Peto's paradox and the hallmarks of cancer: constructing an evolutionary framework for understanding the incidence of cancer.

An evolutionary perspective can help unify disparate observations and make testable predictions. We consider an evolutionary model in relation to two mechanistic frameworks of cancer biology: multistage carcinogenesis and the hallmarks of cancer. The multistage model predicts that cancer risk increases with body size and longevity; however, this is not observed across species (Peto's paradox), but the paradox is resolved by invoking the evolution of additional genetic mechanisms to suppress cancer in large, long-lived species. It is when cancer cells overcome these defence mechanisms that they exhibit the hallmarks of cancer, driving the ongoing evolution of these defences, which in turn is expected to create the differences observed in the genetics of cancer across species and tissues. To illustrate the utility of an evolutionary model we examined some recently published data linking stem-cell divisions and cancer incidence across a range of tissues and show why the original analysis was faulty, and demonstrate that the data are consistent with a multistage model varying from three to seven mutational hits across different tissues. Finally, we demonstrate how an evolutionary model can both define patterns of inherited (familial) cancer and explain the prevalence of cancer in post-reproductive years, including the dominance of epithelial cancers.