title: High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk.
abstract: BACKGROUND
  Risk prediction of gastric cancers is important to implement appropriate screening procedures. Although aberrant DNA methylation is deeply involved in gastric carcinogenesis, its induction by Helicobacter pylori, a strong gastric carcinogen, is unclear. Here, we analyzed the effect of H. pylori infection on the quantity of methylated DNA molecules in noncancerous gastric mucosae and examined its association with gastric cancer risk.
  
  
  METHODS
  Gastric mucosae were collected from 154 healthy volunteers (56 H. pylori negative and 98 H. pylori positive) and 72 cases with differentiated-type gastric cancers (29 H. pylori negative and 43 H. pylori positive) by endoscopy. The numbers of DNA molecules methylated and unmethylated for eight regions of seven CpG islands (CGI) were quantified by quantitative PCR after bisulfite modification, and fractions of methylated molecules (methylation levels) were calculated.
  
  
  RESULTS
  Among healthy volunteers, methylation levels of all the eight regions were 5.4- to 303-fold higher in H. pylori positives than in H. pylori negatives (P < 0.0001). Methylation levels of the LOX, HAND1, and THBD promoter CGIs and p41ARC exonic CGI were as high as 7.4% or more in H. pylori-positive individuals. Among H. pylori-negative individuals, methylation levels of all the eight regions were 2.2- to 32-fold higher in gastric cancer cases than in age-matched healthy volunteers (P < or = 0.01). Among H. pylori-positive individuals, methylation levels were highly variable, and that of only HAND1 was significantly increased in gastric cancer cases (1.4-fold, P = 0.02).
  
  
  CONCLUSIONS
  It was indicated that H. pylori infection potently induces methylation of CGIs to various degrees. Methylation levels of specific CGIs seemed to reflect gastric cancer risk in H. pylori-negative individuals.
authors.affiliation: Carcinogenesis Division, National Cancer Center Research Institute, Tsukiji, Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Maekita
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nakazawa
authors.forename: Mami
authors.initials: M
authors.lastname: Mihara
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakajima
authors.forename: Kimihiko
authors.initials: K
authors.lastname: Yanaoka
authors.forename: Mikitaka
authors.initials: M
authors.lastname: Iguchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Arii
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kaneda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Masae
authors.initials: M
authors.lastname: Tatematsu
authors.forename: Gen
authors.initials: G
authors.lastname: Tamura
authors.forename: Daizo
authors.initials: D
authors.lastname: Saito
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugimura
authors.forename: Masao
authors.initials: M
authors.lastname: Ichinose
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Ushijima
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D019175:DNA Methylation; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism* / Q000382:microbiology; D015870:Gene Expression; D016481:Helicobacter Infections / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D016480:Helicobacter pylori / Q000472:pathogenicity; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000379:methods; D012307:Risk Factors; D012737:Sex Factors; D013274:Stomach Neoplasms / Q000150:complications* / Q000235:genetics / Q000382:microbiology