Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.
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., 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) None., Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) None., Colon Cancer Family Registry (CCFR) None., Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT) None., Endometrial Cancer Association Consortium (ECAC) None., Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) None., Melanoma Genetics Consortium (GenoMEL) None., Glioma International Case-Control Study (GICC) None., International Lung Cancer Consortium (ILCCO) None., Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium None., International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph) None., Ovarian Cancer Association Consortium (OCAC) None., Oral Cancer GWAS None., Pancreatic Cancer Case-Control Consortium (PanC4) None., Pancreatic Cancer Cohort Consortium (PanScan) None., Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) None., Renal Cancer GWAS None., Testicular Cancer Consortium (TECAC) None., Chanock SJ., Chatterjee N., Garcia-Closas M.
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.