Assessing the Mutational Landscape of BRAF- and KRAS-Wild Type Colorectal Cancer

Colorectal cancer is one of the most deadly cancers and is the second leading cause of death in the United States. As incidence of colorectal cancer is higher among developed countries, research continues in hopes to make marked advancements in the way cancer is treated. A number of targeted therapies have been developed and are in clinical use; increasingly these require genomic analyses as a companion diagnostic or a predictive biomarker. This is the concept of precision cancer therapy: genomic sequencing of patients’ tumors to assess for known mutations in a certain cancer type, which allows doctors to prescribe more effective therapeutics based on the drivers of that patient’s individual cancer. Data from genomic studies has shown that over half of colorectal adenocarcinomas are driven by activating mutations in KRAS or BRAF oncogenes. However, the other 50% of colorectal cancer cases are wild type for both genes; thus identification and characterization of the landscape of mutations in non-BRAF and KRAS-mutated colorectal cancer is helpful to propose suitable therapies for these patients. This study assesses the mutational landscape, including potential driver events, in cases of colorectal cancer that are wild type for both KRAS and BRAF mutations. Tumor genomic data from the Profile research initiative from Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Boston Children’s Hospital was used for analysis. We describe the landscape of alterations- including mutations, copy number changes, and structural rearrangements- and compare between our two cohorts of colorectal cancer patients. NRAS and TP53 mutations, as well as ERBB2, FGFR1, and EGFR amplifications, occurred more frequently in the wild-type cohort than the mutant cohort. We also assessed the number of cases in the wild-type cohort that would be eligible for clinical trials at Dana-Farber Cancer Institute. Using a matching algorithm, we found that 71% of cases that were wild-type for BRAF and KRAS were potential candidates for currently available clinical trials. We show that patients that have KRAS/BRAF wild-type colorectal cancer have non-standard therapies that may be relevant for treatment and highlight the utility of genomic screening for driver alterations in colorectal cancer patients beyond KRAS and BRAF.

Name thesis:degree_name

ALM

Level thesis:degree_level

Masters

Grantor

Harvard Extension School

Year dc:date.issued

2018

Author dc:creator

• Rizvi, Neda Z.

Committee members dc:contributor.committeemember

• Morris, James
• MacConaill, Laura E.

• Biology, General
• Biology, Bioinformatics

Repository record dc:identifier.uri

http://nrs.harvard.edu/urn-3:HUL.InstRepos:37799742

OAI identifier oai:identifier

oai:dash.harvard.edu:1/37799742