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Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

About this Publication
Title
Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.
Pubmed ID
32620889 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Nat Commun. 2020 Jul 3; Volume 11 (Issue 1): Pages 3353
Authors
Zhang YD, Hurson AN, Zhang H, Choudhury PP, Easton DF, Milne RL, Simard J, Hall P, Michailidou K, Dennis J, Schmidt MK, Chang-Claude J, Gharahkhani P, Whiteman D, Campbell PT, Hoffmeister M, Jenkins M, Peters U, Hsu L, Gruber SB, ...show more Casey G, Schmit SL, O'Mara TA, Spurdle AB, Thompson DJ, Tomlinson I, De Vivo I, Landi MT, Law MH, Iles MM, Demenais F, Kumar R, MacGregor S, Bishop DT, Ward SV, Bondy ML, Houlston R, Wiencke JK, Melin B, Barnholtz-Sloan J, Kinnersley B, Wrensch MR, Amos CI, Hung RJ, Brennan P, McKay J, Caporaso NE, Berndt SI, Birmann BM, Camp NJ, Kraft P, Rothman N, Slager SL, Berchuck A, Pharoah PDP, Sellers TA, Gayther SA, Pearce CL, Goode EL, Schildkraut JM, Moysich KB, Amundadottir LT, Jacobs EJ, Klein AP, Petersen GM, Risch HA, Stolzenberg-Solomon RZ, Wolpin BM, Li D, Eeles RA, Haiman CA, Kote-Jarai Z, Schumacher FR, Al Olama AA, Purdue MP, Scelo G, Dalgaard MD, Greene MH, Grotmol T, Kanetsky PA, McGlynn KA, Nathanson KL, Turnbull C, Wiklund F, Breast Cancer Association Consortium (BCAC), Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), Colon Cancer Family Registry (CCFR), Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT), Endometrial Cancer Association Consortium (ECAC), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Melanoma Genetics Consortium (GenoMEL), Glioma International Case-Control Study (GICC), International Lung Cancer Consortium (ILCCO), Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph), Ovarian Cancer Association Consortium (OCAC), Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium (PanC4), Pancreatic Cancer Cohort Consortium (PanScan), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), Renal Cancer GWAS, Testicular Cancer Consortium (TECAC), Chanock SJ, Chatterjee N, Garcia-Closas M
Affiliations
  • Department of Statistics and Actuarial Science, Faculty of Science, The University of Hong Kong, Hong Kong SAR, China.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
  • Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
  • Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Québec City, QC, Canada.
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
  • Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
  • Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
...show more
  • Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
  • Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
  • Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institution, Tampa, FL, USA.
  • Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
  • Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
  • Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
  • Université de Paris, UMRS-1124, Institut National de la Santé et de la Recherche Médicale (INSERM), 75006, Paris, France.
  • Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK.
  • Centre for Genetic Origins of Health and Disease, School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia.
  • Department of Medicine, Section of Epidemiology and Population Sciences, Baylor College of Medicine, Houston, TX, USA.
  • Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Department of Neurological Surgery, School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Department of Radiation Sciences Oncology, Umeå University, Umeå, Sweden.
  • Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • Institute for Clinical and Translational Research, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
  • Lunenfeld-Tanenbuaum Research Institute, Sinai Health System, Toronto, ON, Canada.
  • International Agency for Research on Cancer, World Health Organization, Lyon, France.
  • Division of Hematology and Hematological Malignancies, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Division of Biomedical Statistics & Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
  • Department of Gynecologic Oncology, Duke University Medical Center, Durham, NC, USA.
  • Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Division of Epidemiology, Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
  • Rollins School of Public Health, Emory University, Atlanta, GA, USA.
  • Division of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
  • Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • Chronic Disease Epidemiology, Yale School of Medicine, New Haven, CT, USA.
  • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Division of Cancer Medicine, GI Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, UK.
  • Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
  • Strangeways Research Laboratory, Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
  • Department of Growth and Reproduction, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
  • Clinical Genetics Branch, Division of Cancer Genetics and Epidemiology, National Cancer Institute, Rockville, MD, USA.
  • Cancer Registry of Norway, Oslo, Norway.
  • Division of Translational Health and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. nchatte2@jhu.edu.
Abstract

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.

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