High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk.
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.
Maekita
Takao
T
Carcinogenesis Division, National Cancer Center Research Institute, Tsukiji, Tokyo, Japan.
Nakazawa
Kazuyuki
K
Mihara
Mami
M
Nakajima
Takeshi
T
Yanaoka
Kimihiko
K
Iguchi
Mikitaka
M
Arii
Kenji
K
Kaneda
Atsushi
A
Tsukamoto
Tetsuya
T
Tatematsu
Masae
M
Tamura
Gen
G
Saito
Daizo
D
Sugimura
Takashi
T
Ichinose
Masao
M
Ushijima
Toshikazu
T
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