Journal of the National Cancer Institute, 17 3 2023, Pages djad043 Genome-Wide Analyses Characterize Shared Heritability Among Cancers and Identify Novel Cancer Susceptibility Regions. Lindström S, Wang L, Feng H, Majumdar A, Huo S, Macdonald J, Harrison T, Turman C, Chen H, Mancuso N, Bammler T, Breast Cancer Association Consortium (BCAC), Gallinger S, Gruber SB, Gunter MJ, Le Marchand L, Moreno V, Offit K, Colorectal Transdisciplinary Study (CORECT), Colon Cancer Family Registry Study (CCFR), Genetics And Epidemiology Of Colorectal Cancer Consortium (GECCO), de Vivo I, O'Mara TA, Spurdle AB, Tomlinson I, Endometrial Cancer Association Consortium (ECAC), Fitzgerald R, Gharahkhani P, Gockel I, Jankowski J, Macgregor S, Schumacher J, Barnholtz-Sloan J, Bondy ML, Houlston RS, Jenkins RB, Melin B, Wrensch M, Brennan P, Christiani D, Johansson M, Mckay J, Aldrich MC, Amos CI, Landi MT, Tardon A, International Lung Cancer Consortium (ILCCO), Bishop DT, Demenais F, Goldstein AM, Iles MM, Kanetsky PA, Law MH, Ovarian Cancer Association Consortium (OCAC), Amundadottir LT, Stolzenberg-Solomon R, Wolpin BM, Pancreatic Cancer Cohort Consortium (Panscan), Klein A, Petersen G, Risch H, Pancreatic
Background
The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from twelve cancer genome-wide association studies (GWAS) to quantify pair-wise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.
Methods
We collected GWAS summary statistics for twelve solid cancers based on 376,759 cancer cases and 532,864 controls 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 (TWAS) 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.
Results
We observed wide-spread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and TWAS, 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 two cancer types by testing for pleiotropy at known cancer susceptibility loci.
Conclusions
Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer- 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.
