
There is evidence for the accumulation of thousands of mutations in cancer cells derived from human tumors. For example, examination of the colon tumor–derivedDNA from patients with hereditary non-polyposis colon cancer (HNPCC) reveals that as many as 100,000 repetitive DNA sequences are altered from the mismatch DNA repair defects that these patients’ cells harbor. Mismatch repair defects have also been noted in ‘‘sporadic’’ (not known to be hereditary) cancers.
As noted earlier, one hypothesis explaining the genetic instability of transformed cells is the mutator phenotype hypothesis, championed by Loeb and colleagues. This hypothesis states that an ‘‘initial mutator [gene] mutation generates further mutations including mutations in additional genetic stability genes, resulting in a cascade of mutations throughout the genome.’’ The molecular defect that could provide this phenotype could be a mutation in DNA polymerases that leads to error-prone DNA replication. The mutator phenotype would have to be generated early in tumorigenesis for this hypothesis to be valid. There are a number of arguments against this idea, such as observations that there is not necessarily an increased mutation rate in cancer cells over that of normal cells and that a similar ‘‘evolution’’ of genetically altered cancer cells could arise by clonal selection followed by clonal expansion of cells with a genetic alteration that provides a proliferative advantage.
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