Abstract 2751: Frequent BRCA2 somatic mutations in colorectal cancer patients with microsatellite instability (MSI)
Authors: Deihimi Safoora , Lev Avital , Shagisultanova Elena , Xiu Joanne , Slifker Michael , Xu Qifang , Dicker David T. , Ross Eric A. , Dunbrack Roland , El-Deiry Wafik S. 
Published: July 2016

Microsatellite instability (MSI) is a hallmark of mismatch repair (MMR)-deficient cancers including colorectal cancer (CRC). MSI represents 15% of CRCs as a result of either epigenetic silencing of MLH1 or mutations in one of the MMR genes: MLH1, MSH2, MSH6 and PMS2. MSI tumors have a better prognosis than microsatellite stable (MSS) tumors while responding differently to treatments, including relative resistance to 5-FU and high clinical benefit from immune checkpoint therapy. Deficient MMR can lead to deficient DNA double-strand-break repair. We recently reported on 26 MSI-High and 558 non-MSI-High CRCs profiled by Caris Life Sciences. MSI-High CRCs had a high mutation rate (50%) in BRCA2 (Shagisultanova et al., 2015 ASCO Annual Meeting Abstract No. e14684 “Association of increase in BRCA2 gene mutations in microsatellite instable (MSI-H) colorectal cancer (CRC) with increased c-MET expression”). We hypothesized there might be a pattern with specific BRCA2 mutations in MSI-H CRCs targeting the coding microsatellites in BRCA2. BRCA2 mutations could be potential targets in clinical therapy. We further investigated functional mutation patterns in BRCA2 in both MSI-H and MSS groups. Of 1104 profiled CRCs in the COSMIC v73 database, somatic BRCA2 mutations were mapped for 101 MSI-High versus 916 MSS CRCs. MSI-High CRCs showed a significantly higher mutation rate in BRCA2 as compared to MSS (38% vs 6%, P&lt;0.0000001). A higher rate of damaging mutations (42% vs. 2%, P&lt; 0.0001) and a relatively distinct pattern of protein mutation distribution could be clearly mapped in MSI-High CRCs versus the MSS group. We found that specific mutations in coding microsatellites of BRCA2 can be impacted by MMR defects. We found 72 unique BRCA2 mutations in MSI-H CRCs not previously seen in either breast cancer or pancreatic cancer as reported in COSMIC v73. However, using the BIC database (http://research.nhgri.nih.gov/bic/) we detected 5 BRCA2 deleterious mutations that have been reported as germline mutations in breast cancer. We used the consensus result from five predictors and available 3-D structural information to predict deleterious properties of mutations including damaging BRCA2 protein structure and disruption of interactions with partner proteins including DSS1 and RAD51. Targeting BRCA2 mutations in MSI tumors and using the concept of synthetic lethality might be effective in BRCA-deficient CRCs with MSI.

Citation Format: Safoora Deihimi, Avital Lev, Elena Shagisultanova, Joanne Xiu, Michael Slifker, Qifang Xu, David T. Dicker, Eric A. Ross, Roland Dunbrack, Wafik S. El-Deiry. Frequent BRCA2 somatic mutations in colorectal cancer patients with microsatellite instability (MSI). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2751.