Introduction: 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. Experimental Design: 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, andTHBD 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 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). 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.Gastric cancer is one of the most common malignancies worldwide and remains a leading cause of cancer death in Asia and some European countries (1). To reduce its mortality, early detection by endoscopy and curative resection are important (2). However, considering the potential risk and costs of early detection by endoscopic examination, implementation reflecting an individual's risk for developing a gastric cancer would be ideal. Also, endoscopic mucosal resection, which conserves the noncancerous gastric mucosae, is becoming popular, and the problem of metachronous gastric cancer recurrence is being recognized (3). Again, if the future risk of developing metachronous cancers in a specific case can be estimated, the information will be useful in the decision on either surgical resection or endoscopic mucosal resection for the case.The major etiologic risk factor for gastric cancers is Helicobacter pylori infection, which increases gastric cancer risk 2.2-to 21-fold (4 -6). In an animal model with Mongolian gerbil chronic infection with H. pylori rarely induces gastric cancers by itself, but markedly enhances their incidences after initiation with a mutagen, such as N-methyl-N-nitrosourea (7). Thi...
Sox2 may play an important role in maintaining a gastric phenotype in stomach cancers as well as in normal tissue, in cooperation with other cofactor(s).
Gene silencing by methylation of promoter CpG islands is deeply involved in cancers, but its involvement in polyclonal disorders is still unclear. Here, we analyzed the presence of gene silencing in intestinal metaplasia (IM) of the stomach, a polyclonal disorder, in which multiple gastric glands aberrantly differentiate into those with intestinal characteristics. By a genome-wide screening, CpG islands in the putative promoter regions of four genes (ZIK1, ZNF141, KAL1, and FGF14) were found to be specifically methylated in glands with IM, and their expression was markedly decreased. When demethylation was induced in cell lines with their methylation by 5-aza-2-deoxycytidine, expression of ZIK1, KAL1, and FGF14 was restored, supporting causal roles of methylation in their silencing. Analysis of ZIK1 methylation in a single gland showed that the vast majority of DNA molecules isolated from a gland with IM were methylated and that those from a gland without IM were not. ZIK1 methylation was present in glands isolated from physically distant positions within a stomach, showing that methylation occurred multifocally. These data indicate that methylation of multiple genes occurs independently in multiple glands, each of which has its own stem cell, demonstrating that involvement of aberrant gene silencing in noninherited polyclonal human disorders needs more attention. (Am J Pathol
To evaluate the genetic factors of familial predisposition to gastric cancer, genetic alterations in the surgically resected stomach samples from gastric-cancer-prone families were investigated. Familial gastric cancer (FGC) was defined as gastric cancer occurring in a family with 3 or more gastric cancer patients over at least two successive generations. We examined replication error (RER) of six microsatellite markers and screened mutations of the 10-(A) repeat sequence in the transforming growth factor-β receptor type II (TGF-βRII) gene in individuals from seven unrelated FGC families. Three cases showed RER at one of the six (CA)n microsatellite markers but the other 4 cases showed no RER at any of these loci. No mutation was found in the 10-(A) repeat of the TGF-βRII gene. Additionally, no germline mutation was found by polymerase chain reaction-single strand conformation polymorphism in exons 1–16 of E-cadherin, exons 5–8 of p53 and in the mutation cluster region of APC. These results indicate that disorders in the DNA mismatch repair system, E-cadherin, p53 and APC may be infrequently involved in the carcinogenesis of Japanese FGC.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.