Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features: Association of Gleason score and tumor stage

BACKGROUND: DNA repair gene mutations are present in 8–10% of localized prostate cancers. It is unknown if this is influenced by clinicopathologic factors. METHODS: We interrogated localized prostate adenocarcinomas with tumor DNA sequencing from the TCGA validated (n=333) and Nature Genetics (n=377) datasets. Homologous recombination repair genes included: ATM, BRCA1/2, CDK12, CHEK1/2, FANCA, FANCD2, FANCL, GEN1, NBN, PALB2, RAD51 and RAD51C. Proportions of cases with pathogenic DNA repair mutations (and in ATM/BRCA1/2 specifically) were reported by Gleason grade group, clinical T stage, pathological T and pathological N stage. Odds ratios and Fisher’s exact tests were used to compare proportions between categories. RESULTS: Those with Gleason Grade Groups 3 and higher were 2.2 times more likely to harbor any DNA repair mutation (95% CI 1.2–4.2; 10.3% versus 5.0%) and 2.7 times more likely to have BRCA1/2 or ATM mutations (95% CI 1.3–6.6; 7.0% versus 2.7%) as those in Gleason Grade Groups 1–2. Patients with pathologic stage pT3/pT4 were 2.6 times more likely to have any DNA repair mutation (95% CI 1.3–6.6; 13.0% versus 5.5%) and 3.2 times more likely to have BRCA1/2 or ATM mutations (95% CI 1.2–11.3; 9.5% versus 3.1%) compared to those with pT2 disease. There was no difference by clinical tumor or nodal stage. Among men with Gleason Grade Group ≥3 and clinical stage >cT3, 21.3% (1 in 5) had a DNA repair mutation in any gene and 11.7% (1 in 9) had a mutation in ATM/BRCA1/2. CONCLUSIONS: The prevalence of pathogenic DNA repair gene alterations is enriched in men with advanced tumor stages and higher Gleason Grade groups, with maximal enrichment observed in those with Gleason Grade group ≥3 and clinical stage ≥cT3 disease. This information can be used to guide eligibility criteria for genomically-targeted clinical trials in the neoadjuvant/adjuvant settings.