Precision Approaches to Early-Onset Colorectal Cancer Therapy Through Germline Variation
Abstract
Enclosed is the second annual report. This proposal seeks to address the PRCRP topic area of colorectal cancer, and addresses the gap that exists in therapeutic options and genetic testing available for service members and their families at risk for early-onset colorectal cancer. Large population genetic studies have demonstrated an excess of rare, pathogenic mutations in the germlines of individuals. These germline mutations are routinely discarded in most cancer genomics workflows, and can often have driver effects in tumorigenesis even when not Mendelian in nature. Our preliminary data suggests that certain pathways in DNA damage repair are particularly enriched in individuals with early-onset colorectal cancer, and while potentially cancer-predisposing, may make subsequent tumors exquisitely sensitive to select precision chemotherapeutics, a relationship called synthetic lethality. Our overall hypothesis is that in addition to Mendelian cancer syndromes such as Lynch Syndrome, routine exploitation of synthetic lethal relationships derived from driver germline mutations in non-Mendelian cases of early-onset colorectal cancer will improve the efficacy and utilization of precision therapeutics. These data may provide proof-of-principle for routine precision cancer therapeutics based on patients inherited genetic profile in addition to the molecular features of their tumor. If successful, this approach would represent a paradigm shift in genetic testing and treatment for early-onset colorectal cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2021
- Accession Number
- AD1152641
Entities
People
- Manish Gala
Organizations
- Massachusetts General Hospital