Abstract
A novel type of genetic instability characterized by length alterations within simple repeated sequences, termed microsatellite instability (MSI), occurs in the majority of HNPCC and in a subset of sporadic cancers. Recent studies have revealed that there are two types of MSI: high-frequency MSI (MSI-H) and low-frequency MSI (MSI-L). Cancers with MSI-H and those without MSI-H have been shown to exhibit fundamental differences in clinical, pathological, and molecular characteristics. For instance, colorectal cancers with MSI-H exhibit low frequencies of somatic mutations in the p53, K-ras, and APC genes. Inactivation of the DCC gene and overexpression of COX-2 are also less frequent in colorectal cancers with MSI-H. On the other hand, gastrointestinal cancers with MSI-H have a high rate of slippage-induced frameshift mutations in target genes such as TGFβRII and BAX and high frequencies of aberrant DNA hypermethylation of tumor suppressor genes, including hMLH1 gene. Pancreatic cancer with MSI-H has been shown to exhibit characteristic features such as a wild-type K-ras gene and a medullary phenotype. A frequent loss of imprinting of the IGFII gene has been reported in colorectal cancer tissues as well as in the matched normal colonic mucosa of patients with MSI-H or MSI-L cancer. From biological and clinical points of view, it is important to characterize the MSI status of given tumors.
