幽门螺杆菌感染患者非肿瘤性胃黏膜中的异常DNA甲基化及根除效果

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

作者信息

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

机构信息

Department of Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy.

出版信息

Am J Gastroenterol. 2007 Jul;102(7):1361-71. doi: 10.1111/j.1572-0241.2007.01284.x. Epub 2007 May 17.

DOI:10.1111/j.1572-0241.2007.01284.x

PMID:17509026

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 (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.

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.

摘要

背景

基因启动子甲基化是一种导致基因沉默的表观遗传事件。该机制在癌症中尤为重要，因为它可干扰特定“抑制”基因的活性。

目的

评估幽门螺杆菌（Hp）感染患者根除前后CDH1、p16、APC、MLH1和COX2的启动子甲基化情况。

方法

57例既往未行内镜检查或Hp检测及治疗的消化不良门诊患者接受临床访谈、内镜检查并从胃窦、胃角和胃体获取3对胃活检标本，以及进行¹³C - 尿素呼气试验（UBT）。对活检标本进行Hp和肠化生（IM）评分。通过甲基化特异性PCR评估每个活检标本中5个肿瘤相关基因（CDH1、p16、MLH1、APC和COX2）的DNA甲基化情况。感染患者接受标准根除治疗，1年后再次接受内镜检查及活检和UBT。

结果

45例患者发现Hp感染。45例感染患者中有17例（38%）检测到IM。在12例Hp⁻/IM⁻、28例Hp⁺/IM⁻和17例Hp⁺/IM⁺患者中，甲基化基因的平均数量分别为0、1.1±0.9和1.6±0.9（P<0.0001）。具体而言，在Hp⁺/IM⁻患者中，CDH1、p16、APC、MLH1和COX2启动子高甲基化的发生率分别为68%、25%、7%、0%和14%；在Hp⁺/IM⁺患者中分别为71%、29%、35%、12%和12%。就年龄、吸烟、饮酒、肉类和蔬菜消费以及胃癌家族史而言，三组患者之间未发现显著差异。45例（51%）感染患者中的23例接受了1年的随访内镜检查：23例中有17例（74%）成功根除。Hp根除后，CDH1、p16和APC甲基化显著降低，而COX2甲基化完全消失。相反，IM患者中MLH1甲基化无显著变化。