Therapeutic implications of DNA mismatch repair in adjuvant colorectal cancer chemotherapy

Abstract

SUMMARY Microsatellite instability (MSI) is a molecular marker of defective DNA mismatch repair (MMR) and constitutes an important oncogenic molecular pathway in colorectal cancer that is present in approximately 12–15% of all colorectal malignant tumors. Defective MMR status in colorectal cancer occurs as a result of germline mutations in MMR genes (less than one third of cases) or, more commonly, from somatic hypermethylation of the MLH1 promoter (more than two thirds). MMR deficiency accelerates colorectal oncogenesis by accumulation of secondary mutations in specific target genes. Patients with defective MMR tumors have distinct clinicopathologic characteristics and have been associated with a better stage-adjusted prognosis than patients with proficient MMR tumors. MMR deficiency may predict tumor chemoresistance to adjuvant 5-fluorouracil treatment. Preliminary clinical data suggested that adding oxaliplatin to 5-fluorouracil could restore the benefit of adjuvant chemotherapy in MSI patients. Further studies are needed to clarify the differential chemosensitivity of MSI patients depending on the mechanism of MMR deficiency and the adjuvant chemotherapeutic regimen used.