Pan-cancer analysis reveals age-associated genetic alterations in protein domains

Cancer incidence and mortality differ among individuals of different ages, but the functional consequences of genetic alterations remain largely unknown. We systematically characterized genetic alterations within protein domains stratified by affected individual's age and showed that the mutational effects on domains varied with age. We further identified potential age-associated driver genes with hotspots across 33 cancers. The candidate drivers involved numerous cancer-related genes that participate in various oncogenic pathways and play central roles in human protein-protein interaction (PPI) networks. We found widespread age biases in protein domains and identified the associations between hotspots and age. Age-stratified PPI networks perturbed by hotspots were constructed to illustrate the function of mutations enriched in domains. We found that hotspots in young adults were associated with premature senescence. In summary, we provided a catalog of age-associated hotspots and their perturbed networks, which may facilitate precision diagnostics and treatments for cancer.