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.
We sequenced 175 genes in the DNA damage response and repair pathways using an Agilent custom capture kit and Illumina technology in PrCa cases diagnosed at
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.
We have shown that there is a higher percentage of DNA damage response and repair gene germline mutations in PrCa cases occurring at
Clinical trial identification
UKGPCS - CCR0848 & 06/MRE02/4
Legal entity responsible for the study
The Institute of Cancer Research
All authors have declared no conflicts of interest.