Convergent Evolution in Tumor Genomes Targets Functional Domains.

Area of Science:

• Evolutionary biology
• Genomics
• Cancer research

Background:

• Cancer evolution involves selective pressures favoring similar outcomes across diverse genetic backgrounds.
• Convergent evolution in cancer is typically studied at the gene level.

Purpose of the Study:

• Investigate protein domain selection in cancer evolution.
• Identify functionally convergent targets for cancer therapy.

Main Methods:

• Analyzed >9,500 primary tumor exomes from The Cancer Genome Atlas.
• Quantified selection strengths on missense and truncating mutations aggregated by protein domain.
• Classified positively selected domains by evolutionary antiquity.

Main Results:

• Identified 818 protein domains under significant positive selection across tumor types.
• Half of selected domains belong to genes missed by gene-centric approaches.
• Ancient domains (pre-eukaryotes) involved in core processes accumulated most mutations.
• Eukaryotic domains enriched for regulatory control; metazoan domains for signaling.
• Cancer preferentially exploits deeply conserved biology.

Conclusions:

• A domain-centered framework aids understanding of cancer mechanisms and therapeutic strategies.
• Focusing on shared functional domains identifies convergent therapeutic targets.
• Provides new perspectives on drug resistance, tumor recurrence, and relapse.