DNA repair gene panel mutations in young onset and aggressive vs non aggressive prostate cancer cases in the UK

Abstract

Background: Prostate cancer (PrCa) is the most common solid tumour in men in the Western world. There is evidence that PrCa predisposition is due to germline common and rare variation. Methods: We sequenced 175 genes in the DNA damage response and repair pathways using an Agilent customcapture kit and Illumina technology in PrCa cases diagnosed at<65 years compared with controls in the UK (mean coverage 76X). Data were analysed from 1346 PrCa cases and 1186 controls using a GATK 2.8 analysis pipeline. Results: We identified 5,118 single nucleotide variants (SNVs) and 172 indels; 216 unique protein truncating variants (PTVs) were in 96 genes of the 175 gene panel. The total number of PTVs in cases was significantly higher (181) than in controls (122); in particular, in the BROCA gene set of 22 tumour suppressor genes (P=0.002). Mutations in BRCA1, BRCA2, ATM, MSH5 and CHEK2 were 3 times more common in cases compared with controls (P=0.0018). To investigate if aggressive cases had a different mutation burden we compared 204 aggressive (Gleason score>8) versus 1049 non-aggressive (Gleason score ≤7) cases. In the single variant analysis, one variant in BRCA2, rs28897754 (K2950N) showed association with a more aggressive phenotype (P=0.0016). Gene burden testing showed BRCA2, MSH2, PALB2 and CHEK2 had an OR>3 in aggressive v non aggressive cases (14% v 4%respectively). Men who died of PrCa had a 17% incidence of mutation in a subset of the 175 gene panel. Conclusions: We have shown that there is a higher percentage of DNA damage response and repair gene germline mutations in PrCa cases occurring at<65 years, in those with aggressive and lethal disease and this result will enable us to develop a testing panel for use in clinical care in the near future.