Frequency of DNA repair gene mutations in localized and metastatic prostate cancer.

10 Background: DNA repair gene mutations are important molecular alterations in prostate cancer pathogenesis. Germline mutations in DNA repair genes, particularly BRCA2, were recently recognized as associated with metastatic prostate cancer and may also be particularly sensitive to platinum based chemotherapy and PARP inhibitor therapy. We sought to characterize alterations in DNA repair pathway genes in both primary and metastatic prostate tumors. Methods: We studied the distribution of DNA repair gene mutations in 936 prostate cancers harvested from localized and metastatic tumors. Tumor DNA underwent hybrid capture for all coding exons of 395 cancer-related genes plus select introns from 19 or 31 genes frequently rearranged in cancer and sequenced to a median exon coverage depth of >500x using Illumina sequencing and were analyzed for base substitutions/insertions, copy number alterations and rearrangements. We utilized two described lists of genes involved in DNA repair : our own in-house list of 74 (UCD) and a list of 20 DNA repair genes associated with cancer predisposition syndromes utilized in a recent publication by Pritchard et al. We further stratified the frequency of mutations by tissue site (prostate versus metastases). Results: We identified 228/936 unique samples with at least one likely functional mutation in a DNA repair gene (24.4%). Mutations were identified in 20.1% of prostate tumors (13% UCD, 18.4% Pritchard et al.) and in 18.8% of bone metastases. The highest rates of DNA repair mutations were found in visceral metastases including brain, pelvis and liver, higher than either prostate tissue or bone sites (p=<0.01). The most commonly (≥1% of samples) mutated genes in the DNA repair pathways are: BRCA2 (11.43%), ATM (5.77%), MSH6 (2.46%), MSH2 (2.14%), ATR (1.60%), MLH1 (1.28%), and BRCA1(1.18%). Conclusions: DNA repair gene mutations are more common in metastatic than localized prostate tumors. Visceral metastases appear enriched for these mutations compared with localized tumors or bone metastases. Genomic profiling may identify prostate cancers potentially sensitive to platinum-based chemotherapy or PARP inhibition.