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

被引：39

作者：

Arai, Eri ^{[1
]}

Gotoh, Masahiro ^{[1
]}

Tian, Ying ^{[1
]}

Sakamoto, Hiromi ^{[2
]}

Ono, Masaya ^{[3
]}

Matsuda, Akio ^{[4
]}

Takahashi, Yoriko ^{[5
]}

Miyata, Sayaka ^{[5
]}

Totsuka, Hirohiko ^{[6
]}

Chiku, Suenori ^{[7
]}

Komiyama, Motokiyo ^{[8
]}

Fujimoto, Hiroyuki ^{[8
]}

Matsumoto, Kenji ^{[4
]}

Yamada, Tesshi ^{[3
]}

Yoshida, Teruhiko ^{[2
]}

Kanai, Yae ^{[1
]}

机构：

[1] Natl Canc Ctr, Div Mol Pathol, Tokyo 1040045, Japan

[2] Natl Canc Ctr, Div Genet, Tokyo 1040045, Japan

[3] Natl Canc Ctr, Div Chemotherapy & Clin Res, Tokyo 1040045, Japan

[4] Natl Res Inst Child Hlth & Dev, Dept Allergy & Immunol, Tokyo, Japan

[5] Mitsui Knowledge Ind Co Ltd, Business Dev Div, Biosci Dept, Tokyo, Japan

[6] Hitachi Govt & Publ Corp Syst Engn Ltd, Solut Div 4, Ctr Res & Dev, Bioinformat Grp, Tokyo, Japan

[7] Mizuho Informat & Res Inst Inc, Sci Solut Div, Tokyo, Japan

[8] Natl Canc Ctr, Dept Urol, Tokyo, Japan

来源：

INTERNATIONAL JOURNAL OF CANCER | 2015年 / 137卷 / 11期

基金：

日本学术振兴会;

关键词：

aurora kinases; spindle checkpoint; clear cell renal cell carcinoma (RCC); CpG island methylator phenotype (CIMP); multi-layer omics analysis; PRECANCEROUS CONDITIONS; WHOLE-EXOME; AURORA; COMPLEX; PROTEIN; PROFILES; PROGNOSTICATION; OVEREXPRESSION; EPIGENETICS; INHIBITOR;

D O I：

10.1002/ijc.29630

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 x 10(-6))," "Role of Anaphase Promoting Complex in cell cycle regulation (p=7.444 x 10(-6))" and " Spindle assembly and chromosome separation (p=9.260 x 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.

引用

页码：2589 / 2606

页数：18

共 50 条

[1] Regional DNA hypermethylation and DNA methyltransferase (DNMT) 1 protein overexpression in both renal tumors and corresponding nontumorous renal tissues [J].