, 0.14-0.56%). Sporadic autism spectrum disorder cases showed only a slightly higher prevalence than familial cases. CONCLUSION: The number needed to test to identify one such variant is 132 patients (95% CI, 89-198). Such information, especially as it pertains to diagnostic yield in genetic testing, should prove useful to clinicians considering chromosomal microarray analysis in subjects with autism spectrum disorders.

Authors
Walsh, KM; Bracken, MB
MLA Citation
Walsh, KM, and Bracken, MB. "Copy number variation in the dosage-sensitive 16p11.2 interval accounts for only a small proportion of autism incidence: a systematic review and meta-analysis." Genetics in medicine : official journal of the American College of Medical Genetics 13.5 (May 2011): 377-384. (Review)
PMID
21289514
Source
epmc
Published In
Genetics in Medicine
Volume
13
Issue
5
Publish Date
2011
Start Page
377
End Page
384
DOI
10.1097/gim.0b013e3182076c0c

A pilot genome-wide association study shows genomic variants enriched in the non-tumor cells of patients with well-differentiated neuroendocrine tumors of the ileum.

Genetic studies of midgut carcinoid cancer have exclusively focused on genomic changes of the tumor cells. We investigated the role of constitutional genetic polymorphisms in predisposing individuals to ileal carcinoids. In all, 239 cases and 110 controls were collected from three institutions: the Uppsala University Hospital; the Dana-Farber Cancer Institute; and the MD Anderson Cancer Center, and were genotyped using microarrays assaying >300 000 single nucleotide polymorphisms. Association with rs2208059 in KIF16B approached statistical significance (Mantel-Haenszel odds ratio=2.42, P=4.16×10(-7)) at a Bonferroni-corrected level (<1.62×10(-7)). Using two computational algorithms, four copy-number variants (CNVs) were identified in multiple cases that were absent in study controls and markedly less frequent in ∼1500 population-based controls. Of these four constitutional CNVs identified in blood-derived DNA, a 40 kb heterozygous deletion in Chr18q22.1 corresponded with a region frequently showing loss of heterozygosity (LOH) in ileal carcinoid tumor cells based on our meta-analysis of previously published cytogenetic studies (69.7% LOH, 95% confidence interval=60.0-77.9%). We analyzed the constitutional 40 kb deletion on chr18 in our study samples with a real-time quantitative PCR assay; 14/226 cases (6.19%) and 2/97 controls (2.06%) carried the CNV, although the exact boundaries of each deletion have not been determined. Given the small sample size, our findings warrant an independent cohort for a replication study. Owing to the rarity of this disease, we believe these results will provide a valuable resource for future work on this serious condition by allowing others to make efficient use of their samples in targeted studies.

Authors
Walsh, KM; Choi, M; Oberg, K; Kulke, MH; Yao, JC; Wu, C; Jurkiewicz, M; Hsu, L-I; Hooshmand, SM; Hassan, M; Janson, ET; Cunningham, JL; Vosburgh, E; Sackler, RS; Lifton, RP; Dewan, AT; Hoh, J
MLA Citation
Walsh, KM, Choi, M, Oberg, K, Kulke, MH, Yao, JC, Wu, C, Jurkiewicz, M, Hsu, L-I, Hooshmand, SM, Hassan, M, Janson, ET, Cunningham, JL, Vosburgh, E, Sackler, RS, Lifton, RP, Dewan, AT, and Hoh, J. "A pilot genome-wide association study shows genomic variants enriched in the non-tumor cells of patients with well-differentiated neuroendocrine tumors of the ileum." Endocrine-related cancer 18.1 (February 2011): 171-180.
PMID
21139019
Source
epmc
Published In
Endocrine-Related Cancer
Volume
18
Issue
1
Publish Date
2011
Start Page
171
End Page
180
DOI
10.1677/erc-10-0248

Attempted replication of 50 reported asthma risk genes identifies a SNP in RAD50 as associated with childhood atopic asthma.

OBJECTIVES: Asthma is a childhood disease that is strongly influenced by genetic factors. We sought to replicate an association between single nucleotide polymorphisms (SNPs) of the top-ranked candidate genes and childhood atopic asthma in Perinatal Risk of Asthma in Infants of Asthmatic Mothers (PRAM) study subjects. METHODS: Using data from a systematic literature search and an exploratory genome-wide association study conducted in a subset of the PRAM cohort, we followed a strict procedure to generate a ranked list of candidate genes. SNPs in the top 50 genes were genotyped in the full PRAM cohort (n = 103 cases with doc- tor-diagnosed atopic asthma at age 6, and n = 499 controls). RESULTS: The literature search identified 251 prior risk genes from 469 publications. RAD50 (rs2706347) and PTPRE (rs10830196) revealed crude associations with asthma at a Bonferroni-corrected level of significance (p < 0.0011). IL4R (rs1801275), CCL5 (rs2280788), and TBXA2R (rs4523) revealed nominal significance (p < 0.05). When adjusted for race and gender, only rs2706347 in RAD50 remained significantly associated with asthma. SNPs in frequently replicated asthma risk genes, including TNF, IL13, ADAM33, TGFB1, and MS4A2, revealed no association. CONCLUSION: RAD50 may be a promising candidate asthma risk gene. Lack of evidence of highly reported polymorphisms in the present study highlights the genetic heterogeneity of asthma and emphasizes the need for robust replication of candidate genes.

Authors
Murk, W; Walsh, K; Hsu, L-I; Zhao, L; Bracken, MB; Dewan, AT
MLA Citation
Murk, W, Walsh, K, Hsu, L-I, Zhao, L, Bracken, MB, and Dewan, AT. "Attempted replication of 50 reported asthma risk genes identifies a SNP in RAD50 as associated with childhood atopic asthma." Human heredity 71.2 (January 2011): 97-105.
PMID
21734400
Source
epmc
Published In
Human heredity
Volume
71
Issue
2
Publish Date
2011
Start Page
97
End Page
105
DOI
10.1159/000319536

Disease risk prediction with rare and common variants

Authors
Wu, C; Walsh, KM; DeWan, AT; Hoh, J; Wang, Z
MLA Citation
Wu, C, Walsh, KM, DeWan, AT, Hoh, J, and Wang, Z. "Disease risk prediction with rare and common variants." BMC Proceedings 5.Suppl 9 (2011): S61-S61.
Source
crossref
Published In
BMC Proceedings
Volume
5
Issue
Suppl 9
Publish Date
2011
Start Page
S61
End Page
S61
DOI
10.1186/1753-6561-5-S9-S61

Association between reduced copy-number at T-cell receptor gamma (TCRgamma) and childhood allergic asthma: A possible role for somatic mosaicism.

Asthma is a chronic inflammatory disease of the lungs which affects more than 6.5 million American children. A family-based genome-wide association study of copy-number variation identified an association between decreased copy-number at TCRgamma and childhood allergic asthma. TCRgamma encodes the T-cell receptor gamma glycoprotein, a cell-surface protein found on T-cells and involved in cell-mediated immunity. Using quantitative real-time PCR, we sought to determine if copy-number variation at TCRalpha, TCRbeta or TCRgamma was associated with childhood allergic asthma in an independent cohort of 94 cases and 455 controls using DNA from buccal swabs. Copy-number variation at these loci is well-known, but appears to be dominated by somatic mutations. Genotyping results indicated that copy-number variants at these genes are largely somatic mutations, as inheritance did not show Mendelian consistency. In these mosaic cell populations, copy-number was significantly reduced among asthmatic children at TCRgamma (p=0.0199), but was not associated at TCRalpha or TCRbeta (p=0.7972 and 0.8585, respectively). These findings support the association between reduced copy-number at TCRgamma and childhood allergic asthma. Further work is needed to resolve whether reduced copy-number at TCRgamma predisposes individuals to asthma, or whether deletion of this gene is a somatic response to the disease.

Authors
Walsh, KM; Bracken, MB; Murk, WK; Hoh, J; Dewan, AT
MLA Citation
Walsh, KM, Bracken, MB, Murk, WK, Hoh, J, and Dewan, AT. "Association between reduced copy-number at T-cell receptor gamma (TCRgamma) and childhood allergic asthma: A possible role for somatic mosaicism." Mutation research 690.1-2 (August 2010): 89-94.
PMID
20553737
Source
epmc
Published In
Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume
690
Issue
1-2
Publish Date
2010
Start Page
89
End Page
94
DOI
10.1016/j.mrfmmm.2010.05.005

Origins and prevalence of the American Founder Mutation of MSH2.

Large germline deletions within the mismatch repair gene MSH2 account for a significant proportion (up to 20%) of all deleterious mutations of this gene which are associated with Lynch syndrome. An exons 1 to 6 deletion of MSH2, originally reported in nine families, has been associated with a founding event within the United States, which genealogic studies had previously dated to 1727, and the number of present day carriers was estimated to be 18,981. Here, we report the development of a robust multiplex PCR which has assisted in the detection of 32 new families who carry the MSH2 American Founder Mutation (AFM). By offering testing to family members, 126 carriers of the AFM have been identified. Extensive genealogic studies have connected 27 of the 41 AFM families into seven extended pedigrees. These extended families have been traced back to around the 18th century without any evidence of further convergence between them. Characterization of the genomic sequence flanking the deletion and the identification of a common disease haplotype of between 0.6 and 2.3 Mb in all probands provides evidence for a common ancestor between these extended families. The DMLE+2.2 software predicts an age of approximately 500 years (95% confidence interval, 425-625) for this mutation. Taken together, these data are suggestive of an earlier founding event than was first thought, which likely occurred in a European or a Native American population. The consequences of this finding would be that the AFM is significantly more frequent in the United States than was previously predicted.

Authors
Clendenning, M; Baze, ME; Sun, S; Walsh, K; Liyanarachchi, S; Fix, D; Schunemann, V; Comeras, I; Deacon, M; Lynch, JF; Gong, G; Thomas, BC; Thibodeau, SN; Lynch, HT; Hampel, H; de la Chapelle, A
MLA Citation
Clendenning, M, Baze, ME, Sun, S, Walsh, K, Liyanarachchi, S, Fix, D, Schunemann, V, Comeras, I, Deacon, M, Lynch, JF, Gong, G, Thomas, BC, Thibodeau, SN, Lynch, HT, Hampel, H, and de la Chapelle, A. "Origins and prevalence of the American Founder Mutation of MSH2." Cancer research 68.7 (April 2008): 2145-2153.
PMID
18381419
Source
epmc
Published In
Cancer Research
Volume
68
Issue
7
Publish Date
2008
Start Page
2145
End Page
2153
DOI
10.1158/0008-5472.can-07-6599

Non-additive and epistatic effects of HLA polymorphisms contributing to risk of adult glioma

Authors
Zhang, C; de Smith, AJ; Smirnov, IV; Wiencke, JK; Wiemels, JL; Witte, JS; Walsh, KM
MLA Citation
Zhang, C, de Smith, AJ, Smirnov, IV, Wiencke, JK, Wiemels, JL, Witte, JS, and Walsh, KM. "Non-additive and epistatic effects of HLA polymorphisms contributing to risk of adult glioma (Published online)." Journal of Neuro-Oncology.
Source
crossref
Published In
Journal of Neuro-Oncology
DOI
10.1007/s11060-017-2569-7

Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia

Authors
de Smith, AJ; Ojha, J; Francis, SS; Sanders, E; Endicott, AA; Hansen, HM; Smirnov, I; Termuhlen, AM; Walsh, KM; Metayer, C; Wiemels, JL
MLA Citation
de Smith, AJ, Ojha, J, Francis, SS, Sanders, E, Endicott, AA, Hansen, HM, Smirnov, I, Termuhlen, AM, Walsh, KM, Metayer, C, and Wiemels, JL. "Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia (Published online)." Oncotarget.
Website
http://hdl.handle.net/10161/15152
Source
crossref
Published In
Oncotarget
DOI
10.18632/oncotarget.12238

Understanding inherited genetic risk of adult glioma – a review

Authors
Rice, T; Lachance, DH; Molinaro, AM; Eckel-Passow, JE; Walsh, KM; Barnholtz-Sloan, J; Ostrom, QT; Francis, SS; Wiemels, J; Jenkins, RB; Wiencke, JK; Wrensch, MR
MLA Citation
Rice, T, Lachance, DH, Molinaro, AM, Eckel-Passow, JE, Walsh, KM, Barnholtz-Sloan, J, Ostrom, QT, Francis, SS, Wiemels, J, Jenkins, RB, Wiencke, JK, and Wrensch, MR. "Understanding inherited genetic risk of adult glioma – a review (Published online)." Neuro-Oncology Practice: npv026-npv026.
Source
crossref
Published In
Neuro-oncology practice
Start Page
npv026
End Page
npv026
DOI
10.1093/nop/npv026

A germ-line deletion of APOBEC3B does not contribute to subtype-specific childhood acute lymphoblastic leukemia etiology

Authors
Wallace, AD; Francis, SS; Shao, X; de Smith, AJ; Walsh, KM; Mckean-Cowdin, R; Ma, X; Dahl, G; Barcellos, LF; Wiemels, JL; Metayer, C
MLA Citation
Wallace, AD, Francis, SS, Shao, X, de Smith, AJ, Walsh, KM, Mckean-Cowdin, R, Ma, X, Dahl, G, Barcellos, LF, Wiemels, JL, and Metayer, C. "A germ-line deletion of APOBEC3B does not contribute to subtype-specific childhood acute lymphoblastic leukemia etiology (Published online)." Haematologica: haematol.2017.179317-haematol.2017.179317.
Source
crossref
Published In
Haematologica
Start Page
haematol.2017.179317
End Page
haematol.2017.179317
DOI
10.3324/haematol.2017.179317
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