Large-scale pathogenicity prediction analysis of cancer-associated kinase mutations reveals variability in sensitivity and specificity of computational methods.

BACKGROUND: Mutations in kinases are the most frequent genetic alterations in cancer; however, experimental evidence establishing their cancerous nature is available only for a small fraction of these mutants. AIMS: Predicition analysis of kinome mutations is the primary aim of this study. Further objective is to compare the performance of various softwares in pathogenicity prediction of kinase mutations. MATERIALS AND METHODS: We employed a set of computational tools to predict the pathogenicity of over forty-two thousand mutations and deposited the kinase-wise data in Mendeley database (Estimated Pathogenicity of Kinase Mutants [EPKiMu]). RESULTS: Mutations are more likely to be drivers when being present in the kinase domain (vs. non-kinase domain) and belonging to hotspot residues (vs. non-hotspot residues). We identified that, while predictive tools have low specificity in general, PolyPhen-2 had the best accuracy. Further efforts to combine all four tools by consensus, voting, or other simple methods did not significantly improve accuracy. DISCUSSION: The study provides a large dataset of kinase mutations along with their predicted pathogenicity that can be used as a training set for future studies. Furthermore, a comparative sensitivity and selectivity of commonly used computational tools is presented. CONCLUSION: Primary-structure-based in silico tools identified more cancerous/deleterious mutations in the kinase domains and at the hot spot residues while having higher sensitivity than specificity in detecting deleterious mutations.

Comparative proteogenomic analysis of right-sided colon cancer, left-sided colon cancer and rectal cancer reveals distinct mutational profiles.

Right-sided colon cancer (RCC) has worse prognosis compared to left-sided colon cancer (LCC) and rectal cancer. The reason for this difference in outcomes is not well understood. We performed comparative somatic and proteomic analyses of RCC, LCC and rectal cancers to understand the unique molecular features of each tumor sub-types. Utilizing a novel in silico clonal evolution algorithm, we identified common tumor-initiating events involving APC, KRAS and TP53 genes in RCC, LCC and rectal cancers. However, the individual role-played by each event, their order in tumor development and selection of downstream somatic alterations were distinct in all three anatomical locations. Some similarities were noted between LCC and rectal cancer. Hotspot mutation analysis identified a nonsense mutation, APC R1450* specific to RCC. In addition, we discovered new significantly mutated genes at each tumor location, Further in silico proteomic analysis, developed by our group, found distinct central or hub proteins with unique interactomes among each location. Our study revealed significant differences between RCC, LCC and rectal cancers not only at somatic but also at proteomic level that may have therapeutic relevance in these highly complex and heterogeneous tumors.