Abstract 3285: COSMIC-3D: Impacts of cancer mutations on protein structure, function, and druggability

Abstract

Abstract In recent years there has been an explosion in cancer genomic data that has enabled understanding of the incidence and patterns of mutations in cancer patients. The challenge is to translate this vast resource of genomic research and data into precision medicines that target specific mutations in patient populations and improve clinical outcomes. Delivering personalised cancer medicines requires greater understanding of how cancer mutations impact the structure, function, and druggability of known and potential protein drug targets. In this study we annotate each missense mutation in COSMIC, via COSMIC-3D (http://cancer.sanger.ac.uk/cosmic3d), with protein structural features derived from the wwPDB, and rich functional features derived from the UniProt protein database. The structural features include small molecule binding sites (including drug binding sites), protein-protein interaction interfaces, protein-nucleic acid interactions, solvent inaccessible protein “core” versus solvent exposed areas, and predicted small-molecule druggability. The UniProt-derived functional features represent high quality functional site annotations, including post-translational modification sites, functional domains and motifs, and regions of biological interest. In addition, we explore the relationship between mutation occurrence in protein structural and functional sites, and recurrence in cancer. We found that recurrent missense mutations are significantly enriched in specific structural and functional environments, including small-molecule binding sites and predicted druggable pockets. These results provide promising hypotheses that recurrent, cancer driving mutations may be targeted by small-molecule drugs. We posit that further characterisation of the structure-function implications of each mutation in COSMIC-3D will increasingly aid mutation-guided target discovery and drug design. Citation Format: Harry C. Jubb, Harpreet K. Saini, Marcel L. Verdonk, Simon A. Forbes. COSMIC-3D: Impacts of cancer mutations on protein structure, function, and druggability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3285.