Challenging the axiom: does the occurrence of oncogenic mutations truly limit cancer development with age?

A widely accepted paradigm in cancer research holds that the development of cancers is rate limited by the occurrence of oncogenic mutations. In particular, the exponential rise in the incidence of most cancers with age is thought to reflect the time required for cells to accumulate the multiple oncogenic mutations needed to confer the cancer phenotype. Here I will argue against the axiom that the occurrence of oncogenic mutations limits cancer incidence with age, based on several observations, including that the rate of mutation accumulation is maximal during ontogeny, oncogenic mutations are frequently detected in normal tissues, the evolution of complex multicellularity was not accompanied by reductions in mutation rates, and that many oncogenic mutations have been shown to impair stem cell activity. Moreover, although evidence that has been used to support the current paradigm includes increased cancer incidence in individuals with inherited DNA repair deficiencies or exposed to mutagens, the pleotropic effects of these contexts could enhance tumorigenesis at multiple levels. I will further argue that age-dependent alteration of selection for oncogenic mutations provides a more plausible explanation for increased cancer incidence in the elderly. Although oncogenic mutations are clearly required for cancer evolution, together these observations counter the common view that age dependence of cancers is largely explained by the time required to accumulate sufficient oncogenic mutations.