Precision Approaches to Early-Onset Colorectal Cancer Therapy Through Germline Variation
Abstract
Genome-wide characterization of somatic alterations in human cancers has led to hopes of precision medicine approaches to identify optimal molecularly-targeted treatments, particularly through exploitation of synthetic lethal (SL) interactions. Several computational strategies exist to identify SL interactions from genomic alterations found in tumors by subtracting the individuals genome from the tumor. As such, these approaches ignore the contribution of germline variation to disease pathogenesis. However, population-wide, exome sequencing projects have demonstrated that each person harbors several, rare loss-of-function (LoF) mutations in her germline. These germline alterations may have potentially profound therapeutic consequences as shown by the recent approval of PARP inhibitors for those with ovarian cancer and germline defects in homologous recombination (HR) DNA repair genes, such as BRCA1/2 mutations. Thus, our overall hypothesis is that in addition to Mendelian cancer syndromes, routine exploitation of synthetic lethal relationships derived from driver germline variants in DNA-repair genes will improve the efficacy and utilization of precision therapeutics particularly for those individuals with early-onset colorectal cancer, whose incidence rates have been sharply increasing over the past decade. The work encompasses ex-vivo testing of human/normal early-onset colorectal cancers, and modeling of cancers generated from human tissue by genomic engineering techniques.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2020
- Accession Number
- AD1117704
Entities
People
- Manish Gala
Organizations
- Massachusetts General Hospital