Abstract 3375: leveraging protein dynamics to identify mutational hotspot communities in cancer driver genes

Abstract

Abstract Large-scale exome sequencing of tumor genomes has enabled the identification of cancer driver genes using recurrence analysis and clustering-based approaches. Some of these methods also employ 3D protein structural data to identify missense mutational hotspots in many cancer-associated genes. However, in determining such mutational clusters in protein structures, a majority of these approaches overlook the role of protein dynamics. In this work, we present a novel framework to identify cancer driver genes using a more sensitive search of mutational hotspot communities on protein structures by incorporating models of protein dynamics. We applied our method to the TCGA pan-cancer atlas missense mutation catalog to identify cancer genes with hotspot mutational clusters within their associated PDB structures. Overall, our analysis predicts one or more mutational hotspot within the resolved structures of known as well as novel cancer driver genes. Ontological enrichment analysis implicates the roles of genes with predicted hotspots in vital biological processes, including cell differentiation, cell proliferation, signal transduction, kinase activity, and nucleotide binding. Furthermore, a comparison between our approach with previous 3D structure-based cancer hotspot detection methods suggests that the including protein dynamics significantly improves the identification of additional putative driver genes. In summary, our proposed framework predicts novel cancer driver genes and provides mechanistic insight into cancer progression through the lens mutational hotspots. Citation Format: Sushant Kumar, Declan Clarke, Mark Gerstein. leveraging protein dynamics to identify mutational hotspot communities in cancer driver genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3375.