ABSTRACT
Recently, it has been showed that cancer missense mutations selectively target the neighborhood of hinge residues, which are key sites in protein dynamics. Here, we show that this approach can be extended to find previously unknown candidate mutations and genes. To this aim, we developed a computational pipeline to detect significantly enriched three-dimensional (3D) clustering of missense mutations around hinge residues. The hinge residues were detected by applying a Gaussian network model. By systematically analyzing the PanCancer compendium of somatic mutations in nearly 10 000 tumors from the Cancer Genome Atlas, we identified candidate genes and mutations in addition to well known ones. For instance, we found significantly enriched 3D clustering of missense mutations in known cancer genes including CDK4, CDKN2A, TCL1A, and MAPK1. Beside these known genes, we also identified significantly enriched 3D clustering of missense mutations around hinge residues in PLA2G4A, which may lead to excessive phosphorylation of the extracellular signal-regulated kinases. Furthermore, we demonstrated that hinge-based features improves pathogenicity prediction for missense mutations. Our results show that the consideration of clustering around hinge residues can help us explain the functional role of the mutations in known cancer genes and identify candidate genes.
Subject(s)
Computational Biology/methods , Group IV Phospholipases A2/genetics , Mutation, Missense , Neoplasm Proteins/genetics , Neoplasms/genetics , Atlases as Topic , Cyclin-Dependent Kinase 4/genetics , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Gene Expression Regulation, Neoplastic , Group IV Phospholipases A2/metabolism , Humans , Mitogen-Activated Protein Kinase 1/genetics , Mitogen-Activated Protein Kinase 1/metabolism , Models, Molecular , Multigene Family , Neoplasm Proteins/metabolism , Neoplasms/metabolism , Neoplasms/pathology , Phosphorylation , Protein Conformation , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolismABSTRACT
Missense mutations have various effects on protein structures, also leading to distorted protein dynamics that plausibly affects the function. We hypothesized that missense mutations in cancer-related genes selectively target hinge-neighboring residues that orchestrate collective structural dynamics. To test our hypothesis, we selected 69 cancer-related genes from the Cancer Gene Census database and their representative protein structures from the Protein Data Bank. We first identified the hinge residues in two global modes of motion by applying the Gaussian Network Model. We then showed that missense mutations are significantly enriched on hinge-neighboring residues in oncogenes and tumor suppressor genes. We observed that several oncogenes (eg, MAP2K1, PTPN11, and KRAS) and tumor suppressor genes (eg, EZH2, CDKN2C, and RHOA) strongly exhibit this phenomenon. This study highlights and rationalizes the functional importance of missense mutations on hinge-neighboring residues in cancer.
