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

Hum Mol Genet
Authors
Keywords
Abstract

Prostate cancer is the most common non-skin cancer in males, 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 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)) and PTPRR 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 do not 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.

Year of Publication
2016
Journal
Hum Mol Genet
Volume
25
Issue
2
Pages
371-81
Date Published
2016 Jan 15
ISSN
1460-2083
URL
DOI
10.1093/hmg/ddv462
PubMed ID
26604137
PubMed Central ID
PMC4865031
Links
Grant list
ES011126 / ES / NIEHS NIH HHS / United States
CA54281 / CA / NCI NIH HHS / United States
RC2 CA148085 / CA / NCI NIH HHS / United States
ES007784 / ES / NIEHS NIH HHS / United States
CA88164 / CA / NCI NIH HHS / United States
CA127298 / CA / NCI NIH HHS / United States
CA092579 / CA / NCI NIH HHS / United States
CA1326792 / CA / NCI NIH HHS / United States
UM1 CA164973 / CA / NCI NIH HHS / United States
R01 CA165862 / CA / NCI NIH HHS / United States
U01-CA98233 / CA / NCI NIH HHS / United States
U01-CA98710 / CA / NCI NIH HHS / United States
U01-CA98216 / CA / NCI NIH HHS / United States
1U58DP000807-3 / DP / NCCDPHP CDC HHS / United States
CA056678 / CA / NCI NIH HHS / United States
CA37429 / CA / NCI NIH HHS / United States
HG004726 / HG / NHGRI NIH HHS / United States
CA68578 / CA / NCI NIH HHS / United States
CA63464 / CA / NCI NIH HHS / United States
RC2 CA 148085 / CA / NCI NIH HHS / United States
C5047/A8384 / Cancer Research UK / United Kingdom
CA082664 / CA / NCI NIH HHS / United States
Intramural NIH HHS / United States
CA148537 / CA / NCI NIH HHS / United States
CA164973 / CA / NCI NIH HHS / United States
CA148085 / CA / NCI NIH HHS / United States
R01 CA 165862 / CA / NCI NIH HHS / United States
U01-CA98758 / CA / NCI NIH HHS / United States
CA092447 / CA / NCI NIH HHS / United States
CA68485 / CA / NCI NIH HHS / United States
U01 CA164973 / CA / NCI NIH HHS / United States
S06GM08016 / GM / NIGMS NIH HHS / United States