AUA 2017: Frequency Of DNA Repair Gene Mutations in Localized and Metastatic Prostate Cancer

Boston, MA (UroToday.com) Studies have shown that DNA repair gene mutations are important in 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. Dr. Glass presented her study in which alterations in DNA repair pathway genes in both primary and metastatic prostate cancer were assessed.

Distribution of DNA repair gene mutations was analyzed 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. The authors utilized two described lists of genes involved in DNA repair: their own in-house list of 74 University California Davis(UCD) and a recently published list of 20 DNA repair genes associated with cancer predisposition syndromes (Pritchared et. Al, NEJM 2016). Due to the fact that nine genes were in common between the two lists, a total of 85 unique DNA repair genes were finally used. Further stratification was performed demonstrating the frequency of mutations by tissue site (prostate versus metastases).

Overall 228/936 unique samples were identified with at least one likely functional mutation in a DNA repair gene (24.4%). Mutations were identified in 20.1% of prostate tumors 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 mutated genes in the DNA repair pathways were BRCA2 (11.43%), ATM (5.77%), MSH6 (2.46%), MSH2 (2.14%), ATR (1.60%), MLH1 (1.28%),
and BRCA1 (1.18%).

In summary, DNA repair gene mutations occur at 20% of primary prostate cancer but are even more common in metastatic prostate tumors. Visceral metastases have the highest number of these mutations compared with localized tumors or bone and lymph node metastases. In the future, these results might lead us to identify prostate cancer that are potentially sensitive to platinum-based chemotherapy or PARP inhibition.

Presented By: Allison Glass, Sacramento, CA

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre

at the 2017 AUA Annual Meeting - May 12 - 16, 2017 – Boston, Massachusetts, USA
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