Declining cellular fitness with age promotes cancer initiation by selecting for adaptive oncogenic mutations.

Age is the single most important prognostic factor in the development of many cancers. The major reason for this age-dependence is thought to be the progressive accumulation of oncogenic mutations and epigenetic changes. Similarly, mutagens are thought to be carcinogenic primarily by engendering oncogenic mutations. Yet while the accumulation of heritable somatic changes is expected to augment the incidence of oncogenic mutations, a major effect of increased mutation load is reduced fitness. We propose that the fitness of progenitor cell compartments substantially impacts on the selective advantage conferred by particular mutations. We hypothesize that reduced cellular fitness within aged stem cell pools can select for adaptive oncogenic events and thereby promote the initiation of cancer. Thus, certain oncogenic mutations may be adaptive within aged but not young stem cell pools. We further argue that accumulating genetic alterations with age or mutagen exposure might promote cancer not only by causing oncogenic hits within cells but also by leading to eventual reduction in stem cell fitness, which then selects for oncogenic events. Therefore, initial stages of cancer development may not be limited by the incidence of initiating oncogenic changes, but instead by contexts of reduced cellular fitness that select for these changes.