Longer-lived mammals exhibit greater evolutionary conservatism and epigenetic modification at cancer-associated loci

Peto’s paradox underscores the puzzling disconnect between organismal lifespan, body size, and cancer incidence. Here, we investigate this relationship by examining the evolutionary rates of human cancer-associated sites across 58 mammalian species. While overall evolutionary rates at cancer-associated loci do not differ significantly between long-lived and short-lived species, cancer-associated sites show greater evolutionary conservation relative to non-cancer sites within long-lived mammals but not within short-lived mammals. Furthermore, long-lived species exhibit a pronounced enrichment of m6A at cancer-associated loci (based on m6A modification sites derived exclusively from male samples) despite lower global m6A levels. Notably, tumor suppressor genes in long-lived mammals harbor proportionally more m6A-modified transcripts, suggesting a potential association between mRNA methylation and post-transcriptional regulation at cancer-relevant loci. Together, these results suggest that enhanced sequence conservation at cancer loci, coupled with targeted mRNA modification, may be part of a multilayered molecular strategy that reduces cancer risk in long‑lived mammals. Peto’s paradox establishes how cancer incidence mostly does not scale predictably with body size or lifespan among different species. Here, the authors explore this relationship by examining the evolutionary rates of human cancer-associated sites across 58 mammalian species, finding greater conservation of cancer-associated sites relative to cancer-unrelated sites within long-lived mammals, as well as an association with mRNA methylation.