Convergent Evolution in Tumor Genomes Targets Functional Domains

Tumor evolution is shaped by selective pressures that repeatedly favor similar functional outcomes across genetically distinct cancers. While convergent evolution in cancer has been studied at the gene level, this work investigates selection on smaller functional units, namely protein domains. Using >9,500 primary tumor exomes from The Cancer Genome Atlas, we quantified selection strengths acting on missense and truncating mutations aggregated by protein domain. This analysis identified 818 domains under significant positive selection across tumor types. Notably, approximately half of these domains belonged to genes that would be difficult to implicate using conventional gene-centric approaches due to low mutational recurrence or mutations outside functionally critical regions. We classified positively selected domains by evolutionary antiquity. The most ancient domains trace back to pre-eukaryotes and are involved in core cellular processes (e.g., DNA mismatch repair and metabolism) and tend to accumulate the highest numbers of mutations. The majority of positively selected domains originated in early eukaryotes and are enriched for regulatory control and cellular organization, whereas metazoan-specific domains are primarily associated with signaling and cell-cell communication. These results suggest that cancer preferentially exploits deeply conserved biology, with regulatory complexity driving tumor adaptation, while recent evolutionary innovations are relatively fragile and dispensable. Collectively, these findings establish a domain-centered framework for understanding disease mechanisms and developing therapeutic strategies. By focusing on shared functional domains, this framework enables the identification of functionally convergent therapeutic targets and provides a new perspective for interpreting drug resistance, tumor recurrence, and relapse.