Selective pressures on human cancer genes along the evolution of mammals

Abstract Cancer is a disease of the genome caused by somatic mutation and subsequent clonal selection. Several genes associated to cancer in humans, hereafter cancer genes, also show evidence of (germline) positive selection among species. Taking advantage of a large collection of mammalian genomes, we systematically looked for statistically significant signatures of positive selection using dN/dS models in a list of 430 cancer genes. Among these, we identified 63 genes under putative positive selection in mammals, which are significantly enriched in processes like crosslinking DNA repair. We also found evidence of a higher incidence of positive selection in cancer genes bearing germline mutations, like BRCA2, where positively selected residues are physically linked with known pathogenic variants, suggesting a potential association between germline positive selection and risk of hereditary cancer. Overall, our results suggest that genes associated with hereditary cancer have less selective constraints than genes related to sporadic cancer. Also, that the adaptive evolution of human cancer genes in mammals has been most likely driven by adaptive changes in important traits not directly related to cancer.