A Pan-cancer catalogue of driver protein interaction interfaces

Abstract

Despite their critical importance in maintaining the integrity of all cellular pathways, the specific role of mutations on protein-protein interaction (PPI) interfaces as cancer drivers, though known for some specific examples, has not been systematically studied. We analyzed missense somatic mutations in a pan-cancer cohort of 5,989 tumors from 23 projects of The Cancer Genome Atlas (TCGA) for enrichment on PPI interfaces using e-Driver, an algorithm to analyze the mutation pattern of specific protein regions such as PPI interfaces. We identified 128 PPI interfaces enriched in somatic cancer mutations. Our results support the notion that many mutations in well-established cancer driver genes, particularly those in critical network positions, act by altering PPI interfaces. Finally, focusing on individual interfaces we are also able to show how tumors driven by the same gene can have different behaviors, including patient outcomes, depending on whether specific interfaces are mutated or not.