Realities of microsatellite instability in human cancer

S Oda,MDa, Y Maehara,MD,PhDb, K Sugimachi,MD,PhDb

aInstitute for Clinical Research, National Cancer Centre, Fukuoka, Japan, b Cancer Centre, Kyushu University Hospital, Fukuoka, Japan

AIM: Microsatellite instability (MSI) is regarded as an important phenotype of defective DNA mismatch repair (MMR) and, consequently, as a marker of a high risk for cancer. Despite numerous studies, reported rates for MSI in each malignancy differ widely in the literature. These discrepancies may derive from methodological problems left in the conventional assay technique. We have established a new fluorescent technique where these methodological problem have been overcome. To elucidate realities of MSI in human cancer, this systems has been applied to samples derived from a wide variety of human malignancies. METHODS: Alteration in microsatellite sequences was examined in detail, using the High Resolution Fluorescent Microsatellite Analysis (HRFMA). RESULTS: The patterns of microsatellite changes observed in human cancer can be classified into two subtypes, one showing relatively small changes within 6 base pairs (Type A) and the other exhibiting drastic changes over 8 base pairs (Type B). Based upon analyses on microsatellite changes in mouse or human cell lines with a known defect in MMR genes, Type A has been connected to defective MMR. CONCLUSIONS: Use of HRFMA has shed light on the realities of MSI in human cancer. Among the two subtypes of MSI, Type A has been connected to defective MMR. On the other hand, the relationship between Type B and defective MMR remains unclear. Nevertheless, as in Hereditary Non-Polyposis Colorectal Cancer, Type B MSI is frequently observed in some cancers. Molecular backgrounds of Type B MSI warrants particular attention.

KEY WORDS: Replication error, DNA mismatch repair, Hereditary Non-Polyposis Colorectal Cancer.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Prognostic Markers.