Abstract 3522: Population estimates of prostate cancer risk and prognosis for carriers of germline pathogenic variants in disease implicated genes, using 200,000 UK Biobank whole exomes

Abstract

Abstract Germline deleterious variants in DNA Damage Response (DDR) genes such as BRCA2 and ATM have been associated with high risk of disease, poor prognosis and the development of metastatic prostate cancer. These associations have been reported in studies of individuals selected for family history or cancer diagnosis and, therefore, with limited potential to estimate accurate population disease risk. Here we evaluate the clinical significance of germline deleterious variants in 20 DDR genes and four known prostate cancer susceptibility coding variants in POUF51B, HOXB13 and KLK3 using germline whole exome sequencing (WES) data from (1) the UK Biobank (UKBB), a population-based cohort (200,000 with WES) and (2) prostate cancer patients recruited in AZ clinical trials. WES data from 4,975 prostate cancer patients (3,954 UKBB and 1,021 AZ) and 44,818 controls (cancer-free UKBB male participants) was analysed. We identified 218 carriers with deleterious variants in DDR genes. Of these, 190 carried known pathogenic variants (ClinVar, BIC and ENIGMA consortium) and 28 had novel, pathogenic protein truncating variants. Population disease risk, risk of metastatic disease and overall survival (UKBB patients only) were estimated (multiplicity corrected P value <0.005). Analysis of deleterious variants revealed significant associations with prostate cancer risk for ATM (OR 4.14, 95% CI 2.97-5.72, p=1.77E-15) and BRCA2 (OR 3.47, 95% CI 2.49-4.77, p=1.70E-12), each contributing to a similar number of cases (1.15% vs 1.11%, respectively). Damaging variants within the remaining DDR genes were less frequent with none reaching significance. A trend for increased disease risk was observed in CHEK2 carriers (OR 2.03, 95% CI 1.18-3.33, p=9.30E-03). Coding variant analysis confirmed associations between variants in POU5F1B, HOXB13 and KLK3 and prostate cancer risk. HOXB13 G84E carriers (1.29%) were at comparable risk to BRCA2 and ATM carriers (OR 3.88, 95% CI 2.85-5.24, p=4.29E-16). Assesment of patient outcomes showed that BRCA2 carriers were more likely to develop metastatic disease (OR 3.32, 95% CI 1.74-6.45, p=9.94E-05) and had poorer overall survival (Log Rank p=1.33E-08; 85% of patients dying from prostate cancer vs 53% of non BRCA2 carriers). No other gene reached significance. A trend towards poorer survival was observed for PALB2 carriers (Log Rank p=7.91E-03) suggesting that PALB2 could act as a modifier gene once the disease has developed. This is the largest study to date providing population based estimates of prostate cancer risk, metastasis and survival highlighting mutations in BRCA2, ATM and HOXB13 G48E as the largest contributors to disease risk and confirming the poor prognosis of BRCA2 carriers. Analyses will be updated with data from the full 500,000 UKBB participants (expected January 2020; total of 11,000 prostate cancer cases). Citation Format: Niedzica Camacho, Liqin Dong, Athena Matakidou. Population estimates of prostate cancer risk and prognosis for carriers of germline pathogenic variants in disease implicated genes, using 200,000 UK Biobank whole exomes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3522.