Abstract
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. 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. 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). 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.
Highlights
Risk prediction of gastric cancers is important to implement appropriate screening procedures
We analyzed methylation levels of two regions of the p16 promoter CpG islands (CGI) and one region of six genes (LOX, FLNc, HRASLS, HAND1, THBD, and p41ARC; Fig. 1A), which could be methylated in human gastric cancers [18, 19]
It was shown here that significantly higher levels of aberrant methylation (5.4- to 303-fold) were present in multiple CGIs in the gastric mucosae of healthy volunteers with H. pylori infection. This finding strongly indicated that H. pylori infection potently induces aberrant methylation in multiple CGIs, there has been controversy [10, 11]
Summary
Risk prediction of gastric cancers is important to implement appropriate screening procedures. 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. Results: Among healthy volunteers, methylation levels of all the eight regions were 5.4- to 303fold higher in H. pylori positives than in H. pylori negatives (P < 0.0001). 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 V 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). Methylation levels of specific CGIs seemed to reflect gastric cancer risk in H. pylori ^ negative individuals
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