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Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas

CpG‐island methylator phenotype (CIMP)‐positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poor patient outcome. The aim of this study was to clarify the molecular pathways participating in...

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Autores principales: Arai, Eri, Gotoh, Masahiro, Tian, Ying, Sakamoto, Hiromi, Ono, Masaya, Matsuda, Akio, Takahashi, Yoriko, Miyata, Sayaka, Totsuka, Hirohiko, Chiku, Suenori, Komiyama, Motokiyo, Fujimoto, Hiroyuki, Matsumoto, Kenji, Yamada, Tesshi, Yoshida, Teruhiko, Kanai, Yae
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755138/
https://www.ncbi.nlm.nih.gov/pubmed/26061684
http://dx.doi.org/10.1002/ijc.29630
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author Arai, Eri
Gotoh, Masahiro
Tian, Ying
Sakamoto, Hiromi
Ono, Masaya
Matsuda, Akio
Takahashi, Yoriko
Miyata, Sayaka
Totsuka, Hirohiko
Chiku, Suenori
Komiyama, Motokiyo
Fujimoto, Hiroyuki
Matsumoto, Kenji
Yamada, Tesshi
Yoshida, Teruhiko
Kanai, Yae
author_facet Arai, Eri
Gotoh, Masahiro
Tian, Ying
Sakamoto, Hiromi
Ono, Masaya
Matsuda, Akio
Takahashi, Yoriko
Miyata, Sayaka
Totsuka, Hirohiko
Chiku, Suenori
Komiyama, Motokiyo
Fujimoto, Hiroyuki
Matsumoto, Kenji
Yamada, Tesshi
Yoshida, Teruhiko
Kanai, Yae
author_sort Arai, Eri
collection PubMed
description CpG‐island methylator phenotype (CIMP)‐positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poor patient outcome. The aim of this study was to clarify the molecular pathways participating in CIMP‐positive renal carcinogenesis. Genome (whole‐exome and copy number), transcriptome and proteome (two‐dimensional image converted analysis of liquid chromatography‐mass spectrometry) analyses were performed using tissue specimens of 87 CIMP‐negative and 14 CIMP‐positive clear cell RCCs and corresponding specimens of non‐cancerous renal cortex. Genes encoding microtubule‐associated proteins, such as DNAH2, DNAH5, DNAH10, RP1 and HAUS8, showed a 10% or higher incidence of genetic aberrations (non‐synonymous single‐nucleotide mutations and insertions/deletions) in CIMP‐positive RCCs, whereas CIMP‐negative RCCs lacked distinct genetic characteristics. MetaCore pathway analysis of CIMP‐positive RCCs revealed that alterations of mRNA or protein expression were significantly accumulated in six pathways, all participating in the spindle checkpoint, including the “The metaphase checkpoint (p = 1.427 × 10(−6)),” “Role of Anaphase Promoting Complex in cell cycle regulation (p = 7.444 × 10(−6))” and “Spindle assembly and chromosome separation (p = 9.260 × 10(−6))” pathways. Quantitative RT‐PCR analysis revealed that mRNA expression levels for genes included in such pathways, i.e., AURKA, AURKB, BIRC5, BUB1, CDC20, NEK2 and SPC25, were significantly higher in CIMP‐positive than in CIMP‐negative RCCs. All CIMP‐positive RCCs showed overexpression of Aurora kinases, AURKA and AURKB, and this overexpression was mainly attributable to increased copy number. These data suggest that abnormalities of the spindle checkpoint pathway participate in CIMP‐positive renal carcinogenesis, and that AURKA and AURKB may be potential therapeutic targets in more aggressive CIMP‐positive RCCs.
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spelling pubmed-47551382016-02-25 Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas Arai, Eri Gotoh, Masahiro Tian, Ying Sakamoto, Hiromi Ono, Masaya Matsuda, Akio Takahashi, Yoriko Miyata, Sayaka Totsuka, Hirohiko Chiku, Suenori Komiyama, Motokiyo Fujimoto, Hiroyuki Matsumoto, Kenji Yamada, Tesshi Yoshida, Teruhiko Kanai, Yae Int J Cancer Cancer Genetics CpG‐island methylator phenotype (CIMP)‐positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poor patient outcome. The aim of this study was to clarify the molecular pathways participating in CIMP‐positive renal carcinogenesis. Genome (whole‐exome and copy number), transcriptome and proteome (two‐dimensional image converted analysis of liquid chromatography‐mass spectrometry) analyses were performed using tissue specimens of 87 CIMP‐negative and 14 CIMP‐positive clear cell RCCs and corresponding specimens of non‐cancerous renal cortex. Genes encoding microtubule‐associated proteins, such as DNAH2, DNAH5, DNAH10, RP1 and HAUS8, showed a 10% or higher incidence of genetic aberrations (non‐synonymous single‐nucleotide mutations and insertions/deletions) in CIMP‐positive RCCs, whereas CIMP‐negative RCCs lacked distinct genetic characteristics. MetaCore pathway analysis of CIMP‐positive RCCs revealed that alterations of mRNA or protein expression were significantly accumulated in six pathways, all participating in the spindle checkpoint, including the “The metaphase checkpoint (p = 1.427 × 10(−6)),” “Role of Anaphase Promoting Complex in cell cycle regulation (p = 7.444 × 10(−6))” and “Spindle assembly and chromosome separation (p = 9.260 × 10(−6))” pathways. Quantitative RT‐PCR analysis revealed that mRNA expression levels for genes included in such pathways, i.e., AURKA, AURKB, BIRC5, BUB1, CDC20, NEK2 and SPC25, were significantly higher in CIMP‐positive than in CIMP‐negative RCCs. All CIMP‐positive RCCs showed overexpression of Aurora kinases, AURKA and AURKB, and this overexpression was mainly attributable to increased copy number. These data suggest that abnormalities of the spindle checkpoint pathway participate in CIMP‐positive renal carcinogenesis, and that AURKA and AURKB may be potential therapeutic targets in more aggressive CIMP‐positive RCCs. John Wiley and Sons Inc. 2015-06-30 2015-12-01 /pmc/articles/PMC4755138/ /pubmed/26061684 http://dx.doi.org/10.1002/ijc.29630 Text en © 2015 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Cancer Genetics
Arai, Eri
Gotoh, Masahiro
Tian, Ying
Sakamoto, Hiromi
Ono, Masaya
Matsuda, Akio
Takahashi, Yoriko
Miyata, Sayaka
Totsuka, Hirohiko
Chiku, Suenori
Komiyama, Motokiyo
Fujimoto, Hiroyuki
Matsumoto, Kenji
Yamada, Tesshi
Yoshida, Teruhiko
Kanai, Yae
Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas
title Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas
title_full Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas
title_fullStr Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas
title_full_unstemmed Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas
title_short Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas
title_sort alterations of the spindle checkpoint pathway in clinicopathologically aggressive cpg island methylator phenotype clear cell renal cell carcinomas
topic Cancer Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755138/
https://www.ncbi.nlm.nih.gov/pubmed/26061684
http://dx.doi.org/10.1002/ijc.29630
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