Priority Research Papers:
BRCA2, EGFR, and NTRK mutations in mismatch repair-deficient colorectal cancers with MSH2 or MLH1 mutations
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Safoora Deihimi1,2,3,7, Avital Lev1,2,3, Michael Slifker4, Elena Shagisultanova3,9, Qifang Xu2, Kyungsuk Jung5, Namrata Vijayvergia3, Eric A. Ross4,6, Joanne Xiu8, Jeffrey Swensen8, Zoran Gatalica8, Mark Andrake2, Roland L. Dunbrack2 and Wafik S. El-Deiry1,2,3,7
1 Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA
2 Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA
3 Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
4 Biostatistics and Bioinformatics Department, Fox Chase Cancer Center, Philadelphia, PA, USA
5 Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA, USA
6 Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, USA
7 Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA
8 Caris Life Science, Phoenix, AZ, USA
9 University of Colorado Denver Cancer Center, Denver, CO, USA
Wafik S. El-Deiry, email:
Keywords: BRCA2, EGFR, NTRK, colorectal cancer, MLH1
Received: April 14, 2017 Accepted: April 26, 2017 Published: May 23, 2017
Deficient mismatch repair (MMR) and microsatellite instability (MSI) contribute to ~15% of colorectal cancer (CRCs). We hypothesized MSI leads to mutations in DNA repair proteins including BRCA2 and cancer drivers including EGFR. We analyzed mutations among a discovery cohort of 26 MSI-High (MSI-H) and 558 non-MSI-H CRCs profiled at Caris Life Sciences. Caris-profiled MSI-H CRCs had high mutation rates (50% vs 14% in non-MSI-H, P < 0.0001) in BRCA2. Of 1104 profiled CRCs from a second cohort (COSMIC), MSH2/MLH1-mutant CRCs showed higher mutation rates in BRCA2 compared to non-MSH2/MLH1-mutant tumors (38% vs 6%, P < 0.0000001). BRCA2 mutations in MSH2/MLH1-mutant CRCs included 75 unique mutations not known to occur in breast or pancreatic cancer per COSMIC v73. Only 5 deleterious BRCA2 mutations in CRC were previously reported in the BIC database as germ-line mutations in breast cancer. Some BRCA2 mutations were predicted to disrupt interactions with partner proteins DSS1 and RAD51. Some CRCs harbored multiple BRCA2 mutations. EGFR was mutated in 45.5% of MSH2/MLH1-mutant and 6.5% of non-MSH2/MLH1-mutant tumors (P < 0.0000001). Approximately 15% of EGFR mutations found may be actionable through TKI therapy, including N700D, G719D, T725M, T790M, and E884K. NTRK gene mutations were identified in MSH2/MLH1-mutant CRC including NTRK1 I699V, NTRK2 P716S, and NTRK3 R745L. Our findings have clinical relevance regarding therapeutic targeting of BRCA2 vulnerabilities, EGFR mutations or other identified oncogenic drivers such as NTRK in MSH2/MLH1-mutant CRCs or other tumors with mismatch repair deficiency.
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