학술논문
Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions
Document Type
article
Author
Lindström, Sara; Wang, Lu; Feng, Helian; Majumdar, Arunabha; Huo, Sijia; Macdonald, James; Harrison, Tabitha; Turman, Constance; Chen, Hongjie; Mancuso, Nicholas; Bammler, Theo; Consortium, Breast Cancer Association; Gallinger, Steve; Gruber, Stephen B; Gunter, Marc J; Le Marchand, Loic; Moreno, Victor; Offit, Kenneth; Study, Genetics And Epidemiology Of Colorectal Cancer Consortium Colorectal Transdisciplinary Study Colon Cancer Family Registry; De Vivo, Immaculata; O’Mara, Tracy A; Spurdle, Amanda B; Tomlinson, Ian; Consortium, Endometrial Cancer Association; Fitzgerald, Rebecca; Gharahkhani, Puya; Gockel, Ines; Jankowski, Janusz; Macgregor, Stuart; Schumacher, Johannes; Barnholtz-Sloan, Jill; Bondy, Melissa L; Houlston, Richard S; Jenkins, Robert B; Melin, Beatrice; Wrensch, Margaret; Brennan, Paul; Christiani, David C; Johansson, Mattias; Mckay, James; Aldrich, Melinda C; Amos, Christopher I; Landi, Maria Teresa; Tardon, Adonina; Consortium, International Lung Cancer; Bishop, D Timothy; Demenais, Florence; Goldstein, Alisa M; Iles, Mark M; Kanetsky, Peter A; Law, Matthew H; Consortium, Ovarian Cancer Association; Amundadottir, Laufey T; Stolzenberg-Solomon, Rachael; Wolpin, Brian M; Consortium, Pancreatic Cancer Cohort; Klein, Alison; Petersen, Gloria; Risch, Harvey; Consortium, The PRACTICAL Consortium Pancreatic Cancer Case-Control; Chanock, Stephen J; Purdue, Mark P; Scelo, Ghislaine; Pharoah, Paul; Kar, Siddhartha; Hung, Rayjean J; Pasaniuc, Bogdan; Kraft, Peter
Source
Journal of the National Cancer Institute. 115(6)
Subject
Language
Abstract
BackgroundThe shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.MethodsWe collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci.ResultsWe observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci.ConclusionsOverall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.