Assessment of Polygenic Architecture and Risk Prediction based on Common Variants Across Fourteen Cancers
Authors: Zhang Yan , Wilcox 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 , Birmann Brenda M. , Camp Nicola J. , Kraft Peter , Rothman Nathaniel , Slager Susan L. , Berchuck Andrew , Pharoah Paul DP. , 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. , Olama Ali Amin Al , 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 ,   BCAC,   BEACON,   CCFR,   CORECT,   ECAC,   GECCO,   GenoMEL,   GICC,   ILCCO,   Integral,   InterLymph,   OCAC,   Oral Cancer GWAS,   PANC4,   PanScan,   PRACTICAL,   Renal Cancer GWAS,   TECAC, Chanock Stephen J. , Chatterjee Nilanjan , Garcia-Closas Montserrat 
Published: August 2019

We analyzed summary-level data from genome-wide association studies (GWAS) of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) contributing to risk, as well as the distribution of their associated effect sizes. All cancers evaluated showed polygenicity, involving at a minimum thousands of independent susceptibility variants. For some malignancies, particularly chronic lymphoid leukemia (CLL) and testicular cancer, there are a larger proportion of variants with larger effect sizes than those for other cancers. In contrast, most variants for lung and breast cancers have very small associated effect sizes. For different cancer sites, we estimate a wide range of GWAS sample sizes, required to explain 80% of GWAS heritability, varying from 60,000 cases for CLL 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, compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that polygenic risk scores have substantial potential for risk stratification for relatively common cancers such as breast, prostate and colon, but limited potential for other cancer sites because of modest heritability and lower disease incidence.