ABSTRACT: An accumulation of driver mutations is important for cancer formation and progression, and leads to the disruption of genes and signaling pathways. The identification of driver mutations and genes has been the subject of numerous previous studies. The present study was performed to identify cancer-driving mutations and genes in renal cell carcinoma (RCC), prioritizing noncoding variants with a high functional impact, in order to analyze the most informative features. Sorting Intolerant From Tolerant (SIFT), Polymorphism Phenotyping version 2 (Polyphen2) and MutationAssessor were applied to predict deleterious mutations in the coding genome. OncodriveFM and OncodriveCLUST were used to detect potential driver genes and signaling pathways. The functional impact of noncoding variants was evaluated using Combined Annotation Dependent Depletion, FunSeq2 and Genome-Wide Annotation of Variants. Noncoding features were analyzed with respect to their enrichment of high-scoring variants. A total of 1,327 coding mutations in clear cell RCC, 258 in chromophobe RCC and 1,186 in papillary RCC were predicted to be deleterious by all three of MutationAssessor, Polyphen2 and SIFT. In total, 77 genes were positively selected by OncodriveFM and 1 by OncodriveCLUST, 45 of which were recurrently mutated genes. In addition, 10 signaling pathways were recurrently mutated and had a high functional impact bias (FM bias), and 31 novel signaling pathways with high FM bias were identified. Furthermore, noncoding regulatory features and conserved regions contained numerous high-scoring variants, and expression, replication time, GC content and recombination rate were positively correlated with the densities of high-scoring variants. In conclusion, the present study identified a list of cancer-driving genes and signaling pathways, features like regulatory elements, conserved regions, replication time, expression, GC content and recombination rate are major factors that affect the distribution of high-scoring non-coding mutations in kidney cancer.
