Multilayer-omics analysis of renal cell carcinoma, including the whole exome, methylome and transcriptome

Eri Arai, Hiromi Sakamoto, Hitoshi Ichikawa, Hirohiko Totsuka, Suenori Chiku, Masahiro Gotoh, Taisuke Mori, Tamao Nakatani, Sumiko Ohnami, Tohru Nakagawa, Hiroyuki Fujimoto, Linghua Wang, Hiroyuki Aburatani, Teruhiko Yoshida, Yae Kanai

Research output: Contribution to journalArticle

31 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)1330-1342
Number of pages13
JournalInternational Journal of Cancer
Volume135
Issue number6
DOIs
Publication statusPublished - 2014 Sep 15
Externally publishedYes

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Exome
Catenins
Transcriptome
Renal Cell Carcinoma
Wnt Signaling Pathway
Carcinogenesis
Kidney
Mediator Complex
Gene Expression Profiling
Mutation
INDEL Mutation
Neoplasms
Systems Biology
Reverse Transcription
Biomedical Research
Exons
Software
Nucleotides
Carcinoma
Gene Expression

Keywords

  • CDK8 mediator complex
  • clear cell renal cell carcinoma (RCC)
  • multilayer-omics analysis
  • whole exome analysis
  • Wnt/β-catenin signaling pathway

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Multilayer-omics analysis of renal cell carcinoma, including the whole exome, methylome and transcriptome. / Arai, Eri; Sakamoto, Hiromi; Ichikawa, Hitoshi; Totsuka, Hirohiko; Chiku, Suenori; Gotoh, Masahiro; Mori, Taisuke; Nakatani, Tamao; Ohnami, Sumiko; Nakagawa, Tohru; Fujimoto, Hiroyuki; Wang, Linghua; Aburatani, Hiroyuki; Yoshida, Teruhiko; Kanai, Yae.

In: International Journal of Cancer, Vol. 135, No. 6, 15.09.2014, p. 1330-1342.

Research output: Contribution to journalArticle

Arai, E, Sakamoto, H, Ichikawa, H, Totsuka, H, Chiku, S, Gotoh, M, Mori, T, Nakatani, T, Ohnami, S, Nakagawa, T, Fujimoto, H, Wang, L, Aburatani, H, Yoshida, T & Kanai, Y 2014, 'Multilayer-omics analysis of renal cell carcinoma, including the whole exome, methylome and transcriptome', International Journal of Cancer, vol. 135, no. 6, pp. 1330-1342. https://doi.org/10.1002/ijc.28768
Arai, Eri ; Sakamoto, Hiromi ; Ichikawa, Hitoshi ; Totsuka, Hirohiko ; Chiku, Suenori ; Gotoh, Masahiro ; Mori, Taisuke ; Nakatani, Tamao ; Ohnami, Sumiko ; Nakagawa, Tohru ; Fujimoto, Hiroyuki ; Wang, Linghua ; Aburatani, Hiroyuki ; Yoshida, Teruhiko ; Kanai, Yae. / Multilayer-omics analysis of renal cell carcinoma, including the whole exome, methylome and transcriptome. In: International Journal of Cancer. 2014 ; Vol. 135, No. 6. pp. 1330-1342.
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AU - Chiku, Suenori

AU - Gotoh, Masahiro

AU - Mori, Taisuke

AU - Nakatani, Tamao

AU - Ohnami, Sumiko

AU - Nakagawa, Tohru

AU - Fujimoto, Hiroyuki

AU - Wang, Linghua

AU - Aburatani, Hiroyuki

AU - Yoshida, Teruhiko

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N2 - 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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