Exploring the relationship between neutral and selective mutations in cancer.
The transformation of normal cells into cancerous cells is an evolutionary process. Populations of precancerous cells reproduce, mutate, and compete for resources. Some of these mutations eventually lead to cancer. We calculate the probability of developing cancer under a set of simplifying assumptions and then elaborate these calculations, culminating in a simple simulation of the cell dynamics. The agent-based model allows us to examine the interactions of mutations critical for the development of cancer that are either evolutionarily neutral or selective. We can also examine the interaction of these mutations with a "mutator phenotype" derived from mutations that raise the mutation rate for the entire cell. The simulations suggest that there must be at least two selectively neutral mutations necessary for the development of cancer and that preventive treatments will be most effective when they increase this number. The model also suggests that selective mutations facilitate the development of cancer, so that the more selective mutations necessary for the development of cancer, the greater the chance of developing it.
Maley
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Fred Hutchinson Cancer Research Center, 1100 Fairview Ave., N. Seattle, WA 98109, USA. cmaley@alum.mit.edu
Forrest
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D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics*; D001471:Barrett Esophagus / Q000235:genetics / Q000503:physiopathology; D005075:Biological Evolution; D003198:Computer Simulation; D004938:Esophageal Neoplasms / Q000209:etiology / Q000235:genetics*; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011230:Precancerous Conditions; D011336:Probability; D012307:Risk Factors