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- Title
Whole-exome sequencing of over 4100 men of African ancestry and prostate cancer risk.
- Authors
Rand, Kristin A.; Rohland, Nadin; Tandon, Arti; Stram, Alex; Xin Sheng; Do, Ron; Pasaniuc, Bogdan; Allen, Alex; Quinque, Dominique; Mallick, Swapan; Le Marchand, Loic; Kaggwa, Sam; Lubwama, Alex; Stram, Daniel O.; Watya, Stephen; Henderson, Brian E.; Conti, David V.; Reich, David; Haiman, Christopher A.
- Abstract
Prostate cancer is themost common non-skin cancer inmales,with a∼1.5–2-foldhigher incidence inAfricanAmericanmenwhen 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 contribution of 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% non-synonymous (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 for multiple hypothesis testing) in single variant or gene-level testing in the overall case–control or case–case analyses of disease aggressiveness. In this first whole-exome sequencing study of prostate cancer, our findings donot provide strong support for the hypothesis that NS 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.
- Publication
Human Molecular Genetics, 2016, Vol 25, Issue 2, p371
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddv462