Aberrant DNA methylation in non-neoplastic gastric mucosa of H. pylori infected patients and effect of eradication

Francesco Perri, Rosa Cotugno, Ada Piepoli, Antonio Merla, Michele Quitadamo, Annamaria Gentile, Alberto Pilotto, Vito Annese, Angelo Andriulli

Research output: Contribution to journalArticle

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Abstract

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. AIM: 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 13C-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. CONCLUSION: 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.

Original languageEnglish
Pages (from-to)1361-1371
Number of pages11
JournalAmerican Journal of Gastroenterology
Volume102
Issue number7
DOIs
Publication statusPublished - Jul 2007

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Pylorus
DNA Methylation
Gastric Mucosa
Metaplasia
Methylation
Endoscopy
Biopsy
Stomach
Breath Tests
Genes
Urea
Carcinogenesis
Infection
Suppressor Genes
p16 Genes
Gene Silencing
Gastritis
Epigenomics
Vegetables
Meat

ASJC Scopus subject areas

  • Gastroenterology

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Aberrant DNA methylation in non-neoplastic gastric mucosa of H. pylori infected patients and effect of eradication. / Perri, Francesco; Cotugno, Rosa; Piepoli, Ada; Merla, Antonio; Quitadamo, Michele; Gentile, Annamaria; Pilotto, Alberto; Annese, Vito; Andriulli, Angelo.

In: American Journal of Gastroenterology, Vol. 102, No. 7, 07.2007, p. 1361-1371.

Research output: Contribution to journalArticle

Perri, Francesco ; Cotugno, Rosa ; Piepoli, Ada ; Merla, Antonio ; Quitadamo, Michele ; Gentile, Annamaria ; Pilotto, Alberto ; Annese, Vito ; Andriulli, Angelo. / Aberrant DNA methylation in non-neoplastic gastric mucosa of H. pylori infected patients and effect of eradication. In: American Journal of Gastroenterology. 2007 ; Vol. 102, No. 7. pp. 1361-1371.
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title = "Aberrant DNA methylation in non-neoplastic gastric mucosa of H. pylori infected patients and effect of eradication",
abstract = "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. AIM: 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 13C-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. CONCLUSION: 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.",
author = "Francesco Perri and Rosa Cotugno and Ada Piepoli and Antonio Merla and Michele Quitadamo and Annamaria Gentile and Alberto Pilotto and Vito Annese and Angelo Andriulli",
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T1 - Aberrant DNA methylation in non-neoplastic gastric mucosa of H. pylori infected patients and effect of eradication

AU - Perri, Francesco

AU - Cotugno, Rosa

AU - Piepoli, Ada

AU - Merla, Antonio

AU - Quitadamo, Michele

AU - Gentile, Annamaria

AU - Pilotto, Alberto

AU - Annese, Vito

AU - Andriulli, Angelo

PY - 2007/7

Y1 - 2007/7

N2 - 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. AIM: 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 13C-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. CONCLUSION: 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.

AB - 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. AIM: 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 13C-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. CONCLUSION: 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.

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