PURPOSE In studies of men of European ancestry, rare pathogenic variants in DNA repair pathway genes have been shown to be associated with risk of aggressive prostate cancer. The contribution of rare coding variation to prostate cancer risk in men of African ancestry has not been established. METHODS We sequenced a panel of 19 DNA repair and cancer predisposition genes in 2,453 African American and 1,151 Ugandan cases and controls with prostate cancer. Rare variants were classified as pathogenic or putatively functionally disruptive and examined in association with prostate cancer risk and disease aggressiveness in gene and pathway-level association analyses. RESULTS Pathogenic variants were found in 75 of 2,098 cases (3.6%) and 31 of 1,481 controls (2.1%; odds ratio [OR], 1.82; 95% CI, 1.19 to 2.79; P = .0044), with the association being stronger for more aggressive disease phenotypes (OR, 3.10; 95% CI, 1.54 to 6.23; P = .0022). The highest risks for aggressive disease were observed with pathogenic variants in the ATM, BRCA2, PALB2, and NBN genes, with ORs ranging from approximately 4 to 15 in the combined study sample of African American and Ugandan men. Rare, nonpathogenic, nonsynonymous variants did not have a major impact on risk of overall prostate cancer or disease aggressiveness. CONCLUSION Rare pathogenic variants in DNA repair genes have appreciable effects on risk of aggressive prostate cancer in men of African ancestry. These findings have potential implications for panel testing and risk stratification in this high-risk population.

Background Prostate disorders are among the leading causes of morbidity and mortality in men above the age of 40 years globally. Serum prostate-specific antigen (PSA) levels may be used to screen men at risk of prostate cancer and determine choice of medical treatment in benign prostatic hyperplasia (BPH) and evaluation of patients with prostatitis, while prostate sonography determines prostate volume (PV) and detects nodules. BPH may exhibit distinct hypoechoic, isoechoic, or hyperechoic nodules in the transition zone, whereas hypoechoic nodules in the peripheral zone are diagnostic for prostate cancer in over 50% of cases. In this study, we aimed at determining the relationship between serum PSA levels and transrectal prostate sonographic findings among asymptomatic Ugandan males. Methods Ugandan males above 30 years of age or older without lower urinary tract symptoms were cross-sectionally enrolled into the study. Serum PSA determination and transrectal ultrasound were performed. Association between PSA levels and PV was assessed using Spearman’s correlation coefficients (ρ). Results A total of 277 men were studied. The median serum PSA level was 1 (95% CI: 1–2). Most (n = 217, 78.3%) participants had serum PSA levels ≤ 4 ng/ml. The median sonographic PV was 26 (95% CI: 26–29) mls. One hundred and fifty-five (56.0%) participants had PV between 25 and 50 mls. Both PSA levels and PV progressively increased with age from 0.9 ng/ml and 22 mls in the 30–39 year age group to 7 ng/ml and 38 mls in the 60–69 year age group, respectively. PSA levels weakly correlated with PV (ρ = 0.27) (p < 0.0001). One hundred and thirty (47%) participants had prostatic nodules. Of these, 100 (77%) had features of benign nodules and 23% had suspicious nodules for prostate cancer. The median (range) serum PSA level in those with nodules was 2.0 (0.1–16.0) ng/ml and for those without nodules was 1.1 (0.1–8.0) ng/ml (p < 0.0001). Conclusions Serum PSA has a weak direct correlation with PV and not a reliable marker for the prediction of presence or absence of prostatic nodules in asymptomatic adult males.