Patterns of mutation in cancer cells.
The discovery of powerful mutator phenotypes in a subset of colon cancers provides direct support for the hypothesis that destabilization of replication fidelity and repair drive the accumulation of mutations in tumour suppressor or proto-oncogenes. Nevertheless, many important questions remain. The tumour cell lines in which these mutator genes were characterized have many other mutations that may contribute to the mutator phenotype and the characteristic pattern of mutations found in these cells. Thus, mismatch repair deficiency may be necessary for the mutator phenotype, but is it sufficient? Certainly, changes in DNA replication fidelity or cell cycle checkpoint controls may contribute to the mutator phenotype. This question also has important implications for the effect of mismatch repair deficiency on tumour development. Does the mutator phenotype in HNPCC patients arise as a very early event resulting from the loss of the wild type allele or does it arise in later stages only after alterations of cell cycle controls or replication fidelity? Given that eukaryotic cells have numerous homologues of the mismatch repair genes, what are the roles of all these genes? Are these involved in the repair of very specific types of replication errors or do they have other roles in cells? Finally, what mechanisms underlie the accumulation of mutations in other types of tumours? Given the rapid progress made since the isolation of the human homologues of the E coli mismatch repair genes less than 3 years ago, we can look forward to the answers to many of these questions in the near future.
Meuth
M
M
Department of Oncological Sciences, Eccles Institute of Human Genetics, University of Utah, Salt Lake City 84112, USA.
D000818:Animals; D002872:Chromosome Deletion; D003110:Colonic Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D015321:Gene Rearrangement / Q000235:genetics; D005809:Genes, Regulator / Q000235:genetics*; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D016296:Mutagenesis / Q000235:genetics*; D010641:Phenotype; D014407:Tumor Cells, Cultured