HYPERMUTABILITY AND MISMATCH REPAIR DEFICIENCY IN RER-CELLS( TUMOR)

A subset of sporadic colorectal tumors and most tumors developing in h ereditary nonpolyposis colorectal cancer patients display frequent alt erations in microsatellite sequences. Such tumors have been thought to manifest replication errors (RER+), but the basis for the alterations has remained conjectural. We demonstrate that the mutation rate of (C A)n repeats in RER+ tumor cells is at least 100-fold that in RER- tumo r cells and show by in vitro assay that increased mutability of RER+ c ells is associated with a profound defect in strand-specific mismatch repair. This deficiency was observed with microsatellite heteroduplexe s as well as with heteroduplexes containing single base-base mismatche s and affected an early step in the repair pathway. Thus, a true mutat or phenotype exists in a subset of tumor cells, the responsible defect is likely to cause transitions and transversions in addition to micro satellite alterations, and a biochemical basis for this phenotype has been identified.