Functional consequences of somatic mutations in cancer using protein pocket-based prioritization approach

Abstract

BackgroundRecently, a number of large-scale cancer genome sequencing projects have generated a large volume of somatic mutations; however, identifying the functional consequences and roles of somatic mutations in tumorigenesis remains a major challenge. Researchers have identified that protein pocket regions play critical roles in the interaction of proteins with small molecules, enzymes, and nucleic acid. As such, investigating the features of somatic mutations in protein pocket regions provides a promising approach to identifying new genotype-phenotype relationships in cancer.MethodsIn this study, we developed a protein pocket-based computational approach to uncover the functional consequences of somatic mutations in cancer. We mapped 1.2 million somatic mutations across 36 cancer types from the COSMIC database and The Cancer Genome Atlas (TCGA) onto the protein pocket regions of over 5,000 protein three-dimensional structures. We further integrated cancer cell line mutation profiles and drug pharmacological data from the Cancer Cell Line Encyclopedia (CCLE) onto protein pocket regions in order to identify putative biomarkers for anticancer drug responses.ResultsWe found that genes harboring protein pocket somatic mutations were significantly enriched in cancer driver genes. Furthermore, genes harboring pocket somatic mutations tended to be highly co-expressed in a co-expressed protein interaction network. Using a statistical framework, we identified four putative cancer genes (RWDD1, NCF1, PLEK, and VAV3), whose expression profiles were associated with overall poor survival rates in melanoma, lung, or colorectal cancer patients. Finally, genes harboring protein pocket mutations were more likely to be drug-sensitive or drug-resistant. In a case study, we illustrated that the BAX gene was associated with the sensitivity of three anticancer drugs (midostaurin, vinorelbine, and tipifarnib).ConclusionsThis study provides novel insights into the functional consequences of somatic mutations during tumorigenesis and for anticancer drug responses. The computational approach used might be beneficial to the study of somatic mutations in the era of cancer precision medicine.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-014-0081-7) contains supplementary material, which is available to authorized users.

Tissue-Specific Signaling Networks Rewired by Major Somatic Mutations in Human Cancer Revealed by Proteome-Wide Discovery

“…The distribution is shown in Figure 2B and 2C. We defined the mutations with SIFT scores < 0.95 or PolyPhen-2 score > 0.909 as deleterious mutations based on previous studies (4). We found that phosphorylation site mutations were more likely to be deleterious than non-phosphorylation site mutations when they were evaluated using both SIFT ( P = 1.47×10 −6 , Fisher’s exact test, Fig.…”

“…Currently, how to assess the impact of these somatic mutations in the process of tumorigenesis and disease progression is a main challenge. Considering the existing observations that many somatic mutations promote tumorigenesis by rewiring protein signaling networks (3), one potential strategy is to incorporate somatic mutations with the protein structure information and investigate them at functional sites (e.g., phosphorylation sites) (4–8). Phosphorylation-dependent signaling network is fundamental in cellular physiology and its dysfunction plays a critical role in tumorigenesis.…”

Proteome-Scale Investigation of Protein Allosteric Regulation Perturbed by Somatic Mutations in 7,000 Cancer Genomes

“…66 Our observations on protein allosteric dysregulation by somatic variants (Figure 3) are consistent with those previous studies. 7,65,66 In addition, we further developed a permutation statistical model AlloDriver to focus on identifying disease-associated cancer mutated allosteric proteins at particular function regions, allosteric sites, when analyzing more than 47,000 somatic missense mutations. We identified a series of mutated allosteric proteins that harbor enriched somatic variants at their allosteric sites during our pan-cancer and individual cancer-type analyses.…”

“…6 Identifying the variants altering protein function is a promising strategy for deciphering the biological consequences of somatic mutations during tumorigenesis and would provide novel targets for the development of targeted cancer therapies. 7 Receptors are a class of proteins with dual roles in the recognition of a drug or environmental factors and the transduction of these stimuli into cellular responses. Although most studies on receptor function have focused on how ligands modulate receptor signaling pathways by binding to orthosteric sites, receptor conformation and signal transduction can also be regulated by ligands acting on unique allosteric sites.…”

Small-molecule binding sites to explore protein–protein interactions in the cancer proteome

“…A recent study explored the role of mutations on tumorigenesis (71) and more recently using a structural genomics based approach (72,73). Our work complements these studies by identifying druggable binding pockets and classifying pockets into whether they occur at enzyme active sites or protein-protein interaction sites.…”