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Epigenetics. 2013 Nov;8(11):1153-61. doi: 10.4161/epi.26072. Epub 2013 Aug 22.

Virulence of infecting Helicobacter pylori strains and intensity of mononuclear cell infiltration are associated with levels of DNA hypermethylation in gastric mucosae.

Author information

1
Division of Gastroenterology; Department of Medicine; Vanderbilt University Medical Center; Nashville, TN USA.
2
Division of Gastroenterology; Department of Medicine; Vanderbilt University Medical Center; Nashville, TN USA; Holmes Regional Medical Center; Melbourne, FL USA.
3
Department of Surgery; Vanderbilt University Medical Center; Nashville, TN USA.
4
Department of Pathology; School of Medicine; Pontificia Universidad Catolica de Chile; Santiago, Chile.
5
Department of Pathology; School of Medicine; Universidad del Valle; Cali, Colombia.
6
Division of Gastroenterology; Department of Medicine; Vanderbilt University Medical Center; Nashville, TN USA; Veterans Affairs Tennessee Valley Healthcare System and Office of Medical Research; Department of Veterans Affairs; Nashville, TN USA.
7
Department of Surgery; Vanderbilt University Medical Center; Nashville, TN USA; Veterans Affairs Tennessee Valley Healthcare System and Office of Medical Research; Department of Veterans Affairs; Nashville, TN USA.

Abstract

DNA methylation changes are known to occur in gastric cancers and in premalignant lesions of the gastric mucosae. In order to examine variables associated with methylation levels, we quantitatively evaluated DNA methylation in tumors, non-tumor gastric mucosae, and in gastric biopsies at promoters of 5 genes with methylation alterations that discriminate gastric cancers from non-tumor epithelia (EN1, PCDH10, RSPO2, ZIC1, and ZNF610). Among Colombian subjects at high and low risk for gastric cancer, biopsies from subjects from the high-risk region had significantly higher levels of methylation at these 5 genes than samples from subjects in the low risk region (p ≤ 0.003). When results were stratified by Helicobacter pylori infection status, infection with a cagA positive, vacA s1m1 strain was significantly associated with highest methylation levels, compared with other strains (p = 0.024 to 0.001). More severe gastric inflammation and more advanced precancerous lesions were also associated with higher levels of DNA methylation (p ≤ 0.001). In a multivariate model, location of residence of the subject and the presence of cagA and vacA s1m1 in the H. pylori strain were independent variables associated with higher methylation in all 5 genes. High levels of mononuclear cell infiltration were significantly related to methylation in PCDH10, RSPO2, and ZIC1 genes. These results indicate that for these genes, levels of methylation in precancerous lesions are related to H. pylori virulence, geographic region and measures of chronic inflammation. These genes seem predisposed to sustain significant quantitative changes in DNA methylation at early stages of the gastric precancerous process.

KEYWORDS:

Helicobacter; Pyrosequencing; biopsy; chronic inflammation; gastric cancer; methylation

PMID:
24128875
PMCID:
PMC3927747
DOI:
10.4161/epi.26072
[Indexed for MEDLINE]
Free PMC Article

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