Abstract
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Highlights
The theoretical foundations of the modern Multi-Stage Model of Carcinogenesis (MMC) originate from early observations by Fisher and Hollomon (Fisher and Hollomon, 1951) and Nordling (Nordling, 1953) that the age distribution of cancer death rates follows the sixth power of age
We can conclude that even with rapidly decelerating stem cell division rates causing early accumulation of mutations, under select assumptions for numbers of required driver mutations and mutation rate, the current MMC model is still capable of replicating higher late-life rates of somatic evolution, perhaps due to the waiting time necessary for initiated cells to expand into larger clones
Our results indicate that the general principle of successive cell transformations proposed by Nordling, Armitage and Doll (Nordling, 1953; Armitage and Doll, 1954) and later developed into the modern Multi-Stage Model of Carcinogenesis (MMC) recapitulates the late-life exponential increases in the rates of somatic evolution regardless of the non-linear pre-maturity shifts in stem cell division rates
Summary
The theoretical foundations of the modern MMC originate from early observations by Fisher and Hollomon (Fisher and Hollomon, 1951) and Nordling (Nordling, 1953) that the age distribution of cancer death rates follows the sixth power of age. As nothing was known about stem cells and the organization of tissue renewal at the time, Armitage and Doll’s model explained the probability of sequential mutation accumulation from a single cell perspective, being unaware of the effects of clonal selection on these probabilities. Armitage and Doll’s model, as they acknowledged, required that the rate of mutation accumulation is the same throughout lifespan, which was a reasonable assumption at the time. Multiple studies have later challenged this assumption, showing that ~50% of mutations accumulate before maturity (Dolleet al., 2000; Finette et al, 1994; Giese et al, 2002; Horvath, 2013), this early life pattern of mutation accumulation is not universally observed (Welch et al, 2012; Blokzijl et al, 2016; Osorio et al, 2018).
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