Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers
Yan Zhang(University of Hong Kong), Amber N. Hurson(University of North Carolina at Chapel Hill), Haoyu Zhang(Johns Hopkins University), Parichoy Pal Choudhury(National Cancer Institute), Douglas F. Easton(University of Cambridge), Roger L. Milne(The University of Melbourne), Jacques Simard(Centre hospitalier universitaire de Québec), Per Hall(Karolinska Institutet), Kyriaki Michailidou(University of Cambridge), Joe Dennis(University of Cambridge), Marjanka K. Schmidt(The Netherlands Cancer Institute), Jenny Chang‐Claude(Universität Hamburg), Puya Gharahkhani(QIMR Berghofer Medical Research Institute), David C. Whiteman(QIMR Berghofer Medical Research Institute), Peter T. Campbell(American Cancer Society), Michael Hoffmeister(German Cancer Research Center), Mark Jenkins(The University of Melbourne), Ulrike Peters(Fred Hutch Cancer Center), Li Hsu(Fred Hutch Cancer Center), Stephen B. Gruber(University of Southern California), Graham Casey(Office of Public Health Genomics), Stephanie L. Schmit(Moffitt Cancer Center), Tracy A. O’Mara(QIMR Berghofer Medical Research Institute), Amanda B. Spurdle(QIMR Berghofer Medical Research Institute), Deborah J. Thompson(University of Cambridge), Ian Tomlinson(Centre for Human Genetics), Immaculata De Vivo(Brigham and Women's Hospital), Maria Teresa Landi(National Cancer Institute), Matthew H. Law(QIMR Berghofer Medical Research Institute), Mark M. Iles(University of Leeds), Florence Démenais(Inserm), Rajiv Kumar(German Cancer Research Center), Stuart MacGregor(QIMR Berghofer Medical Research Institute), D. Timothy Bishop(University of Leeds), Sarah V. Ward(The University of Western Australia), Melissa L. Bondy(Baylor College of Medicine), Richard S. Houlston(Institute of Cancer Research), John K. Wiencke(University of California, San Francisco), Beatrice Melin(Umeå University), Jill S. Barnholtz‐Sloan(Case Western Reserve University), Ben Kinnersley(Institute of Cancer Research), Margaret Wrensch(University of California, San Francisco), Christopher I. Amos(Baylor College of Medicine), Rayjean J. Hung(Lunenfeld-Tanenbaum Research Institute), Paul Brennan(Centre international de recherche sur le cancer), James McKay(Centre international de recherche sur le cancer), Neil E. Caporaso(National Cancer Institute), Sonja I. Berndt(National Cancer Institute), Brenda M. Birmann(Brigham and Women's Hospital), Nicola J. Camp(University of Utah), Peter Kraft(Harvard University), Nathaniel Rothman(National Cancer Institute), Susan L. Slager(Mayo Clinic in Florida), Andrew Berchuck(Duke Medical Center), Paul D.P. Pharoah(University of Cambridge), Thomas A. Sellers(Moffitt Cancer Center), Simon A. Gayther(Cedars-Sinai Medical Center), Celeste Leigh Pearce(University of Southern California), Ellen L. Goode(Mayo Clinic in Florida), Joellen M. Schildkraut(Roswell Park Comprehensive Cancer Center), Kirsten B. Moysich(Roswell Park Comprehensive Cancer Center), Laufey T. Ámundadóttir(American Cancer Society), Eric J. Jacobs(American Cancer Society), Alison P. Klein(Johns Hopkins University), Gloria M. Petersen(Yale University), Harvey A. Risch(Yale University), Rachel Z. Stolzenberg-Solomon(Dana-Farber Cancer Institute), Brian M. Wolpin(The University of Texas MD Anderson Cancer Center), Donghui Li(The University of Texas MD Anderson Cancer Center), Rosalind A. Eeles(University of Southern California), Christopher A. Haiman(University of Southern California), Zsofia Kote‐Jarai(Institute of Cancer Research), Fredrick R. Schumacher(University of Cambridge), Ali Amin Al Olama(University of Cambridge), Mark P. Purdue(National Cancer Institute), Ghislaine Scelo(Copenhagen University Hospital), Marlene Dalgaard(Copenhagen University Hospital), Mark H. Greene(Cancer Registry of Norway), Tom Grotmol(Moffitt Cancer Center), Peter A. Kanetsky(Moffitt Cancer Center), Katherine A. McGlynn(Translational Therapeutics (United States)), Katherine L. Nathanson(Institute of Cancer Research), Clare Turnbull(Institute of Cancer Research), Fredrik Wiklund(University of Cambridge), Douglas F. Easton(The University of Melbourne), Roger L. Milne(The University of Melbourne), Jacques Simard(Karolinska Institutet), Per Hall(Karolinska Institutet), Kyriaki Michailidou(University of Cambridge), Joe Dennis(University of Cambridge), Marjanka K. Schmidt(Universität Hamburg), Jenny Chang‐Claude(Universität Hamburg), Puya Gharahkhani(QIMR Berghofer Medical Research Institute), David C. Whiteman(American Cancer Society), Colon Cancer Family Registry (CCFR)(German Cancer Research Center), Peter T. Campbell(American Cancer Society), Michael Hoffmeister(German Cancer Research Center), Mark Jenkins(The University of Melbourne), Ulrike Peters(University of Southern California), Li Hsu(Office of Public Health Genomics), Stephen B. Gruber(University of Southern California), Graham Casey(American Cancer Society), Stephanie L. Schmit(German Cancer Research Center), Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT)(The University of Melbourne), Peter T. Campbell(American Cancer Society), Michael Hoffmeister(German Cancer Research Center), Mark A. Jenkins(University of Southern California), Ulrike Peters(Office of Public Health Genomics), Li Hsu(Moffitt Cancer Center), Stephen B. Gruber(University of Southern California), Graham Casey(QIMR Berghofer Medical Research Institute), Stephanie L. Schmit(University of Cambridge), Tracy A. O’Mara(Centre for Human Genetics), Amanda B. Spurdle(Harvard University), Deborah J Thompson(American Cancer Society), Ian Tomlinson(Centre for Human Genetics), Immaculata De Vivo(Brigham and Women's Hospital), Peter T. Campbell(American Cancer Society), Michael Hoffmeister(German Cancer Research Center), Mark Jenkins(University of Southern California), Ulrike Peters(Office of Public Health Genomics), Li Hsu(Moffitt Cancer Center), Stephen B. Gruber(University of Southern California), Graham Casey(QIMR Berghofer Medical Research Institute), Stephanie L. Schmit(University of Leeds), Maria Teresa Landi(Inserm), Matthew H. Law(German Cancer Research Center), Mark M. Iles(University of Leeds), Florence Démenais(University of Leeds), Rajiv Kumar(The University of Western Australia), Stuart MacGregor(Baylor College of Medicine), D. Timothy Bishop(University of Leeds), Sarah V. Ward(The University of Western Australia), Glioma International Case-Control Study (GICC)(Umeå University), Melissa L. Bondy(Baylor College of Medicine), Richard S. Houlston(Institute of Cancer Research), John K. Wiencke(University of California, San Francisco), Beatrice Melin(Baylor College of Medicine), Jill S. Barnholtz‐Sloan(Lunenfeld-Tanenbaum Research Institute), Ben Kinnersley(Institute of Cancer Research), Margaret R. Wrensch(University of California, San Francisco), Christopher I. Amos(Baylor College of Medicine), Rayjean J. Hung(Baylor College of Medicine), Paul Brennan(Lunenfeld-Tanenbaum Research Institute), James McKay(Centre international de recherche sur le cancer), Neil E. Caporaso(National Cancer Institute), Christopher I. Amos(Baylor College of Medicine), Rayjean J. Hung(Lunenfeld-Tanenbaum Research Institute), Paul Brennan(Brigham and Women's Hospital), James McKay(University of Utah), Neil E. Caporaso(Harvard University), Sonja I. Berndt(National Cancer Institute), Brenda M. Birmann(Brigham and Women's Hospital), Nicola J. Camp(University of Utah), Peter Kraft(Harvard University), Nathaniel Rothman(Moffitt Cancer Center), Susan L. Slager(Cedars-Sinai Medical Center), Andrew Berchuck(University of Michigan), Paul D. P. Pharoah(University of Cambridge), Thomas A. Sellers(Emory University), Simon A. Gayther(Cedars-Sinai Medical Center), Celeste Leigh Pearce(University of Southern California), Ellen L. Goode(Mayo Clinic in Florida), Joellen M. Schildkraut(Emory University), Kirsten B. Moysich(Roswell Park Comprehensive Cancer Center), Oral Cancer GWAS(American Cancer Society), Christopher I. Amos(Johns Hopkins University), Paul Brennan(Mayo Clinic in Florida), James McKay(Yale University), Laufey T. Amundadottir(National Institutes of Health), Eric J. Jacobs(American Cancer Society), Alison P. Klein(The University of Texas MD Anderson Cancer Center), Gloria M. Petersen(National Institutes of Health), Harvey A. Risch(American Cancer Society), Rachel Z. Stolzenberg-Solomon(Johns Hopkins University), Brian M. Wolpin(Dana-Farber Cancer Institute), Donghui Li(The University of Texas MD Anderson Cancer Center), Laufey T. Amundadottir(National Institutes of Health), Eric J. Jacobs(American Cancer Society), Alison P. Klein(The University of Texas MD Anderson Cancer Center), Gloria M. Petersen(Institute of Cancer Research), Harvey A. Risch(University of Southern California), Rachel Z. Stolzenberg-Solomon(Institute of Cancer Research), Brian M. Wolpin(Dana-Farber Cancer Institute), Donghui Li(The University of Texas MD Anderson Cancer Center), Rosalind A. Eeles(Institute of Cancer Research), Christopher A. Haiman(University of Southern California), Zsofia Kote‐Jarai(Institute of Cancer Research), Fredrick R. Schumacher(National Cancer Institute), Ali Amin Al Olama(University of Cambridge), Renal Cancer GWAS(Moffitt Cancer Center), Mark P. Purdue(National Cancer Institute), Ghislaine Scelo(Translational Therapeutics (United States)), Marlene Dalgaard(Institute of Cancer Research), Mark H. Greene(Karolinska Institutet), Tom Grotmol(Cancer Registry of Norway), Peter A. Kanetsky(Johns Hopkins University), Katherine A. McGlynn(National Cancer Institute), Katherine L. Nathanson(Translational Therapeutics (United States)), Clare Turnbull(Institute of Cancer Research), Fredrik Wiklund(Karolinska Institutet), Stephen J. Chanock(National Cancer Institute), Nilanjan Chatterjee(Johns Hopkins University), Montserrat García‐Closas(National Cancer Institute)
Cited by 132Open Access
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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