Effects of Helicobacter pylori Eradication on Methylation Status of E-Cadherin Gene in Noncancerous Stomach

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, 00, Hong Kong
Clinical Cancer Research (Impact Factor: 8.72). 06/2006; 12(10):3216-21. DOI: 10.1158/1078-0432.CCR-05-2442
Source: PubMed


Promoter hypermethylation of E-cadherin plays an important role on gastric cancer development. Whereas E-cadherin methylation was frequently detected in the stomach of Helicobacter pylori-infected individuals, we tested whether eradication of H. pylori alters the methylation status of the noncancerous gastric epithelium.
Endoscopic biopsies were taken from the antrum and corpus of H. pylori-infected subjects without gastric cancer. Presence of methylated E-cadherin sequences in the gastric specimens was detected by methylation-specific PCR. Bisulfite DNA sequencing was done to determine the topographical distribution and changes in methylation profiles with H. pylori eradication.
Among the 28 H. pylori-infected subjects (median age, 44.5 years), 15 (53.6%) had E-cadherin methylation detected in stomach at baseline. Discordant methylation patterns between the antrum and corpus were noted in six patients. One year after successful H. pylori eradication, there was a significant reduction in the methylation density of the promoter region and exon 1 of the E-cadherin gene as detected by bisulfite DNA sequencing (P < 0.001).
Promoter methylation in E-cadherin was frequently detected in the stomach of H. pylori-infected individuals. Eradication of H. pylori might possibly reduce the methylation density in E-cadherin gene and the chance of subsequent neoplastic transformation.

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    • "We reported that H. pylori eradication reduced the MSI and mAb Das-1 reactivity in IM (Tanaka et al, 2006; Watari et al, 2008), and a case–control study showed that patients in whom these biomarkers persist after eradication might have a high risk of developing MGC (Watari et al, 2012). Several reports showed that H. pylori eradication can significantly reduce gene methylation in chronic gastritis mucosa, thus delaying or reversing H. pyloriinduced gastric carcinogenesis (Leung et al, 2006; Chan et al, 2006; Perri et al, 2007; Nakajima et al, 2010). However, the changes in the molecular phenotype in the background mucosa following H. pylori treatment in patients who have undergone ER for gastric neoplasms remain unclear (Maekita et al, 2006; Watari et al, 2012; Shin et al, 2013). "
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    ABSTRACT: Background: Whether Helicobacter pylori eradication actually suppresses the development of metachronous gastric cancer (MGC) after endoscopic resection (ER) remains controversial. The aims of this study were to clarify (1) the molecular markers related to carcinogenesis in intestinal metaplasia (IM) by a cross-sectional study, and (2) the changes of those markers by an open-label, randomised controlled trial (RCT) of H. pylori treatment. Methods: First, we evaluated microsatellite instability (MSI), the methylation status at hMLH1, CDKN2A and APC genes, and immunoreactivity using the monoclonal antibody (mAb) Das-1 in IM in the background mucosa of 131 patients who underwent ER for gastric neoplasia and 22 chronic gastritis cases (control). Next, we performed an RCT to evaluate the changes of MSI between the H. pylori-eradicated (n=19) and non-eradicated patients (n=17) at 1 year among the H. pylori-positive patients. Results: Microsatellite instability and mAb Das-1 reactivity showed significantly higher incidences in both the H. pylori-positive and -negative patients compared with the control group, thus suggesting that MSI and mAb Das-1 reactivity are associated with gastric neoplasia (OR=5.06 for MSI; OR=2.51 for mAb Das-1 reactivity). The RCT showed that H. pylori eradication did not provide significant reversals of any molecular alterations including MSI (the primary end point) and other methylation statuses and mAb Das-1 reactivity (secondary end points). Conclusions: H. pylori eradication did not produce significant changes in the molecular alterations related to carcinogenesis, suggesting that H. pylori treatment may not prevent the development of MGC in background mucosa with IM.British Journal of Cancer advance online publication, 15 December 2015; doi:10.1038/bjc.2015.418
    Full-text · Article · Dec 2015 · British Journal of Cancer
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    • "Although no mono-allelic hypermethylation of the CDH1 promoter was detected in this study, various levels of methylation of CpG sites in the CDH1 promoter were detected in all of the samples. This finding is compatible with findings reported previously [30,31] and may be related to aging or Helicobacter pylori infection as reported in those papers [30,31]. Interestingly, there were differences between the two alleles in methylation level of the CDH1 promoter in some non-cancerous gastric tissue samples. "
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    ABSTRACT: Germline mono-allelic promoter hypermethylation of the MLH1 or MSH2 gene in families with hereditary nonpolyposis colorectal cancer has recently been reported. The purpose of this study was to evaluate if germline promoter hypermethylation of the tumor suppressor gene CDH1 (E-cadherin) might cause predisposition to gastric cancer. We prepared two groups of samples, a group of blood samples from 22 patients with familial gastric cancer or early-onset gastric cancer selected from among 39 patients, and a group of non-cancerous gastric tissue samples from 18 patients with sporadic gastric cancer showing loss of CDH1 expression selected from among 159 patients. We then investigated the allele-specific methylation status of the CDH1 promoter by bisulfite sequencing of multiple clones. Although there was a difference between the methylation level of the two alleles in some samples, there was no mono-allelic promoter hypermethylation in any of the samples. These results suggest that germline mono-allelic hypermethylation of the CDH1 promoter is not a major predisposing factor for gastric cancer.
    Full-text · Article · Sep 2009 · Molecular Cancer
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    • "Epigenetic silencing of tumour-related genes due to CpG island hypermethylation has emerged as one of the most important alternations in gastric cancer development (Leung et al, 2001; Yu et al, 2003). We have previously shown that tumour-related genes including E-cadherin, p15, and p16 were frequently methylated in gastric cancer (Leung et al, 2001) as well as in pre-malignant gastric lesions (Leung et al, 2006), suggesting dysregulation in CpG-island methylation is likely to be involved in the early gastric carcinogenesis process. Wnt proteins are secreted signalling factors with multiple functions in development and tumourigenesis (Polakis 2007). "
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    ABSTRACT: The role of secreted frizzled-related protein (SFRP) genes in gastric cancer remains largely unknown. We determined the frequency and functional significance of SFRPs hypermethylation in human gastric cancer. The expression and methylation status of four SFRP members (SFRP1, 2, 4, and 5) in primary gastric cancer samples was screened. The biological effects of SFRP were analysed by flow cytometry, cell viability assay and in vivo tumour growth in nude mice. Among the four SFRPs, only SFRP2 was significantly downregulated in gastric cancer as compared to adjacent non-cancer samples (P<0.01). Promoter hypermethylation of SFRP2 was detected in 73.3% primary gastric cancer tissues, 37.5% of samples showing intestinal metaplasia and 20% adjacent normal gastric tissues. Bisulphite DNA sequencing confirmed the densely methylated SFRP2 promoter region. Demethylation treatment restored the expression of SFRP2 in gastric cancer cell lines. Forced expression of SFRP2 induced cell apoptosis, inhibited proliferation of gastric cancer cells and suppressed tumour growth in vivo. Moreover, methylated SFRP2 was detected in 66.7% of serum samples from cancer patients but not in normal controls. In conclusion, epigenetic inactivation of SFRP2 is a common and early event contributing to gastric carcinogenesis and may be a potential biomarker for gastric cancer.
    Preview · Article · Oct 2007 · British Journal of Cancer
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