PMS2 (MRQ-28)

Microsatellite instability (MSI) is characterized by genome-wide alterations in short, repetitive DNA sequences. It is caused by defects in the nucleotide mismatch repair (MMR) system. Biologically, defective MMR results in a general increase in the mutation rate and the development of a “mutator phenotype.” In colorectal cancer (CRC), high-level MSI was first described in tumors from patients with hereditary non-polyposis colorectal cancer (HNPCC). In about 70% of cases, the HNPCC syndrome develops as a result of an inherited germline mutation of one allele, followed by a somatic mutation of the other allele in one of several mismatch repair genes: hMSH2, hMLH1, hPMS1, hPMS2, hMSH6, and hMLH3. Ninety-five percent of the mutations occur in hMSH2 or hMLH1. Most colorectal carcinomas are thought to be of the chromosomal instable (CIN) or microsatellite stable (MSS) genotype. However, approximately 15% are thought to be of the MSI genotype, of which the HNPCC cases represent less than one-third. The MSS and MSI tumors also seem to differ in clinicopathologic features. The MSI tumors are more often located in the proximal colon and may be synchronous. On histologic examination, they are more often mucinous or poorly differentiated. The patients with MSI-type colorectal carcinomas are generally thought to have a better prognosis than patients with MSS-type colorectal carcinomas. On the other hand, MSS tumors are more often located in the distal colon and represent typical adenocarcinomas. Although the results published so far have been conflicting, some studies suggest that patients with MSI-type colorectal carcinomas seem to have a greater benefit from adjuvant chemotherapy than patients with MSS-type colorectal carcinomas. Thus, there are at present three main reasons to test for MSI in patients with CRC: as a screening tool for HNPCC, as a prognostic marker, and as a possible future predictor of therapeutic and follow-up procedures.