BRCA2, EGFR, and NTRK mutations in mismatch repair-deficient colorectal cancers with MSH2 or MLH1 mutations
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Updated: Mar 1, 2026
Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA1
Published on: February 17, 2011
Safoora Deihimi1,2,3,4, Avital Lev1,2,3, Michael Slifker5
1Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.
Abstract:
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.
Insights
Microsatellite instability (MSI) in colorectal cancer (CRC) drives BRCA2 and EGFR mutations, offering new therapeutic targets. MSI-High CRCs show increased mutations in DNA repair genes and cancer drivers, impacting treatment strategies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Deficient mismatch repair (MMR) and microsatellite instability (MSI) are implicated in approximately 15% of colorectal cancers (CRCs).
- The relationship between MSI and mutations in DNA repair genes like BRCA2 and cancer drivers such as EGFR in CRCs requires further investigation.
Purpose of the Study:
- To investigate the hypothesis that MSI in colorectal cancer leads to mutations in DNA repair proteins (BRCA2) and cancer drivers (EGFR).
- To identify novel therapeutic targets in MSI-High CRCs based on observed mutation profiles.
Main Methods:
- Analysis of mutation data from two cohorts of colorectal cancer patients: a discovery cohort (26 MSI-High and 558 non-MSI-High CRCs) profiled by Caris Life Sciences, and a second cohort (1104 CRCs) from the COSMIC database.
- Comparative analysis of mutation rates in BRCA2, EGFR, and NTRK genes between MSI-High/MSH2/MLH1-mutant and non-MSI-H/non-MSH2/MLH1-mutant CRC cohorts.
- In silico prediction of the functional impact of identified BRCA2 mutations on protein interactions.
Main Results:
- MSI-High CRCs exhibited significantly higher mutation rates in BRCA2 (50% vs. 14%, P < 0.0001).
- MSH2/MLH1-mutant CRCs showed increased BRCA2 mutation rates (38% vs. 6%, P < 0.0000001), with 75 unique BRCA2 mutations not previously reported in breast or pancreatic cancer.
- EGFR mutations were more frequent in MSH2/MLH1-mutant CRCs (45.5% vs. 6.5%, P < 0.0000001), with some actionable mutations identified. NTRK gene fusions were also found in MSH2/MLH1-mutant CRCs.
Conclusions:
- MSI in colorectal cancer is associated with a high frequency of BRCA2 mutations, some of which are unique and potentially targetable.
- EGFR and NTRK mutations are also prevalent in MSH2/MLH1-mutant CRCs, presenting additional therapeutic opportunities.
- These findings highlight the clinical relevance of targeting BRCA2 vulnerabilities, EGFR mutations, and NTRK in MSI-deficient colorectal cancers.
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