Conditional mutators and tumorigenesis

The clonal population model of tumorigenesis depends on selection of genetically unstable cells with advantageous mutations. The number of mutations in tumor suppressor genes and proto-oncogenes in many cancers is much higher than can be accounted for by spontaneous mutation rates. This has lead to the idea that a mutator phenotype or increased mutation rate is an early event during tumorigenesis. Tumor samples from patients with hereditary nonpolyposis colorectal cancer (HNPCC) exhibit an increased mutation rate and microsatellite instability and have mutations in genes involved in DNA mismatch repair. The hMSH2 protein is proposed to be the central mismatch repair protein when complexed with either hMSH3 or hMSH6. Biochemical studies using nuclear extracts from hMSH2-deficient cell lines are unable to correct single base pair mismatches or insertion/deletion errors common to microsatellite repeats. We examined hMSH2-deficient cell lines for increased mutation rates at coding sequences and microsatellite repeats to determine the role of hMSH2 protein in maintaining genome stability. Surprisingly, two of the four hMSH2-deficient cell lines tested did not exhibit a mutator phenotype. However, it was discovered that the mutation rate was significantly increased in these cells when they were maintained in suboptimal, high-density culture conditions or in different lots of fetal bovine serum. This conditional mutator phenotype has important implications for understanding accumulation of mutations during tumorigenesis and may mimic conditions of the tumor microenvironment.