Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer

Abstract

Background: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease.

Methods: Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency < 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided.

Results: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4).

Conclusions: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.

Figure 1.

Distribution of 289 rare pathogenic/likely pathogenic/deleterious variants among 24 candidate prostate cancer DNA repair genes. Genes (no. of variants) are shown.

Figure 2.

Carrier frequencies and effects of candidate prostate cancer (PCa) DNA repair genes (DRG). Carrier frequencies (A) and effects (B) of candidate PCa genes by disease aggressiveness (RAD51C, RAD51D, SLX4, and XRCC2 were not evaluated in gene-based tests, as our sample had ≤5 carriers). Aggregate carrier frequencies (C) and aggregate effects (D) of DNA repair genes, sequentially removing the strongest genes. Left panels aggregate all DNA repair genes, including and excluding the 24 candidate PCa DRG genes. Right panels aggregate the 24 candidate PCa DRG genes, sequentially removing the 7 genes with the strongest risk-increasing effects. The remaining PCa DRG genes had no aggregate effect on aggressive disease (excluding top 3 genes: BRCA2, PALB2, and ATM, P = .18; excluding top 7 genes: BRCA2, PALB2, ATM, MLH1, CHEK2, MUTYH, and MSH2, P = .59). CI = confidence interval; OR = odds ratio.