Adaptive oncogenesis
Adaptive oncogenesis is a theory of cancer initiation that explains age-related cancer risk by changes in selection rather than by changes in mutation supply. James DeGregori formulated it.
The argument
An oncogenic mutation is a reproductive advantage or disadvantage for a cell, and which one it is depends on the tissue the cell lives in. In young, healthy tissue, cells carrying oncogenic mutations usually divide more slowly or die more readily than their normal neighbors, so selection removes them. Aging, and the damage that comes with it — inflammation, fibrosis, reduced stem-cell competition, altered signaling — changes the relative fitness of cell phenotypes. Mutations that lost in young tissue can win in old tissue, and clones carrying them expand.
On this account, the rise of cancer with age tracks the degradation of the tissue environment at least as much as the accumulation of mutations. The theory explains observations that mutation-accumulation models handle poorly, including the weak relationship between lifetime cell divisions, measured mutation loads, and cancer risk across tissues. The Tomasetti–Vogelstein model addresses tissue-level mutation supply; adaptive oncogenesis addresses what selection does with it.
Practical implications
If tissue state gates which mutations are selected, prevention includes maintaining the young-tissue environment, and treatment includes restoring competition that disadvantages oncogenic clones. The theory also predicts that the same mutation behaves differently in young and old tissue, which is testable in stem-cell competition assays.
Notes
- Draft stub — maintenance agent to expand with DeGregori’s blood stem cell competition experiments and the 2018 book.