title: Genetic Variants in Epigenetic Pathways and Risks of Multiple Cancers in the GAME-ON Consortium.
abstract: Background:Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, and may be influenced by the genetic background.Methods:In a subsets (ASSET) meta-analytic approach, we investigated associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas using 51,724 cases and 52,001 controls. False discovery rate-correctedPvalues (q values < 0.05) were considered statistically significant.Results:Among 162,887 imputed or genotyped variants in 555 candidate genes, SNPs in eight genes were associated with risk of more than one cancer type. For example, variants inBABAM1were confirmed as a susceptibility locus for squamous cell lung, overall breast, estrogen receptor (ER)-negative breast, and overall prostate, and overall serous ovarian cancer; the most significant variant was rs4808076 [OR = 1.14; 95% confidence interval (CI) = 1.10-1.19; q = 6.87 × 10-5].DPF1rs12611084 was inversely associated with ER-negative breast, endometrioid ovarian, and overall and aggressive prostate cancer risk (OR = 0.93; 95% CI = 0.91-0.96; q = 0.005). Variants inL3MBTL3were associated with colorectal, overall breast, ER-negative breast, clear cell ovarian, and overall and aggressive prostate cancer risk (e.g., rs9388766: OR = 1.06; 95% CI = 1.03-1.08; q = 0.02). Variants inTET2were significantly associated with overall breast, overall prostate, overall ovarian, and endometrioid ovarian cancer risk, with rs62331150 showing bidirectional effects. Analyses of subpathways did not reveal gene subsets that contributed disproportionately to susceptibility.Conclusions:Functional and correlative studies are now needed to elucidate the potential links between germline genotype, epigenetic function, and cancer etiology.Impact:This approach provides novel insight into possible pleiotropic effects of genes involved in epigenetic processes.Cancer Epidemiol Biomarkers Prev; 26(6); 816-25. ©2017 AACR.
authors.affiliation: National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Reka
authors.initials: R
authors.lastname: Toth
authors.affiliation: National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Dominique
authors.initials: D
authors.lastname: Scherer
authors.affiliation: Medical University of South Carolina and Hollings Cancer Center, Charleston, South Carolina.
authors.forename: Linda E
authors.initials: LE
authors.lastname: Kelemen
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Cancer Research and Epigenetics, Department of Molecular Biology, University of Salzburg, Salzburg, Austria.|Cancer Cluster Salzburg, Salzburg, Austria.|Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Risch
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Aditi
authors.initials: A
authors.lastname: Hazra
authors.affiliation: National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Yesilda
authors.initials: Y
authors.lastname: Balavarca
authors.affiliation: School of Medicine, Temple University, Philadelphia, Pennsylvania.
authors.forename: Jean-Pierre J
authors.initials: JJ
authors.lastname: Issa
authors.affiliation: Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Eeles
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.|University of Toronto, Toronto, Canada.
authors.forename: Rayjean J
authors.initials: RJ
authors.lastname: Hung
authors.affiliation: Mayo Clinic College of Medicine, Rochester, Minnesota.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.affiliation: National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany. Neli.ulrich@hci.utah.edu.|Fred Hutchinson Cancer Research Center, Seattle, Washington.|Huntsman Cancer Institute, Salt Lake City, Utah.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
mesh_terms: D057890:Epigenomics / Q000379:methods*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000235:genetics*; D012307:Risk Factors