THE MICROSATELLITE MUTATOR PHENOTYPE OF COLON-CANCER CELLS IS OFTEN RECESSIVE

A new mutator mechanism for tumorigenesis, characterized by somatic ge nomic instability (SGI) at simple repeated sequences (SRS) or microsat ellites, underlies hereditary nonpolyposis colorectal cancer (HNPCC) a nd some sporadic tumors of the colon and other types, To determine whe ther the microsatellite mutator phenotype (MMP) is dominant or recessi ve, we generated somatic cell hybrids between a tumor cell line withou t SGI at SRS (D98OR) and colon carcinoma cell lines with relative low (HCT-15) and high (LS174-T) SGI at SRS, The normal fidelity of replica tion of these unstable sequences was observed in each of these cell hy brids, Fusion of HCT-1S/DLD-1 low instability cells, with LS174-T, HCT 116 and LoVo cell Lines, all exhibiting relative high instability, als o restored the replication fidelity of SRS in all of the hybrids, Hybr ids between the high instability cell lines did not grow possibly beca use of senescence or apoptosis, These results indicate that, in the ce ll lines analysed, the characterized mutator phenotype of the mismatch repair system resulting in high SGI at SRS, and the uncharacterized m utator phenotype underlying low SGI at SRS, are both recessive, The re sults also suggest that different tumor cells of the MMP harbor distin ct altered growth-related genes.