The aim of this study was to identify pathways that have a significant impact during renal carcinogenesis. Sixty-seven paired samples of both noncancerous renal cortex tissue and cancerous tissue from patients with clear cell renal cell carcinomas (RCCs) were subjected to whole-exome, methylome and transcriptome analyses using Agilent SureSelect All Exon capture followed by sequencing on an Illumina HiSeq 2000 platform, Illumina Infinium HumanMethylation27 BeadArray and Agilent SurePrint Human Gene Expression microarray, respectively. Sanger sequencing and quantitative reverse transcription-PCR were performed for technical verification. MetaCore software was used for pathway analysis. Somatic nonsynonymous single-nucleotide mutations, insertions/deletions and intragenic breaks of 2,153, 359 and 8 genes were detected, respectively. Mutations of GCN1L1, MED12 and CCNC, which are members of CDK8 mediator complex directly regulating β-catenin-driven transcription, were identified in 16% of the RCCs. Mutations of MACF1, which functions in the Wnt/β-catenin signaling pathway, were identified in 4% of the RCCs. A combination of methylome and transcriptome analyses further highlighted the significant role of the Wnt/β-catenin signaling pathway in renal carcinogenesis. Genetic aberrations and reduced expression of ERC2 and ABCA13 were frequent in RCCs, and MTOR mutations were identified as one of the major disrupters of cell signaling during renal carcinogenesis. Our results confirm that multilayer-omics analysis can be a powerful tool for revealing pathways that play a significant role in carcinogenesis. What's new? Large-scale systems biology approaches are currently reshaping biomedical research identifying new pathways or reinforcing significance of previously discovered pathways in cancer biology. Here the authors performed multilayer -omics analyses in clear renal carcinoma or healthy control samples. They found frequent tumor-associated genetic aberrations of GCN1L1, MED12, and CCNC, all members of the CDK8 Mediator complex involved in regulating β-catenin- driven transcription, as well as alterations in MACF1, also a member of the Wnt/β-catenin signaling pathway. These findings underscore the significance of the Wnt/β-catenin signaling pathway during renal carcinogenesis and confirm the power of large-scale sequencing efforts in revealing pathways that may become therapeutic targets in specific cancers.
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