title: CpG methylation and reduced expression of O6-methylguanine DNA methyltransferase is associated with Helicobacter pylori infection.
abstract: OBJECTIVE
  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 pylori-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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. asepu@mail.med.upenn.edu
authors.forename: Antonia R
authors.initials: AR
authors.lastname: Sepulveda
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yao
authors.forename: Wen
authors.initials: W
authors.lastname: Yan
authors.forename: Dong Il
authors.initials: DI
authors.lastname: Park
authors.forename: Jae J
authors.initials: JJ
authors.lastname: Kim
authors.forename: William
authors.initials: W
authors.lastname: Gooding
authors.forename: Suhaib
authors.initials: S
authors.lastname: Abudayyeh
authors.forename: David Y
authors.initials: DY
authors.lastname: Graham
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000942:Antigens, Bacterial / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D001706:Biopsy; D016022:Case-Control Studies; D002460:Cell Line; D018899:CpG Islands; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics*; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology; D005756:Gastritis / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000382:microbiology; D015971:Gene Expression Regulation, Enzymologic; D016481:Helicobacter Infections / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000382:microbiology; D016480:Helicobacter pylori / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016296:Mutagenesis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C080866:cagA protein, Helicobacter pylori; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes