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Thesis
Mutation profiling in colorectal cancer patients with microsatellite instability: high frequency of BRCA2 and EGFR somatic mutations
Master of Science (M.S.), Drexel University
Nov 2016
DOI:
https://doi.org/10.17918/etd-7170
Abstract
Microsatellite instability (MSI) is a hallmark of deficient mismatch repair (MMR) and contributes to ~15% of colorectal cancer (CRCs). MSI can lead to mutations in proteins involved in double-strand break repair including BRCA2 and may involve drivers such as EGFR. We analyzed 26 MSI-High (MSI-H) and 558 non-MSI-H CRCs that were profiled at Caris Life Sciences. The MSI-H CRCs had a significantly high mutation rate (50%) in BRCA2. We hypothesized there may be specifically enriched BRCA2 mutations in MSI-H CRCs targeting the coding microsatellites in BRCA2 due to MMR deficiency. We investigated functional mutation patterns in BRCA2 in both MSI-H and non-MSI-H CRCs in a second cohort. Of 1104 profiled CRCs in the COSMIC v73 database, somatic BRCA2 mutations were mapped for 101 MSI-H versus 916 non-MSI-H CRCs. MSI-H CRCs showed a significantly higher mutation rate in BRCA2 as compared to non-MSI-H (38% vs 6%, P<0.0000001) with enrichment in coding microsatellites. EGFR was mutated in 45.5% of MSI-H and 6.5% of non-MSI-H tumors (P<0.0000001). Approximately 15-20% of the EGFR mutations found may be actionable through TKI therapy, including the N700D, L747*, G719D, T790M, and E884K EGFR mutants. BRCA2 mutations in MSI-H CRCs included 75 unique novel mutations not known as somatic mutations in either breast cancer or pancreatic cancer per COSMIC v73. The BIC database (http://research.nhgri.nih.gov/bic/) identified 5 BRCA2 deleterious mutations that have been reported as germ-line mutations in breast cancer. Five predictors and available 3-D structural information were used to predict deleterious properties of BRCA2 mutations including disruption of interactions with partner proteins DSS1 and RAD51. Some CRCs harbored multiple BRCA2 mutations. Therapeutic targeting of BRCA2 or EGFR mutations may be further explored in MSI-H CRCs.
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Details
- Title
- Mutation profiling in colorectal cancer patients with microsatellite instability
- Creators
- Safoora Deihimi - DU
- Contributors
- Wafik S. El-Deiry (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Medicine (Graduate); College of Medicine; Hematology and Oncology; Drexel University
- Other Identifier
- 7170; 991014632944404721