Context-dependent selection as the keystone in somatic evolution of cancer

Somatic evolution of cancer involves a series of mutations, and attendant changes, in one or more clones of cells. A "bad luck" type model assumes chance accumulation of mutations. The clonal expansion model assumes, on the other hand, that any mutation leading to partial loss of regulation of cell proliferation will give a selective advantage to the mutant. However, a number of experiments show that an intermediate pre-cancer mutant has only a conditional selective advantage. Given that tissue microenvironmental conditions differ across individual organisms, this selective advantage to a mutant could be widely distributed over the population of organisms. We evaluate three models, namely "bad luck", context-independent, and -dependent selection, in a comparative framework, on their ability to predict patterns in total incidence, age-specific incidence, and their ability to explain Peto's paradox. Results show that context dependence is necessary and sufficient to explain observed epidemiological patterns, and that cancer incidence is largely selection-limited, rather than mutation-limited. A wide range of physiological, genetic and behavioural factors influence the tissue micro-environment, and could therefore be the source of this context dependence in somatic evolution of cancer. The identification and targeting of these micro-environmental factors that influence the dynamics of selection offer new possibilities for cancer prevention.