Single-CpG-resolution methylome analysis identifies clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas

Arai, Eri; Chiku, Suenori; Mori, Taisuke; Gotoh, Masahiro; Nakagawa, Tohru; Fujimoto, Hiroyuki; Kanai, Yae

doi:10.1093/carcin/bgs177

Cited by 117 publications

(153 citation statements)

References 37 publications

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“…Specific DNA hypermethylation of CpG sites on TRH gene was only reported over last years in RCC (42), and no further clinically relevant data is available at this time.…”

Section: Thyrotropin-releasing Hormone (Prolactin-releasing Hormone-tmentioning

confidence: 98%

Hormone signaling pathways as treatment targets in renal cell cancer (Review)

Czarnecka

Niedzwiedzka

Porta

et al. 2016

International Journal of Oncology

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Abstract. Epidemiological, clinical, biochemical and genetic research has revealed that renal cell cancer (RCC) etiology is hormone-related. It was shown that hormone receptors are abnormally expressed in RCC cells. Abnormal endocrine stimulation also plays a significant role in RCC pathophysiology. Cellular proliferation, migration, angiogenesis, and drug resistance in RCC is modulated by para-and autocrine hormonal stimulation. In particular, RCC overexpression of gonadotropin-releasing hormone and its receptor was reported. On the contrary, corticotropin releasing hormone was reported to inhibit RCC cell proliferation and regulate angiogenesis. Overexpression of luteinizing hormone also promotes RCC tumor angiogenesis. Estrogen receptor α overexpression increases the transcriptional factor activity of hypoxia inducible factor HIF-1α, but estrogen receptor β has a cancer suppressive role. Glucocorticoid receptors and androgen receptor are markers of indolent RCC and assigned tumor suppressive activity. Proopiomelanocortin is upregulated in VHL-mutated renal cell carcinoma via Nur77 transcription factor signaling. In RCC, follicle-stimulating hormone receptor promotes angiogenesis and metastatic formation via VEGF release. Mineralocorticoid receptor overexpression promotes cell survival and increases RCC cell proliferation. Vitamin D receptor expression is downregulated or absent in RCC and differentiate subtypes of renal cell tumors. RAR-β promotes tumorigenesis but retinoic acid receptor γ expression correlates negatively with the TNM stage at diagnosis. Finally, progesterone receptor expression is negatively correlated with the cancer stage. Molecular data analysis revealed the possibility of renal cancer cell proliferation induction via hormone activated pathways. Inhibition of hormonal signaling may thus play a putative role in supportive therapies against this cancer type.

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“…Specific DNA hypermethylation of CpG sites on TRH gene was only reported over last years in RCC (42), and no further clinically relevant data is available at this time.…”

Section: Thyrotropin-releasing Hormone (Prolactin-releasing Hormone-tmentioning

confidence: 98%

Hormone signaling pathways as treatment targets in renal cell cancer (Review)

Czarnecka

Niedzwiedzka

Porta

et al. 2016

International Journal of Oncology

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“…Whether or not aberrations of genes involved in histone modification, such as NCOA1 ,35 participate in the acquisition of epigenetic characteristics in CIMP‐positive RCCs warrants further examination. Aberrations of genes involved in cell adhesion, such as CELSR1, CELSR2 ,36 CTNND1 ,37 LAMC2 38 and TJP1 ,39 may affect the invasiveness and metastatic potential of CIMP‐positive RCCs (CIMP‐positive RCCs show invasive growth and distant metastasis more frequently than CIMP‐negative RCCs13). Moreover, genetic aberrations of microtubule‐associated proteins, such as DNAH2, DNAH5, DNAH10 ,31 RP1 32 and HAUS8 ,33, 34 may be correlated with dysregulation of the spindle checkpoint in CIMP‐positive RCCs.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that DNA methylation alterations play a significant role in renal carcinogenesis 9, 10. Although Morris and Maher previously reported that the relevance of the CIMP‐positive phenotype to RCCs had not yet been clearly defined,11 we first identified CIMP‐positive clear cell RCCs based on genome‐wide DNA methylation (methylome) analysis12 and showed that DNA hypermethylation of CpG islands in the FAM150A, GRM6, ZNF540, ZFP42, ZNF154, RIMS4, PCDHAC1, KHDRBS2, ASCL2, KCNQ1, PRAC, WNT3A, TRH, FAM78A, ZNF671, SLC13A5 and NKX6‐2 genes was the hallmark of CIMP in RCCs 13…”

mentioning

confidence: 99%

“…During the follow‐up period after nephrectomy, the cancer‐free and overall survival rates of patients with CIMP‐positive clear cell RCCs have been shown to be significantly lower than those of patients with CIMP‐negative clear cell RCCs 13. Therefore, the molecular pathways responsible for generating CIMP‐positive clear cell RCCs should be clarified, and therapeutic targets for affected patients should be identified.…”

mentioning

confidence: 99%

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

Arai¹,

Gotoh²,

Tian³

et al. 2015

Intl Journal of Cancer

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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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“…It's a transcription factor with known positive and negative regulatory activities in development and differentiation [84] and seemed to be a tumor suppressor [85] . NKX6.2 is respectively detected in a variety of different neoplasms, like brain tumor [86] , bladder cancer [87] , renal cell carcinoma [88][89] , and lung adenocarcinoma [90] . By so far, no NKX6.2 expression is reported in gastrointestinal neoplasms.…”

Section: Nkx62mentioning

confidence: 99%

The homeobox NKX and Neoplasms in Digestive system: a systematic review.

Yao¹,

Zhu²

2017

RAJAR

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ABSTRACT:The incidence of digestive system neoplasms is increasing over these years due to the limitation of prompt diagnosis and effective treatment. Homeobox genes are usually associated with development of cancer. Previous studies indicate that homeobox NKX transcription factors are partly involved in the development and progression of tumors in gastrointestinal tract. To summarize the different impact of NKX genes have on the digestive system, the interrelationship between each NKX genes and gastric-derived tumors is analyzed as much detail as possible. The results turn out that some of NKX genes may be used as a target to distinguish the primary site of cancer, or as a biomarker to predict the therapeutic effect and survival which is instructive and meaningful to the future medical managements. This review is a systematic synopsis of research on the homeobox genes NKX and digestive system neoplasms, with the focus on their functions and clinical significance.

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Single-CpG-resolution methylome analysis identifies clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas

Cited by 117 publications

References 37 publications

Hormone signaling pathways as treatment targets in renal cell cancer (Review)

Hormone signaling pathways as treatment targets in renal cell cancer (Review)

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

The homeobox NKX and Neoplasms in Digestive system: a systematic review.

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