Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers
Authors: Zhang Yan Dora , Hurson Amber N. , Zhang Haoyu , Choudhury Parichoy Pal , Easton Douglas F. , Milne Roger L. , Simard Jacques , Hall Per , Michailidou Kyriaki , Dennis Joe , Schmidt Marjanka K. , Chang-Claude Jenny , Gharahkhani Puya , Whiteman David , Campbell Peter T. , Hoffmeister Michael , Jenkins Mark , Peters Ulrike , Hsu Li , Gruber Stephen B. , Casey Graham , Schmit Stephanie L. , O’Mara Tracy A. , Spurdle Amanda B. , Thompson Deborah J. , Tomlinson Ian , De Vivo Immaculata , Landi Maria Teresa , Law Matthew H. , Iles Mark M. , Demenais Florence , Kumar Rajiv , MacGregor Stuart , Bishop D. Timothy , Ward Sarah V. , Bondy Melissa L. , Houlston Richard , Wiencke John K. , Melin Beatrice , Barnholtz-Sloan Jill , Kinnersley Ben , Wrensch Margaret R. , Amos Christopher I. , Hung Rayjean J. , Brennan Paul , McKay James , Caporaso Neil E. , Berndt Sonja I. , Birmann Brenda M. , Camp Nicola J. , Kraft Peter , Rothman Nathaniel , Slager Susan L. , Berchuck Andrew , Pharoah Paul D. P. , Sellers Thomas A. , Gayther Simon A. , Pearce Celeste L. , Goode Ellen L. , Schildkraut Joellen M. , Moysich Kirsten B. , Amundadottir Laufey T. , Jacobs Eric J. , Klein Alison P. , Petersen Gloria M. , Risch Harvey A. , Stolzenberg-Solomon Rachel Z. , Wolpin Brian M. , Li Donghui , Eeles Rosalind A. , Haiman Christopher A. , Kote-Jarai Zsofia , Schumacher Fredrick R. , Al Olama Ali Amin , Purdue Mark P. , Scelo Ghislaine , Dalgaard Marlene D. , Greene Mark H. , Grotmol Tom , Kanetsky Peter A. , McGlynn Katherine A. , Nathanson Katherine L. , Turnbull Clare , Wiklund Fredrik ,   Breast Cancer Association Consortium (BCAC), Easton Douglas F. , Milne Roger L. , Simard Jacques , Hall Per , Michailidou Kyriaki , Dennis Joe , Schmidt Marjanka K. , Chang-Claude Jenny ,   Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), Gharahkhani Puya , Whiteman David ,   Colon Cancer Family Registry (CCFR), Campbell Peter T. , Hoffmeister Michael , Jenkins Mark , Peters Ulrike , Hsu Li , Gruber Stephen B. , Casey Graham , Schmit Stephanie L. ,   Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT), Campbell Peter T. , Hoffmeister Michael , Jenkins Mark , Peters Ulrike , Hsu Li , Gruber Stephen B. , Casey Graham , Schmit Stephanie L. ,   Endometrial Cancer Association Consortium (ECAC), O’Mara Tracy A. , Spurdle Amanda B. , Thompson Deborah J. , Tomlinson Ian , De Vivo Immaculata ,   Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Campbell Peter T. , Hoffmeister Michael , Jenkins Mark , Peters Ulrike , Hsu Li , Gruber Stephen B. , Casey Graham , Schmit Stephanie L. ,   Melanoma Genetics Consortium (GenoMEL), Landi Maria Teresa , Law Matthew H. , Iles Mark M. , Demenais Florence , Kumar Rajiv , MacGregor Stuart , Bishop David T. , Ward Sarah V. ,   Glioma International Case-Control Study (GICC), Bondy Melissa L. , Houlston Richard , Wiencke John K. , Melin Beatrice , Barnholtz-Sloan Jill , Kinnersley Ben , Wrensch Margaret R. ,   International Lung Cancer Consortium (ILCCO), Amos Christopher I. , Hung Rayjean J. , Brennan Paul , McKay James , Caporaso Neil E. ,   Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, Amos Christopher I. , Hung Rayjean J. , Brennan Paul , McKay James , Caporaso Neil E. ,   International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph), Berndt Sonja I. , Birmann Brenda M. , Camp Nicola J. , Kraft Peter , Rothman Nathaniel , Slager Susan L. ,   Ovarian Cancer Association Consortium (OCAC), Berchuck Andrew , Pharoah Paul D. P. , Sellers Thomas A. , Gayther Simon A. , Pearce Celeste L. , Goode Ellen L. , Schildkraut Joellen M. , Moysich Kirsten B. ,   Oral Cancer GWAS, Amos Christopher I. , Brennan Paul , McKay James ,   Pancreatic Cancer Case-Control Consortium (PanC4), Amundadottir Laufey T. , Jacobs Eric J. , Klein Alison P. , Petersen Gloria M. , Risch Harvey A. , Stolzenberg-Solomon Rachel Z. , Wolpin Brian M. , Li Donghui ,   Pancreatic Cancer Cohort Consortium (PanScan), Amundadottir Laufey T. , Jacobs Eric J. , Klein Alison P. , Petersen Gloria M. , Risch Harvey A. , Stolzenberg-Solomon Rachel Z. , Wolpin Brian M. , Li Donghui ,   Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), Eeles Rosalind A. , Haiman Christopher A. , Kote-Jarai Zsofia , Schumacher Fredrick R. , Al Olama Ali Amin ,   Renal Cancer GWAS, Purdue Mark P. , Scelo Ghislaine ,   Testicular Cancer Consortium (TECAC), Dalgaard Marlene D. , Greene Mark H. , Grotmol Tom , Kanetsky Peter A. , McGlynn Katherine A. , Nathanson Katherine L. , Turnbull Clare , Wiklund Fredrik , Chanock Stephen J. , Chatterjee Nilanjan , Garcia-Closas Montserrat 
Published: July 2020

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.