The contribution of germline DNA damage response mutations on prostate cancer risk and prognosis: A UK Biobank whole-exome analysis.

Abstract

67 Background: Germline mutations in DNA Damage Response (DDR) genes such as BRCA2 and ATM have been associated with prostate cancer risk and aggressiveness. These associations are largely based on studies that ascertain for cancer diagnosis and family history and provide risk estimates with limited population-level accuracy. Here we evaluate the clinical significance of germline pathogenic variants in 20 DDR genes and a high-risk susceptibility coding variant in HOXB13 using whole exome sequences from (1) the UK Biobank (UKBB), a population-based cohort (300,000 participants) and (2) patients recruited in AZ clinical trials. Methods: Whole exomes from 6,987 prostate cancer patients (5,921 UKBB and 1,066 AZ) and 88,499 cancer-free males were analysed. Known and novel pathogenic variants were identified and associations with disease risk, age of onset, family history, response to hormonal therapy and overall survival were estimated (multiplicity corrected P value < 0.005). Results: HOXB13 G48E (1.36%), ATM (1.03%) and BRCA2 (0.99%) were the largest contributors to prostate cancer risk, each conferring an increase of ~4-fold, followed by CHEK2 with a moderate contribution (0.46%). No significant contributions to prostate cancer risk were observed for any of the other genes analysed. Family history of prostate cancer was not significantly enriched in any of the gene subpopulations of prostate cancer carriers and compared with non-carriers, there was no significant difference in the median age of disease onset. Analysis of clinical outcomes showed that BRCA2 carriers had a 4-fold increased risk of death (Cox PH HR p = 4.11E-12) and poorer overall survival (Log-Rank p = 4.60E-14), with 88% dying from prostate cancer compared to 49% of non- BRCA2 carriers (UKBB analysis). BRCA2 pathogenic mutations were also associated with early failure to hormonal therapy (Cox PH HR 2.38; p = 9.48E-04; AZ cohort analysis). HOXB13, ATM and CHEK2 mutations were not significantly associated with clinical outcomes. Conclusions: This is the largest study to date providing population-based estimates of prostate cancer risk and prognosis, highlighting BRCA2 carriers as a population in clinical need of early identification and targeted intervention. Updated analyses with data from the full 450,000 UKBB participants (9,000 prostate cancers) will be presented.