Computational Approaches to Prioritize Cancer Driver Missense Mutations

Abstract

Cancer is a complex disease that is driven by genetic alterations. There has been a rapid development of genome-wide techniques during the last decade along with a significant lowering of the cost of gene sequencing, which has generated widely available cancer genomic data. However, the interpretation of genomic data and the prediction of the association of genetic variations with cancer and disease phenotypes still requires significant improvement. Missense mutations, which can render proteins non-functional and provide a selective growth advantage to cancer cells, are frequently detected in cancer. Effects caused by missense mutations can be pinpointed by in silico modeling, which makes it more feasible to find a treatment and reverse the effect. Specific human phenotypes are largely determined by stability, activity, and interactions between proteins and other biomolecules that work together to execute specific cellular functions. Therefore, analysis of missense mutations’ effects on proteins and their complexes would provide important clues for identifying functionally important missense mutations, understanding the molecular mechanisms of cancer progression and facilitating treatment and prevention. Herein, we summarize the major computational approaches and tools that provide not only the classification of missense mutations as cancer drivers or passengers but also the molecular mechanisms induced by driver mutations. This review focuses on the discussion of annotation and prediction methods based on structural and biophysical data, analysis of somatic cancer missense mutations in 3D structures of proteins and their complexes, predictions of the effects of missense mutations on protein stability, protein-protein and protein-nucleic acid interactions, and assessment of conformational changes in protein conformations induced by mutations.