Association of rare, recurrent nonsynonymous variants in the germline of prostate cancer patients of African ancestry

Abstract

Background Although men of African ancestry (AA) have the highest mortality rate from prostate cancer (PCa), relatively little is known about the germline variants that are associated with PCa risk in AA men. The goal of this study is to systematically evaluate rare, recurrent nonsynonymous variants across the exome for their association with PCa in AA men. Methods Whole exome sequencing (WES) of germline DNA in two AA PCa patient cohorts of Johns Hopkins Hospital (N = 960) and Wayne State University (N = 747) was performed. All nonsynonymous variants presented in both case cohorts, with a carrier rate between 0.3% and 1%, were identified. Their carrier rates were compared with rates from 8,128 African/African American (AFR) control subjects from The Genome Aggregation Database (gnomAD) using Fisher’s exact test. Significant variants, defined as false discovery rate (FDR) adjusted p-value ≤0.05, were further evaluated in AA PCa cases (N = 132) and controls (N = 1,184) from the UK Biobank (UKB). Results Two variants reached a pre-specified statistical significance level. The first was p.R14Q in GPRC5C (found in 0.47% of PCa cases and 0.01% of population controls); odds ratio (OR) for PCa was 37.46 (95%CI 4.68-299.72), pexact=7.01E-06, FDR adjusted p-value = 0.05. The second was p.R511Q in IGF1R (found in 0.53% of PCa cases and 0.01% of population controls); OR for PCa was 21.54 (95%CI 4.65–99.76), pexact=5.51E-06, FDR adjusted p-value = 0.05. The mean percentage of African ancestry was similar between variant carriers and non-carriers of each variant, p > 0.05. In the UKB AA men, GPRC5C R14Q was 0.76% and 0.08% in cases and controls, respectively, OR for PCa was 9.00 (95%CI 0.56-145.23), pexact =0.19. However, IGF1R R511Q was not found in cases or controls. Conclusions This WES study identified two rare, recurrent nonsynonymous PCa risk-associated variants in AA. Confirmation in additional large populations of AA PCa cases and controls is required.