Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions
Authors: Lindström Sara , Wang Lu , Feng Helian , Majumdar Arunabha , Huo Sijia , Macdonald James , Harrison Tabitha , Turman Constance , Chen Hongjie , Mancuso Nicholas , Bammler Theo ,   Breast Cancer Association Consortium (BCAC), Gallinger Steve , Gruber Stephen B , Gunter Marc J , Le Marchand Loic , Moreno Victor , Offit Kenneth ,   Colorectal Transdisciplinary Study (CORECT), Colon Cancer Family Registry Study (CCFR), Genetics And Epidemiology Of Colorectal Cancer Consortium (GECCO), De Vivo Immaculata , O’Mara Tracy A , Spurdle Amanda B , Tomlinson Ian ,   Endometrial Cancer Association Consortium (ECAC), 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 ,   International Lung Cancer Consortium (ILCCO), Bishop D Timothy , Demenais Florence , Goldstein Alisa M , Iles Mark M , Kanetsky Peter A , Law Matthew H ,   Ovarian Cancer Association Consortium (OCAC), Amundadottir Laufey T , Stolzenberg-Solomon Rachael , Wolpin Brian M ,   Pancreatic Cancer Cohort Consortium (Panscan), Klein Alison , Petersen Gloria , Risch Harvey ,   Pancreatic Cancer Case-Control Consortium (Panc4), The PRACTICAL Consortium, Chanock Stephen J , Purdue Mark P , Scelo Ghislaine , Pharoah Paul , Kar Siddhartha , Hung Rayjean J , Pasaniuc Bogdan , Kraft Peter 
Published: March 2023

Abstract

Background
The 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.

Methods
We 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.

Results
We 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.

Conclusions
Overall, 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.