Aberrant DNA methylation in non-neoplastic gastric mucosa of H. Pylori infected patients and effect of eradication.
BACKGROUND
Gene promoter methylation is an epigenetic event leading to gene silencing. This mechanism is particularly relevant in cancer since it can interfere with the activity of specific "suppressor" genes.


OBJECTIVE
To evaluate promoter methylation of CDH1, p16, APC, MLH1, and COX2 in patients with H. pylori (Hp) infection before and after eradication.


METHODS
Fifty-seven dyspeptic outpatients who had never performed previous endoscopy or Hp testing and treatment underwent clinical interview, endoscopy with three paired gastric biopsy specimens from the antrum, angulus, and corpus, and (13)C-urea breath test (UBT). Biopsies were scored for the presence of Hp and intestinal metaplasia (IM). DNA methylation of five tumor-related genes (CDH1, p16, MLH1, APC, and COX2) was evaluated by methylation-specific PCR in each biopsy. Infected patients were given a standard eradicating treatment and, after 1 yr, underwent endoscopy with biopsies and UBT.


RESULTS
Hp infection was found in 45 patients. IM was detected in 17 out of 45 (38%) infected patients. Mean number of methylated genes was 0, 1.1 +/- 0.9, and 1.6 +/- 0.9 among the 12 Hp-/IM-, the 28 Hp+/IM-, and the 17 Hp+/IM+ patients, respectively (P < 0.0001). Specifically, promoter hypermethylation of CDH1, p16, APC, MLH1, and COX2 was found in 68%, 25%, 7%, 0%, and 14% of Hp+/IM- patients and in 71%, 29%, 35%, 12%, and 12% of Hp+/IM+ patients. No significant difference was found among the three groups of patients as far as age, smoking, alcohol, meat and vegetable consumption, and family history of gastric cancer were considered. Twenty-three out of 45 (51%) infected patients underwent the 1-yr follow-up endoscopy: 17 out of 23 (74%) were successfully eradicated. After Hp eradication, CDH1, p16, and APC methylation significantly decreased while COX2 methylation completely disappeared. Conversely, MLH1 methylation did not change significantly in patients with IM.


CONCLUSIONS
Hp infection is associated with promoter methylation of genes which are relevant in the initiation and progression of gastric carcinogenesis. While CDH1 methylation seems to be an early event in Hp gastritis, MLH1 methylation occurs late along with IM. Hp eradication is able to significantly reduce gene methylation thus delaying or reversing Hp-induced gastric carcinogenesis.
Perri
Francesco
F
Department of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy.
Cotugno
Rosa
R
Piepoli
Ada
A
Merla
Antonio
A
Quitadamo
Michele
M
Gentile
Annamaria
A
Pilotto
Alberto
A
Annese
Vito
V
Andriulli
Angelo
A
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D015703:Antigens, CD; D001706:Biopsy; D015820:Cadherins / Q000235:genetics*; D051546:Cyclooxygenase 2 / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D019175:DNA Methylation; D004260:DNA Repair; D016099:Endoscopy, Gastrointestinal; D005260:Female; D005500:Follow-Up Studies; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005756:Gastritis / Q000188:drug therapy / Q000235:genetics / Q000382:microbiology; D020868:Gene Silencing; D017491:Genes, APC; D016147:Genes, Tumor Suppressor; D019942:Genes, p16; D016481:Helicobacter Infections / Q000188:drug therapy / Q000235:genetics* / Q000382:microbiology; D016480:Helicobacter pylori / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction
D048868:Adaptor Proteins, Signal Transducing; D000900:Anti-Bacterial Agents; D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C501486:MLH1 protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D004247:DNA; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000070957:MutL Protein Homolog 1