Variation in the extent of microsatellite instability in human cell lines with defects in different mismatch repair genes

Mismatch repair deficiency results in the elevation of mutation rates in tumors, which is especially pronounced in simple repeat sequences (microsatellites). We have investigated the relationship between microsatellite muta-genesis and certain combinations of mutations in mismatch repair genes, using a frameshift reversion assay to deter-mine the spontaneous mutation rates of a dinucleotide microsatellite in two cancer cell lines, HCT116, which has defects in hMLH1 and hMSH3, and HEC-1-A, which has defects in hPMS2 and hMSH6. We found a 10-fold differ-ence in mutation rates between these two cell lines. In addition, a mutant hPMS2 allele, PMS134, which has been reported to have a dominant negative effect, was expressed in mismatch repair-proficient telomerase-immortalized hTERT-1604 fibroblasts and mutation rates were deter-mined. Expression of PMS134 did not elevate mutation rates in hTERT-1604. Combined, these results suggest that mutations in different mismatch repair genes can lead to varying degrees of microsatellite instability. It is also likely that there is heterogeneity in the mutations that are acquired in the absence of mismatch repair, such that some mismatch repair-defective cancer cells also contain mutations in other genes coding for proteins involved in the maintenance of genetic stability