Predicting Oncogenic Missense Mutations

With the rapid progress of cancer genome studies, many missense mutations in populations of somatic cells of different cancer types and at different stages have been identified. However, it is challenging to understand the implications of these cancer-related variants. We have developed a computational method that integrates structural, topographical, and evolutionary information for assessments of biochemical effects and the extent of deleteriousness of the cancer-related variants. We have mapped somatic missense mutations from the Catalogue of Somatic Mutations In Cancer (COSMIC) to 3D structures in the Protein Data Bank (PDB). Our results show that a large portion of these missense mutations is located on protein surface pockets, which often serve as a structural and functional unit of cancer variants. We provide detailed analysis of several examples and assessment on the importance of these variants, including prediction of previously unreported cancer-variants, along with independent evidence from the literature. Furthermore, we show our predictions can inform on the functional roles and the mechanism of predicted cancer variants.