Abstract: PD03-02
Sources of Funding: None

Introduction

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. Prostate tumors with DNA repair defects 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. Captured libraries were 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. Nine genes were in common between the two lists yielding a total of 85 unique DNA repair genes. We further stratified the frequency of mutations by tissue site (prostate versus metastases). Only tissues represented by at least 10 samples in the set were included (868). Frequencies of DNA repair defects were compared across metastatic sites by Pearson’s Chi-squared test.

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, which were significantly 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 and lymph node metastases. Genomic profiling may identify prostate cancers potentially sensitive to platinum-based chemotherapy or PARP inhibition.

Funding

None