Abstract
Background
Helicobacter pylori (HP) infection potently induces aberrant DNA methylation in gastric mucosae, and its accumulation is associated with gastric cancer risk. Cross-sectional analysis of methylation levels (fraction of methylated DNA molecules) and temporal analysis of methylation incidence suggested that methylation levels decrease after HP infection discontinues. We aimed to demonstrate the decrease in methylation levels.
Methods
Thirty-five patients with HP infection who had undergone curative endoscopic resection and 11 healthy volunteers were recruited. Methylation levels were quantified by real-time methylation-specific PCR. Histology was evaluated according to the updated Sydney System.
Results
In the 20 patients with successful eradication, the FLNc methylation level, along with infiltration of inflammatory cells, decreased from 0.6 to 0.4% at 6 weeks (P = 0.049) and remained low at 1 year. The THBD methylation level (30.1%) remained high at 6 weeks, but decreased to 19.0% at 1 year (P = 0.0032). Nine healthy volunteers with successful eradication tended to show a decrease of both FLNc and THBD at 6 weeks. However, the methylation levels after the decrease were still higher than those of healthy individuals without HP infection. In the 15 patients with persistent infection, the methylation levels remained the same. Before eradication, the THBD methylation level correlated with the degree of inflammatory cell infiltration (P < 0.05).
Conclusions
Methylation levels in gastric mucosae decreased to certain levels after HP eradication in profiles unique to individual markers. Involvement of chronic inflammation in methylation induction was suggested.
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References
Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, et al. Cancer statistics. CA Cancer J Clin. 2004;54:8–29.
Soetikno R, Kaltenbach T, Yeh R, Gotoda T. Endoscopic mucosal resection for early cancers of the upper gastrointestinal tract. J Clin Oncol. 2005;23:4490–8.
Ono H, Kondo H, Gotoda T, Shirao K, Yamaguchi H, Saito D, et al. Endoscopic mucosal resection for treatment of early gastric cancer. Gut. 2001;48:225–9.
Nakajima T, Oda I, Gotoda T, Hamanaka H, Eguchi T, Yokoi C, et al. Metachronous gastric cancers after endoscopic resection: how effective is annual endoscopic surveillance? Gastric Cancer. 2006;9:93–8.
Watabe H, Mitsushima T, Yamaji Y, Okamoto M, Wada R, Kokubo T, et al. Predicting the development of gastric cancer from combining Helicobacter pylori antibodies and serum pepsinogen status: a prospective endoscopic cohort study. Gut. 2005;54:764–8.
Maekita T, Nakazawa K, Mihara M, Nakajima T, Yanaoka K, Iguchi M, et al. High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk. Clin Cancer Res. 2006;12:989–95.
Nakajima T, Maekita T, Oda I, Gotoda T, Yamamoto S, Umemura S, et al. Higher methylation levels in gastric mucosae significantly correlate with higher risk of gastric cancers. Cancer Epidemiol Biomarkers Prev. 2006;15:2317–21.
Chan AO, Peng JZ, Lam SK, Lai KC, Yuen MF, Cheung HK, et al. Eradication of Helicobacter pylori infection reverses E-cadherin promoter hypermethylation. Gut. 2006;55:463–8.
Leung WK, Man EP, Yu J, Go MY, To KF, Yamaoka Y, et al. Effects of Helicobacter pylori eradication on methylation status of E-cadherin gene in noncancerous stomach. Clin Cancer Res. 2006;12:3216–21.
Perri F, Cotugno R, Piepoli A, Merla A, Quitadamo M, Gentile A, et al. Aberrant DNA methylation in non-neoplastic gastric mucosa of H. Pylori infected patients and effect of eradication. Am J Gastroenterol. 2007;102:1361–71.
Miyazaki T, Murayama Y, Shinomura Y, Yamamoto T, Watabe K, Tsutsui S, et al. E-cadherin gene promoter hypermethylation in H. pylori-induced enlarged fold gastritis. Helicobacter. 2007;12:523–31.
Gotoda T. Endoscopic resection of early gastric cancer. Gastric Cancer. 2007;10:1–11.
Oda I, Gotoda T, Hamanaka H. Endoscopic submucosal dissection for early gastric cancer: technical feasibility, operation time and complications from a large consecutive cases. Dig Endosc. 2005;17:54–8.
Kaneda A, Kaminishi M, Sugimura T, Ushijima T. Decreased expression of the seven ARP2/3 complex genes in human gastric cancers. Cancer Lett. 2004;212:203–10.
Busuttil RA, Boussioutas A. Intestinal metaplasia: a premalignant lesion involved in gastric carcinogenesis. J Gastroenterol Hepatol. 2009;24:193–201.
Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol. 1996;20:1161–81.
Parente F, Maconi G, Sangaletti O, Minguzzi M, Vago L, Bianchi Porro G. Behaviour of acid secretion, gastrin release, serum pepsinogen I, and gastric emptying of liquids over six months from eradication of Helicobacter pylori in duodenal ulcer patients. A controlled study. Gut. 1995;37:210–5.
Chen TS, Tsay SH, Chang FY, Lee SD. Effect of eradication of Helicobacter pylori on serum pepsinogen I, gastrin, and insulin in duodenal ulcer patients: a 12-month follow-up study. Am J Gastroenterol. 1994;89:1511–4.
Ushijima T, Nakajima T, Maekita T. DNA methylation as a marker for the past and future. J Gastroenterol. 2006;41:401–7.
Kaneda A, Kaminishi M, Yanagihara K, Sugimura T, Ushijima T. Identification of silencing of nine genes in human gastric cancers. Cancer Res. 2002;62:6645–50.
Ando T, Yoshida T, Enomoto S, Asada K, Tatematsu M, Ichinose M. DNA methylation of microRNA genes in gastric mucosae of gastric cancer patients: its possible involvement in the formation of epigenetic field defect. Int J Cancer. 2009;124:2367–74.
Nakajima T, Yamashita S, Maekita T, Niwa T, Nakazawa K, Ushijima T. The presence of a methylation fingerprint of Helicobacter pylori infection in human gastric mucosae. Int J Cancer. 2009;124:905–10.
Takeshima H, Yamashita S, Shimazu T, Niwa T, Ushijima T. The presence of RNA polymerase II, active or stalled, predicts epigenetic fate of promoter CpG islands. Genome Res 2009 (in press).
Acknowledgments
This study was supported by Grants-in-Aid for Pioneering Basic Research and for the Third-term Comprehensive Cancer Control Strategy from the Ministry of Health, Labor and Welfare, Japan. T.A. is a recipient of a Research Resident Fellowship from the Foundation for Promotion of Cancer Research.
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535_2009_142_MOESM1_ESM.ppt
Changes of the FLNc methylation level in the three biopsy sites (antrum, middle gastric body, and upper gastric body in the lesser curvature). In the successful eradication group, FLNc methylation levels in the middle and upper gastric bodies showed significant decreases (PPT 264 kb)
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Nakajima, T., Enomoto, S., Yamashita, S. et al. Persistence of a component of DNA methylation in gastric mucosae after Helicobacter pylori eradication. J Gastroenterol 45, 37–44 (2010). https://doi.org/10.1007/s00535-009-0142-7
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DOI: https://doi.org/10.1007/s00535-009-0142-7