Journal
GASTROENTEROLOGY
Volume 138, Issue 5, Pages 1836-U55Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2009.12.042
Keywords
Eradication; MGMT; O6-Methylguanine DNA Methyltransferase; DNA Repair
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Funding
- NIDDK [R01 DK062185]
- Office of Research and Development Medical Research Service Department of Veterans Affairs
- Public Health Service [DK56338]
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BACKGROUND & AIMS: The gastric epithelium genome undergoes extensive epigenetic alterations during Helicobacter pylori-induced gastritis. Expression of the gene encoding the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) might be reduced via hypermethylation of its promoter in patients with H pylori gastritis. We characterized expression of MGMT and its epigenetic regulation via CpG methylation in gastric tissue from patients with H pylori gastritis and investigated the effects of H pylori infection eradication on MGMT expression. METHODS: Gastric biopsy samples were collected from patients with H pylori gastritis before and after eradication and from H pylon-negative control subjects. AGS cells were cocultured with H pylori to study the effects of H pylori infection on MGMT RNA, protein expression, and CpG methylation. RESULTS: CpG methylation of MGMT was more frequent in the gastric mucosa of patients with H pylori gastritis (69.7%) than in those without (28.6%, P = .022). MGMT methylation was significantly reduced after H pylori eradication (from 70% to 48% of cases, P = .039), and mean levels of CpG methylation decreased from 12.6% to 5.7% (P = .025), increasing MGMT expression. MGMT methylation was significantly associated with CagA-positive H pylori (P = .035). H pylori reduced MGMT protein and RNA levels and induced MGMT CpG methylation in gastric AGS cells. CONCLUSIONS: H pylori gastritis, particularly in patients infected with H pylori CagA-positive strains, is associated with hypermethylation of MGMT and reduced levels of MGMT in the gastric epithelium. MGMT promoter methylation is partially reversible after eradication of H pylori infection. These data indicate that DNA repair is disrupted during H pylori gastritis, increasing mutagenesis in H pylori-infected gastric mucosa.
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