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LINE-1 Hypomethylation Is Associated with Increased CpG Island Methylation in Helicobacter pylori–Related Enlarged-Fold Gastritis

¹ First Department of Internal Medicine; ² Department of Molecular Biology, Cancer Research Institute; ³ Department of Public Health, Sapporo Medical University, Sapporo, Japan; ⁴ Division of Molecular Oncology, Aichi Cancer Center, Nagoya, Japan; ⁵ Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Japan; and ⁶ Department of Gastroenterology and Hepatology, Itami City Hospital, Itami, Japan

Requests for reprints: Yasuhisa Shinomura, First Department of Internal Medicine, Sapporo Medical University, South 1,West 16, Chuo-ku, Sapporo 060-8543, Japan. Phone: 81-11-611-2111, ext. 3211; Fax: 81-11-618-3313. E-mail: shinomura{at}sapmed.ac.jp

Background: The molecular mechanism by which Helicobacter pylori infection leads to gastric cancer is not fully understood. Similarly, patients with enlarged-fold (EF+) gastritis, one cause of which is H. pylori infection, have an increased risk for gastric cancer, although again molecular mechanism is unclear. In the present study, we analyzed the methylation status of long interspersed nucleotide elements (LINE-1) and three cancer-related genes in a panel of gastric mucosae, with or without EF+ gastritis.

Methods: We used bisulfite pyrosequencing to assess the levels of LINE-1, CDH1, CDH13, and PGP9.5 methylation in 78 gastric mucosa specimens from 48 patients.

Results: Levels of LINE-1 methylation were significantly reduced in mucosae from patients with EF+ gastritis. This hypomethylation of LINE-1 was associated with increased methylation of the 5' CpG islands of the genes, which suggests that, in EF+ gastritis, the methylation of the promoter regions of certain genes is accompanied by global demethylation of repetitive sequences.

Conclusions: Our results indicate that genomewide hypomethylation and regional hypermethylation occur in EF+ gastritis and may contribute to the tumorigenesis of diffuse-type gastric cancers. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2555–64)