Aggregate effect of P/LP/D carrier status across BRCA2, ATM, NBN, and PALB2 genes on PCa risk in African ancestry men.

Association of PRS and PCa risk in African ancestry men.

Aggregate effect of PRS and P/LP/D variants in BRCA1, RAD50, MLH1, and MSH6 on PCa risk in African ancestry men.

Carrier frequency of P/LP/D variants in BRCA2, ATM, NBN, and PALB2 by PRS category in African ancestry men.

Weighted independent effect of PRS and P/LP/D variants in BRCA2, ATM, NBN, and PALB2 on PCa risk in African ancestry men.

Aggregate effect of PRS and P/LP/D variants in BRCA2, ATM, NBN, and PALB2 on PCa risk in African ancestry men.

Absolute risk of PCa by PRS and P/LP/D variants in BRCA2, ATM, NBN, and PALB2 combined in African ancestry men.

Aggregate effect of P/LP/D carrier status across BRCA1, RAD50, MLH1, and MSH6 genes on PCa risk in African ancestry men.

Abstract Prostate cancer risk is influenced by rare and common germline variants. We examined the aggregate association of rare germline pathogenic/likely pathogenic/deleterious (P/LP/D) variants in ATM, BRCA2, PALB2, and NBN with a polygenic risk score (PRS) on prostate cancer risk among 1,796 prostate cancer cases (222 metastatic) and 1,424 controls of African ancestry. Relative to P/LP/D non-carriers at average genetic risk (33%–66% of PRS), men with low (0%–33%) and high (66%–100%) PRS had Odds Ratios (ORs) for overall prostate cancer of 2.08 [95% confidence interval (CI) = 0.58–7.49] and 18.06 (95% CI = 4.24–76.84) among P/LP/D carriers and 0.57 (95% CI = 0.46–0.71) and 3.02 (95% CI = 2.53–3.60) among non-carriers, respectively. The OR for metastatic prostate cancer was 2.73 (95% CI = 0.24–30.54) and 28.99 (95% CI = 4.39–191.43) among P/LP/D carriers and 0.54 (95% CI = 0.31–0.95) and 3.22 (95% CI = 2.20–4.73) among non-carriers, for men with low and high PRS, respectively. Lifetime absolute risks of overall prostate cancer increased with PRS (low to high) from 9.8% to 51.5% in P/LP/D carriers and 5.5% to 23.9% in non-carriers. Lifetime absolute risks of metastatic prostate cancer increased with PRS from 1.9% to 18.1% in P/LP/D carriers and 0.3% to 2.2% in non-carriers These findings suggest that assessment of prostate cancer risk for rare variant carriers should include PRS status. Significance: These findings highlight the importance of considering rare and common variants to comprehensively assess prostate cancer risk in men of African ancestry.

Rare germline pathogenic, likely pathogenic, or deleterious (P/LP/D) variants (n=51) in BRCA2, ATM, NBN, and PALB2 identified among men of African ancestry.

Absolute risk of metastatic PCa by PRS and P/LP/D variants in BRCA2, ATM, NBN, and PALB2 independently in African ancestry men.

Association of PRS and PCa risk in African American men.

Association of PRS and PCa risk in Ugandan men.

Carrier frequency of P/LP/D variants in BRCA2, ATM, NBN, and PALB2 by family history in African ancestry men.

Descriptive characteristics of prostate cancer cases and controls

Interaction effect of PRS and P/LP/D carrier status across BRCA2, ATM, NBN, and PALB2 genes on PCa risk in African ancestry men. LRT: Likelihood ratio test.

Aggregate effect of P/LP/D carrier status across BRCA2, ATM, NBN, and PALB2 genes on PCa risk in Ugandan men.

Weighted aggregate effects of PRS and P/LP/D variants in BRCA2, ATM, NBN, and PALB2 on PCa risk in African ancestry men.

Aggregate effect of P/LP/D carrier status across BRCA2, ATM, NBN, and PALB2 genes on PCa risk in African American men.

Aggregate effect of PRS and P/LP/D variants in BRCA2, ATM, NBN, and PALB2 on PCa risk in African American men.