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

Abstract

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.

Figure 1. Comparison of the time-courses of mutation accumulation with onset of malignancies in the hematopoietic system in mice

Stylized curves represent the numbers of mutations detected in spleens (gray) (12, 19) and lymphoma incidence (black) (20) in C57BL/6 mice.

Figure 2. Selection-centric model

This model posits that aging is largely associated with cancer due to alterations in selection for oncogenic mutations. The weight of the arrow reflects the proposed contribution to cancer incidence.

Figure 3. The Goldilocks Rule for stem cells

A. Young healthy stem cells are proposed to possess parameters (cell cycle, differentiation, interactions with the niche, etc.) that are near optimal (“just right”) for maintenance as a stem cells. Stem cells are presumed to occupy a local fitness peak on the adaptive landscape; cancer cells in the same tissue could occupy a higher peak, but transitions to this peak would require passage through lower fitness states on the landscape (see (36)). Thus, acquisition of a single oncogenic mutation would typically be disadvantageous, by changing parameters from their optimum (see Table 1). B. For old or damaged stem cells, parameters are suboptimal or abnormal, and the stem cells no longer possess optimal or near optimal fitness. Changes in parameters could result from both cell-autonomous events (damage to the stem cells) or from non-cell autonomous changes (such as degradation of the niche or systemic changes). These changes in the stem cell pool can lead to selection for oncogenic events that are adaptive to this context.