title: Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas.
abstract: 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.
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Arai
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Gotoh
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakamoto
authors.affiliation: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Ono
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Matsuda
authors.affiliation: Bioscience Department, Business Development Division, Mitsui Knowledge Industry Co. Ltd, Tokyo, Japan.
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Bioscience Department, Business Development Division, Mitsui Knowledge Industry Co. Ltd, Tokyo, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Miyata
authors.affiliation: Bioinformatics Group, Research and Development Center, Solution Division 4, Hitachi Government and Public Corporation System Engineering Ltd, Tokyo, Japan.
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Totsuka
authors.affiliation: Science Solutions Division, Mizuho Information and Research Institute, Inc, Tokyo, Japan.
authors.forename: Suenori
authors.initials: S
authors.lastname: Chiku
authors.affiliation: Department of Urology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Motokiyo
authors.initials: M
authors.lastname: Komiyama
authors.affiliation: Department of Urology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fujimoto
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Tesshi
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yae
authors.initials: Y
authors.lastname: Kanai
mesh_terms: D000368:Aged; D064127:Aurora Kinases / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology*; D002869:Chromosome Aberrations; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology*; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype; D020543:Proteome / Q000235:genetics; D059467:Transcriptome / Q000235:genetics
chemical_list: D008869:Microtubule-Associated Proteins; D020543:Proteome; D064127:Aurora Kinases
keywords: CpG island methylator phenotype (CIMP); aurora kinases; clear cell renal cell carcinoma (RCC); multi-layer omics analysis; spindle checkpoint