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BACKGROUNDThe CpG island methylator phenotype (CIMP), which is characterized by simultaneous methylation of the CpG islands of multiple genes, has been recognized as one of the important mechanisms in gastrointestinal carcinogenesis.METHODSMethylation of the 5 methylated‐in‐tumors (MINT) loci and 12 tumor‐related genes in 78 primary gastric carcinomas was examined using combined bisulfite‐restriction analysis. Epstein–Barr virus (EBV)‐associated gastric tumors were detected using real‐time polymerase chain reaction analysis followed by an evaluation of the correlations between CIMP status, EBV‐association, and genetic alteration of p53 and K‐ras. The authors compared the clinicopathologic features of gastric carcinomas that had high CIMP methylation (CIMP‐H) with tumors that had low CIMP methylation (CIMP‐L) or negative CIMP methylation (CIMP‐N).RESULTSThe methylation profiles of 12 genes showed nonrandom methylation, supporting the presence of CIMP in gastric carcinoma. No p53 mutations were detected among CIMP‐H tumors, and no EBV association was detected in tumors that showed mutation of p53 and K‐ras. In a multiple logistic regression model with CIMP‐H as the dependent variable, proximal location (P = .011), diffuse type (P = .019), and less advanced pathologic TNM status (P = .043) contributed significantly to CIMP‐H. Patients who had CIMP‐N gastric tumors had a significantly worse survival than patients who had CIMP‐H tumors (P = .004) or CIMP‐L tumors (P = .012). EBV‐associated tumors were associated strongly with CIMP‐H, hypermethylation of tumor‐related genes, and no p53 or K‐ras mutation.CONCLUSIONSCIMP status appeared to be associated with distinct genetic, epigenetic, and clinicopathologic features in gastric carcinomas. The finding that gastric carcinomas arose through different molecular pathways may affect not only tumor characteristics but also patient prognosis. Cancer 2006. © 2006 American Cancer Society.

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Death-associated protein kinase is a positive regulator of programmed cell death induced by interferon g. To investigate the role of epigenetic inactivation of death-associated protein kinase in gastrointestinal cancer, we examined the methylation status of the 5' CpG island of the death-associated protein kinase gene. Methylation of the 5' CpG island was detected in 3 of 9 colorectal and 3 of 17 gastric cancer cell lines, while among primary tumours, it was detected in 4 of 28 (14%) colorectal and 4 of 27 (15%) gastric cancers. By contrast, methylation of the edge of the CpG island was detected in virtually every sample examined. Death-associated protein kinase expression was diminished in four cell lines that showed dense methylation of the 5' CpG island, and treatment with 5-aza-2'-deoxycitidine, a methyltransferase inhibitor, restored gene expression. Acetylation of histones H3 and H4 in the 5' region of the gene was assessed by chromatin immunoprecipitation and was found to correlate directly with gene expression and inversely with DNA methylation. Thus, aberrant DNA methylation and histone deacetylation of the 5' CpG island, but not the edge of the CpG island, appears to play a key role in silencing death-associated protein kinase expression in gastrointestinal malignancies.

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