title: Mechanisms for the induction of gastric cancer by Helicobacter pylori infection: aberrant DNA methylation pathway.
abstract: Multiple pathogenic mechanisms by which Helicobacter pylori infection induces gastric cancer have been established in the last two decades. In particular, aberrant DNA methylation is induced in multiple driver genes, which inactivates them. Methylation profiles in gastric cancer are associated with specific subtypes, such as microsatellite instability. Recent comprehensive and integrated analyses showed that many cancer-related pathways are more frequently altered by aberrant DNA methylation than by mutations. Aberrant DNA methylation can even be present in noncancerous gastric mucosae, producing an "epigenetic field for cancerization." Mechanistically, H. pylori-induced chronic inflammation, but not H. pylori itself, plays a direct role in the induction of aberrant DNA methylation. The expression of three inflammation-related genes, Il1b, Nos2, and Tnf, is highly associated with the induction of aberrant DNA methylation. Importantly, the degree of accumulated aberrant DNA methylation is strongly correlated with gastric cancer risk. A recent multicenter prospective cohort study demonstrated the utility of epigenetic cancer risk diagnosis for metachronous gastric cancer. Suppression of aberrant DNA methylation by a demethylating agent was shown to inhibit gastric cancer development in an animal model. Induction of aberrant DNA methylation is the major pathway by which H. pylori infection induces gastric cancer, and this can be utilized for translational opportunities.
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.|Department of Gastrointestinal Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.|Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Moro
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan. tushijim@ncc.go.jp.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
mesh_terms: D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D005753:Gastric Mucosa / Q000382:microbiology*; D016481:Helicobacter Infections / Q000150:complications* / Q000235:genetics / Q000382:microbiology; D016480:Helicobacter pylori / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D013274:Stomach Neoplasms / Q000209:etiology* / Q000473:pathology
keywords: Aberrant DNA methylation; Epigenetic cancer risk diagnosis; Helicobacter pylori infection