UCRF 2012 Innovation Award: Characterization of an Epigenetic Variant in the MSH3 Mismatch Repair Gene as a Biomarker of Chemoresistance in African American Breast Cancer Cases
African American (AA) women are diagnosed with more advanced breast cancers and have lower survival than white women even after accounting for known prognostic factors or treatment differences.
In the Carolina Breast Cancer Study, we discovered an unmethylated variant in the MSH3 DNA mismatch repair (MMR) gene promoter in 32% of AA breast cancer patients, but in only 2% of white/non-AA patients. The variant is predicted to lead to higher MSH3 expression, which is expected to cause a MMR deficiency, genome instability, and resistance to certain chemotherapies, thus providing a potential clue as to why AAs have poorer breast cancer outcomes.
This project explores the link between this new MSH3 epigenetic variant and MMR function, therapeutic sensitivity and prognosis. We will first characterize matched germline DNA and frozen/fixed tumor samples from breast cancer patients in the Tissue Procurement Facility for MMR gene and protein expression levels, and will evaluate MSH3 promoter sequence and broader methylation state to examine the relationship with MSH3 epigenotype. In LCCC 9830 breast cancer study patients, we will then evaluate MSH3 epigenotype in relation to neoadjuvant chemotherapy response and survival, and will determine whether immortalized lymphocytes from these patients with the unmethylated MSH3 variant have different MMR function and show resistance to genotoxic chemotherapies.
Understanding the role of the MSH3 variant in breast cancer and its development as a predictive biomarker of chemotherapeutic response to certain drugs could lead to administration of more effective therapies, and potentially improve the survival of AA breast cancer patients.