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Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions.
Pubmed ID
36929942 (View this publication on the PubMed website)
Digital Object Identifier
J Natl Cancer Inst. 2023 Jun 8; Volume 115 (Issue 6): Pages 712-732
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, more 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 DC, 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 Cancer Case-Control Consortium (Panc4), The PRACTICAL Consortium, Chanock SJ, Purdue MP, Scelo G, Pharoah P, Kar S, Hung RJ, Pasaniuc B, Kraft P
  • 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. more
  • 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, San Francisco, CA, USA.
  • 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.
  • University Institute of Oncology of the Principality of Asturias (IUOPA), University of Oviedo and Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Oviedo, Spain.
  • Leeds Institute for Data Analytics, University of Leeds, Leeds, UK.
  • Université Paris Cité, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-1124, 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, MA, USA.
  • 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, ON, Canada.

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.

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