An integrative approach uncovers genes with perturbed interactions in cancers

A major challenge in cancer genomics is to identify genes with functional roles in cancer and uncover their mechanisms of action. Here, we introduce a unified analytical framework that enables rapid integration of multiple sources of information in order to identify cancer-relevant genes by pinpointing those whose interaction or other functional sites are enriched in somatic mutations across tumors. Our accompanying method PertInInt combines knowledge about sites participating in interactions with DNA, RNA, peptides, ions or small molecules with domain, evolutionary conservation and gene-level mutation data. When applied to 10,037 tumor samples across 33 cancer types, PertInInt uncovers both known and newly predicted cancer genes, while simultaneously revealing whether interaction potential or other functionalities are disrupted. PertInInt9s analysis demonstrates that somatic mutations are frequently enriched in binding residues and domains in oncogenes and tumor suppressors, and implicates interaction perturbation as a pervasive cancer driving event.