Suppression of cancer is a necessary component of species longevity, and finding out how exactly cancer incidence is in some cases dramatically reduced is one of the primary goals for the field of comparative biology. Here, researchers survey known cancer-associated sequences across the genomes of long-lived and short-lived species, and see that sequences are more conserved in long-lived species. Patterns of epigenetic modifications to the genome at these locations also exhibit differences in long-lived species. Thus one component of reduced cancer risk in these species involves specific sequence differences in oncogenes and related genes, and different expression of oncogenes in circumstances relevant to induction of cancer.
Recently, accumulated evidence has shown that longer-lived species, such as naked mole rats, elephants, and some bat species display enhanced resistance to cancer. In this study, we identify genomic sites in 58 mammalian species that are homologous to human cancer-associated regions and compare their evolutionary dynamics to those of cancer-unrelated sites. By contrasting mutation rates in longer-lived versus shorter-lived species, we evaluate whether evolutionary constraint at these loci correlates with lifespan or body size. Because epigenetic modifications are intimately linked to oncogenesis, and synonymous changes can affect tumorigenesis by perturbing m6A deposition, we also examine the distribution of 5mC and m6A marks at cancer-associated versus unrelated sites across the two lifespan groups.
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 messenger RNA 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.
