Genome-Wide Analyses Characterize Shared Heritability Among Cancers and Identify Novel Cancer Susceptibility Regions.

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.

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.

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.

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.

Journal of the National Cancer Institute. 2023 Mar 17 [Epub ahead of print]

Sara Lindström, Lu Wang, Helian Feng, Arunabha Majumdar, Sijia Huo, James Macdonald, Tabitha Harrison, Constance Turman, Hongjie Chen, Nicholas Mancuso, Theo Bammler, Breast Cancer Association Consortium (BCAC) , Steve Gallinger, Stephen B Gruber, Marc J Gunter, Loic Le Marchand, Victor Moreno, Kenneth Offit, Colorectal Transdisciplinary Study (CORECT), Colon Cancer Family Registry Study (CCFR), Genetics And Epidemiology Of Colorectal Cancer Consortium (GECCO) , Immaculata de Vivo, Tracy A O'Mara, Amanda B Spurdle, Ian Tomlinson, Endometrial Cancer Association Consortium (ECAC) , Rebecca Fitzgerald, Puya Gharahkhani, Ines Gockel, Janusz Jankowski, Stuart Macgregor, Johannes Schumacher, Jill Barnholtz-Sloan, Melissa L Bondy, Richard S Houlston, Robert B Jenkins, Beatrice Melin, Margaret Wrensch, Paul Brennan, David Christiani, Mattias Johansson, James Mckay, Melinda C Aldrich, Christopher I Amos, Maria Teresa Landi, Adonina Tardon, International Lung Cancer Consortium (ILCCO) , D Timothy Bishop, Florence Demenais, Alisa M Goldstein, Mark M Iles, Peter A Kanetsky, Matthew H Law, Ovarian Cancer Association Consortium (OCAC) , Laufey T Amundadottir, Rachael Stolzenberg-Solomon, Brian M Wolpin, Pancreatic Cancer Cohort Consortium (Panscan) , Alison Klein, Gloria Petersen, Harvey Risch, Pancreatic Cancer Case-Control Consortium (Panc4) , PRACTICAL Consortium , Stephen J Chanock, Mark P Purdue, Ghislaine Scelo, Paul Pharoah, Siddhartha Kar, Rayjean J Hung, Bogdan Pasaniuc, Peter Kraft

Department of Epidemiology, University of Washington, Seattle, WA, USA., Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA., Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA., Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada., Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA., International Agency for Research on Cancer, World Health Organization, Lyon, France., University of Hawaii Cancer Center, Honolulu, HI, USA., Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain., Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA., Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Cancer Research Centre, The University of Edinburgh, Edinburgh, UK., MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK., Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia., Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany., Institute for Clinical Trials, University College London, Holborn, UK., Center for Human Genetics, University Hospital of Marburg, Marburg, Germany., Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Department of Epidemiology and Population Health, Stanford University, Palo Alto, CA, USA., Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK., Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA., Department of Radiation Sciences, Umeå University, Umeå, Sweden., Department of Neurological Surgery, University of California, San Francisco, CA, USA, San Francisco., Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, USA., Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA., IUOPA. University of Oviedo and CIBERESP, Oviedo, Spain., Leeds Institute of Medical Research at St James's, Leeds Institute for Data Analytics, University of Leeds, Leeds, UK., Université Paris Cité, Institut National de la Santé et de la Recherche Médicale (INSERM), Group of Genomic Epidemiology and Multifactorial Diseases, Paris, France., Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA, MA., Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA., Department of Quantitative Health Science, Mayo Clinic, Rochester, MN, USA., Yale School of Public Health, Chronic Disease Epidemiology, New Haven, CT, USA., Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK., Prosserman Centre for Population Health Research, Lunenfeld-Tanenbuaum Research Institute, Sinai Health System, Toronto, Canada, ON.