Significance of multiple mutations in cancer.
There is increasing evidence that in eukaryotic cells, DNA undergoes continuous damage, repair and resynthesis. A homeostatic equilibrium exists in which extensive DNA damage is counterbalanced by multiple pathways for DNA repair. In normal cells, most DNA damage is repaired without error. However, in tumor cells this equilibrium may be skewed, resulting in the accumulation of multiple mutations. Among genes mutated are those that function in guaranteeing the stability of the genome. Loss of this stability results in a mutator phenotype. Evidence for a mutator phenotype in human cancers includes the frequent occurrence of gene amplification, microsatellite instability, chromosomal aberrations and aneuploidy. Current experiments have centered on two mechanisms for the generation of genomic instability, one focused on mutations in mismatch repair genes resulting in microsatellite instability, and one focused on mutations in genes that are required for chromosomal segregation resulting in chromosomal aberrations. This dichotomy may reflect only the ease by which these manifestations can be identified. Underlying both pathways may be a more general phenomenon involving the selection for mutator genes during tumor progression. During carcinogenesis there is selection for cells harboring mutations that can overcome adverse conditions that limit tumor growth. These mutations are produced by direct DNA damage as well as secondarily as a result of mutations in genes that cause a mutator phenotype. Thus, as tumor progression selects for cells with specific mutations, it also selects for cancer cells harboring mutations in genes that normally function in maintaining genetic instability.
Loeb
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Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA. laloeb@u.washington.edu
Loeb
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LA
D000818:Animals; D002869:Chromosome Aberrations; D004249:DNA Damage / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D018740:Genetic Heterogeneity; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D010641:Phenotype
D004259:DNA-Directed DNA Polymerase