LINE-1 Hypomethylation Is Associated with Increased CpG Island Methylation in <i>Helicobacter pylori</i>–Related Enlarged-Fold Gastritis

Yamamoto, Eiko; Toyota, Minoru; Suzuki, Hiromu; Kondo, Yutaka; Sanomura, Tamana; Murayama, Yoko; Ohe-Toyota, Mutsumi; Maruyama, Reo; Nojima, Masanori; Ashida, Masami; Fujii, Kyoko; Sasaki, Yasushi; Hayashi, Norio; Mori, Mitsuru; Imai, Kohzoh; Tokino, Takashi; Shinomura, Yasuhisa

doi:10.1158/1055-9965.epi-08-0112

Cited by 62 publications

(39 citation statements)

References 38 publications

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“…The Pearson correlation coefficient and P value are shown. (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Our results confirm that GISTs exhibit a pattern of hypomethylation that is similar to those exhibited by many other human tumors.…”

Section: Discussionsupporting

confidence: 85%

“…Genomic DNA (1 μg) was modified with sodium bisulfite using an EpiTect Bisulfite kit (Qiagen), and bisulfite pyrosequencing analysis was done as described previously (14). Briefly, PCR was run in a 25-μL volume containing 50 ng of bisulfite-treated DNA, 1× MSP buffer [67 mmol/L Tris-HCl (pH 8.8), 16.6 mmol/L (NH 4 ) 2 SO 4 , 6.7 mmol/L MgCl 2 , and 10 mmol/L 2-mercaptoethanol], 1.25 mmol/L deoxynucleotide triphosphate, 0.4 μmol/L each primer, and 0.5 unit of JumpStart REDTaq DNA Polymerase (SigmaAldrich).…”

Section: Bisulfite Pyrosequencingmentioning

confidence: 99%

“…After addition of 0.3 μmol/L sequencing primer to the purified PCR product, pyrosequencing was carried out using a PSQ96MA system (Biotage) and Pyro Q-CpG software (Biotage). Primer sequences for LINE-1 methylation were as described (14). Primer sequences for Alu Yb8, centromeric satellite-α of chromosome 1 (Sat-α), and NBL2 were as described (20).…”

Section: Translational Relevancementioning

confidence: 99%

“…7), and an earlier study has shown that methylation of such repetitive elements can serve as a surrogate for global methylcytosine content (8). Moreover, LINE-1 hypomethylation is known to occur during the development of various human malignancies (9-13), and we recently reported that LINE-1 methylation is diminished in enlarged fold gastritis, which is a risk factor of gastric cancer (14). Hypomethylation of Alu elements and other repetitive sequences also has been observed in tumors of various origin (15)(16)(17)(18)(19)(20).…”

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confidence: 92%

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A Novel Correlation between LINE-1 Hypomethylation and the Malignancy of Gastrointestinal Stromal Tumors

Igarashi

Suzuki

Niinuma

et al. 2010

Clinical Cancer Research

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Purpose: Gastrointestinal stromal tumors (GIST) are the most important mesenchymal tumors of the gastrointestinal tract. The vast majority of GISTs exhibit activating mutations of KIT or PDGFRA, but epigenetic alteration of GISTs is largely unknown. In this study, we aimed to clarify the involvement of DNA methylation in GIST malignancy.Experimental Design: A total of 106 GIST specimens were studied. Levels of LINE-1 methylation were analyzed using bisulfite pyrosequencing. In addition, methylation of three other repetitive sequences (Alu Yb8, Satellite-α, and NBL2) was similarly analyzed, and CpG island hypermethylation was analyzed using MethyLight. Array-based comparative genomic hybridization (array CGH) was carried out in 25 GIST specimens.Results: LINE-1 hypomethylation was significantly correlated with risk, and high-risk GISTs exhibited significantly lower levels of LINE-1 methylation than low-risk (61.3% versus 53.2%; P = 0.001) or intermediate-risk GISTs (60.8% versus 53.2%; P = 0.002). Hypomethylation of Satellite-α and NBL2 was also observed in high-risk GISTs. By contrast, promoter hypermethylation was relatively infrequent (CDH1, 11.2%; MLH1, 9.8%; SFRP1, 1.2%; SFRP2, 11.0%; CHFR, 9.8%; APC, 6.1%; CDKN2A, 0%; RASSF1A, 0%; RASSF2, 0%) and did not correlate with LINE-1 methylation or risk. Array CGH analysis revealed a significant correlation between LINE-1 hypomethylation and chromosomal aberrations.Conclusions: Our data suggest that LINE-1 hypomethylation correlates significantly with the aggressiveness of GISTs and that LINE-1 methylation could be a useful marker for risk assessment. Hypomethylation may increase the malignant potential of GISTs by inducing accumulation of chromosomal aberrations. Clin Cancer Res; 16(21); 5114-23. ©2010 AACR.

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Section: Discussionsupporting

confidence: 85%

Section: Bisulfite Pyrosequencingmentioning

confidence: 99%

Section: Translational Relevancementioning

confidence: 99%

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confidence: 92%

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A Novel Correlation between LINE-1 Hypomethylation and the Malignancy of Gastrointestinal Stromal Tumors

Igarashi

Suzuki

Niinuma

et al. 2010

Clinical Cancer Research

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“…In addition, aberrant DNA methylation is frequently observed in noncancerous gastric mucosa in H. pylori-infected patients, suggesting aberrant DNA methylation is an early step during gastric carcinogenesis (6,7). We previously showed hypomethylation of LINE-1 repetitive elements and hypermethylation of CDH1 in enlarged-fold gastritis, which is an indicator of a high risk for diffuse type gastric cancer (8). More recently, we and others reported frequent hypermethylation of tumor suppressive miRNA genes in the noncancerous gastric mucosa of patients with gastric cancer (9,10).…”

Section: Introductionmentioning

confidence: 95%

Aberrant Methylation of RASGRF1 Is Associated with an Epigenetic Field Defect and Increased Risk of Gastric Cancer

Takamaru

Yamamoto

Suzuki

et al. 2012

Cancer Prevention Research

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Aberrant DNA methylation is implicated in the epigenetic field defect seen in gastric cancer. Our aim in this study was to identify predictive biomarkers by screening for DNA methylation in noncancerous background gastric mucosa from patients with gastric cancer. Using methylated-CpG island amplification coupled with CpG island microarray (MCAM) analysis, we identified 224 genes that were methylated in the noncancerous gastric mucosa of patients with gastric cancer. Among them, RASGRF1 methylation was significantly elevated in gastric mucosa from patients with either intestinal or diffuse type gastric cancer, as compared with mucosa from healthy individuals (8.3% vs. 22.4%, P < 0.001; 8.3% vs. 19.4%, P < 0.001). RASGRF1 methylation was independent of mucosal atrophy and could be used to distinguish both serum pepsinogen test-positive [sensitivity, 70.0%; specificity, 86.7%; area under the receiver operator characteristic (ROC) curve, AUC, 0.763] and -negative patients with gastric cancer (sensitivity, 72.2%; specificity, 87.0%; AUC, 0.844) from healthy individuals. Ectopic expression of RASGRF1 suppressed colony formation and Matrigel invasion by gastric cancer cells, suggesting it may be involved in gastric tumorigenesis. Collectively, our data suggest that RASGRF1 methylation is significantly involved in an epigenetic field defect in the stomach, and that it could be a useful biomarker to identify individuals at high risk for gastric cancer. Cancer Prev Res; 5(10); 1203-12. Ó2012 AACR.

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Cadherin 13 in cancer

Андреева

Kutuzov

2010

Genes Chromosomes & Cancer

125

113

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We review the evidence suggesting the involvement of Cadherin 13 (CDH13, T-cadherin, H-cadherin) in various cancers. CDH13 is an atypical member of the cadherin family, devoid of a transmembrane domain and anchored to the exterior surface of the plasma membrane via a glycosylphosphatidylinositol anchor. CDH13 is thought to affect cellular behavior largely through its signaling properties. It is often down-regulated in cancerous cells. CDH13 down-regulation has been associated with poorer prognosis in various carcinomas, such as lung, ovarian, cervical and prostate cancer. CDH13 re-expression in most cancer cell lines inhibits cell proliferation and invasiveness, increases susceptibility to apoptosis, and reduces tumor growth in in vivo models. These properties suggest that CDH13 may represent a possible target for therapy in some cancers. At the same time, CDH13 is up-regulated in blood vessels growing through tumors and promotes tumor neovascularization. In contrast to most cancer cell lines, CDH13 overexpression in endothelial cells promotes their proliferation and migration, and has a pro-survival effect. We also discuss molecular mechanisms that may regulate CDH13 expression and underlie its roles in cancer.

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LINE-1 Hypomethylation Is Associated with Increased CpG Island Methylation in Helicobacter pylori–Related Enlarged-Fold Gastritis

Cited by 62 publications

References 38 publications

A Novel Correlation between LINE-1 Hypomethylation and the Malignancy of Gastrointestinal Stromal Tumors

A Novel Correlation between LINE-1 Hypomethylation and the Malignancy of Gastrointestinal Stromal Tumors

Aberrant Methylation of RASGRF1 Is Associated with an Epigenetic Field Defect and Increased Risk of Gastric Cancer

Cadherin 13 in cancer

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