Mechanisms of Selection on Cancer-Causing Mutations

The mainstream thinking in the somatic evolution of cancer is mainly mutation centered. In contrast, the evolutionary idea that selection rather than mutation is rate-limiting in cancers is a recent realization. So far, however, there are few insights into how selection works on cancer-causing mutations in the context of the tissue microenvironment. A cancer-causing mutant also causes one or more disruptions of normal cellular metabolism. Therefore, the mutant is unlikely to be selected in competition with normal cells. However, under specific contexts, when the normal adult stem cell dynamics are altered, the mutant is likely to gain a selective advantage and thereby outgrow normal cells. We suggest a battery of hypotheses about how context-dependent selection is likely to act at the cellular and molecular levels. We also weigh the hypotheses against available evidence and suggest a line of experiments that can test them.