BRCA2, EGFR, and NTRK mutations in mismatch repair-deficient colorectal cancers with MSH2 or MLH1 mutations
| Autor: | Eric A. Ross, Mark Andrake, Namrata Vijayvergia, Roland L. Dunbrack, Jeffrey Swensen, Kyungsuk Jung, Elena Shagisultanova, Qifang Xu, Joanne Xiu, Wafik S. El-Deiry, Avital Lev, Safoora Deihimi, Michael Slifker, Zoran Gatalica |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Oncology Models Molecular medicine.medical_specialty Pathology congenital hereditary and neonatal diseases and abnormalities Colorectal cancer EGFR colorectal cancer Gene mutation MLH1 DNA Mismatch Repair Cohort Studies 03 medical and health sciences 0302 clinical medicine Breast cancer Gene Frequency Protein Domains Internal medicine medicine Humans Receptor trkB Receptor trkC Receptor trkA neoplasms BRCA2 Protein Cancer prevention business.industry Microsatellite instability Cancer nutritional and metabolic diseases medicine.disease BRCA2 digestive system diseases 3. Good health ErbB Receptors 030104 developmental biology MutS Homolog 2 Protein MSH2 030220 oncology & carcinogenesis Mutation Microsatellite Instability business Colorectal Neoplasms MutL Protein Homolog 1 NTRK Priority Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Safoora Deihimi 1,2,3,7 , Avital Lev 1,2,3 , Michael Slifker 4 , Elena Shagisultanova 3,9 , Qifang Xu 2 , Kyungsuk Jung 5 , Namrata Vijayvergia 3 , Eric A. Ross 4,6 , Joanne Xiu 8 , Jeffrey Swensen 8 , Zoran Gatalica 8 , Mark Andrake 2 , Roland L. Dunbrack 2 and Wafik S. El-Deiry 1,2,3,7 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 Correspondence to: Wafik S. El-Deiry, email: // Keywords : BRCA2, EGFR, NTRK, colorectal cancer, MLH1 Received : April 14, 2017 Accepted : April 26, 2017 Published : May 23, 2017 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. |
| Databáze: | OpenAIRE |
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