title: Multilayer-omics analysis of renal cell carcinoma, including the whole exome, methylome and transcriptome.
abstract: 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.
authors: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
authors: Eri
authors: E
authors: Arai
authors: Hiromi
authors: H
authors: Sakamoto
authors: Hitoshi
authors: H
authors: Ichikawa
authors: Hirohiko
authors: H
authors: Totsuka
authors: Suenori
authors: S
authors: Chiku
authors: Masahiro
authors: M
authors: Gotoh
authors: Taisuke
authors: T
authors: Mori
authors: Tamao
authors: T
authors: Nakatani
authors: Sumiko
authors: S
authors: Ohnami
authors: Tohru
authors: T
authors: Nakagawa
authors: Hiroyuki
authors: H
authors: Fujimoto
authors: Linghua
authors: L
authors: Wang
authors: Hiroyuki
authors: H
authors: Aburatani
authors: Teruhiko
authors: T
authors: Yoshida
authors: Yae
authors: Y
authors: Kanai
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics*; D019175:DNA Methylation; D059472:Exome; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D059467:Transcriptome
chemical_list: D012333:RNA, Messenger
keywords: CDK8 mediator complex; Wnt/β-catenin signaling pathway; clear cell renal cell carcinoma (RCC); multilayer-omics analysis; whole exome analysis