Abstract 858: A functional atlas of cancer mutation-rewired protein interactome networks

Abstract

Abstract Somatic mutations in cancer can exert effects on protein-protein interactions (PPIs), leaving some wild-type (WT) interactions perturbed while others unperturbed. The type of PPI perturbations can be used to link the mutation to its phenotypic effects. Here, we apply a technique known as functional variomics to characterize PPI profile changes for around 1,000 cancer missense mutations. Remarkably, our results reveal 5 distinct classes (edgotypes) of mutations: mutations losing PPIs compared to WT (edgetic), gaining PPIs (gain), gaining & losing PPIs (gain/loss), losing all PPIs (quasi-null), and those that do not perturb PPIs (quasi-WT). Notably, gastroenterological cancers have a greater proportion of edgetic mutations, whereas reproductive cancers have a greater proportion of gain edgotype mutations, demonstrating the link between edgotype and cancer type. We further show that more severe cancer stages are associated with interaction-perturbing mutation edgotypes, and the gain/loss edgotype is the most deleterious of all. In addition, pathway enrichment analysis suggests that the edgotypes are predictive of biological effects. For example, mutation edgotypes with loss of interactions are involved in apoptotic process and DNA damage repair, consistent with the expected loss of such functions in cancer. Meanwhile, gain edgotype is linked with cell division and G2/M transition. To our knowledge, this represents the first attempt to perform systematic interactome profiling for cancer mutations. As our results can reveal specific phenotypic attributes and biological functions that are altered for different PPI profiles, our functional platform is important for cancer precision medicine. Our study strengthens the link between genotypes and phenotypes while illustrating the significance of edgotypes in complex disease modeling. Citation Format: Anjali Agrawal, Daniel McGrail, Nidhi Sahni, S. Stephen Yi. A functional atlas of cancer mutation-rewired protein interactome networks [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 858.