Whole-exome sequencing of over 4100 men of African ancestry and prostate cancer risk

Prostate cancer is themost commonnon-skincancer inmales,with a ~1.5-2-fold higher incidence in African American men when compared with whites. Epidemiologic evidence supports a large heritable contribution to prostate cancer, with over 100 susceptibility loci identified to date that can explain ~33% of the familial risk. To explore the contributionof both rare and common variation in coding regions to prostate cancer risk, we sequenced the exomes of 2165 prostate cancer cases and 2034 controls of African ancestry at a mean coverage of 10.1×. We identified 395 220 coding variants down to 0.05% frequency [57% nonsynonymous (NS), 42% synonymous and 1% gain or loss of stop codon or splice site variant] in 16 751 genes with the strongest associations observed in SPARCL1 on 4q22.1 (rs13051, Ala49Asp, OR = 0.78, P=1.8×10-6) andPTPRR on 12q15 (rs73341069, Val239Ile, OR= 1.62, P=2.5×10-5). In gene-level testing, the two most significant genes were C1orf100 (P=2.2×10-4) and GORAB (P=2.3×10-4).We did not observe exome-wide significant associations (after correcting formultiple hypothesis testing) in single variant or gene-level testing in the overall case-control or case-case analyses of disease aggressiveness. In this firstwhole-exome sequencing studyofprostate cancer, our findings donot provide strong support for the hypothesis thatNS coding variants down to 0.5-1.0% frequency have large effects on prostate cancer risk in men of African ancestry. Higher-coverage sequencing efforts in larger samples will be needed to study rarer variants with smaller effect sizes associated with prostate cancer risk.