Genetic, epigenetic, and clinicopathologic features of gastric carcinomas with the CpG island methylator phenotype and an association with Epstein-Barr virus.

The 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. Methylation 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). The 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. CIMP 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.

Kusano M ，Toyota M ，Suzuki H ，Akino K ，Aoki F ，Fujita M ，Hosokawa M ，Shinomura Y ，Imai K ，Tokino T ... -  《CANCER》

CpG island methylation status in gastric carcinoma with and without infection of Epstein-Barr virus.

Chang MS ，Uozaki H ，Chong JM ，Ushiku T ，Sakuma K ，Ishikawa S ，Hino R ，Barua RR ，Iwasaki Y ，Arai K ，Fujii H ，Nagai H ，Fukayama M ... -  《CLINICAL CANCER RESEARCH》

Accumulation of DNA methylation is associated with tumor stage in gastric cancer.

The authors purpose in this study was to clarify the difference in terms of clinicopathologic features between gastric cancer (GC) with high numbers of DNA methylated genes and CpG island methylator phenotype (CIMP)-positive GC as originally defined. We analyzed DNA methylation of 12 tumor-related genes (hMLH1, MGMT, p16(INK4a), CDH1, RAR-beta, HLTF, RIZ1, TM, FLNc, LOX, HRASLS, HAND1) in 75 samples of GC from 75 patients, 25 samples of corresponding nonneoplastic mucosa from 25 patients, and 10 samples of normal gastric mucosa from 10 healthy young individuals by methylation-specific polymerase chain reaction (PCR) and bisulfite PCR. We also investigated CIMP status by examining the methylation of five MINT loci and p53 mutation status by PCR single-strand conformation polymorphism. We measured levels of expression of mRNAs for these 12 genes by quantitative reverse transcription PCR in 50 GC specimens. The average number of methylated genes per tumor was 4.83. DNA methylation of each gene was correlated with low expression of the respective mRNA. High methylation (GC with 5 or more methylated genes) was detected in 39 (52.0%) of 75 GCs. Twenty-nine (37.8%) of 75 GCs were CIMP-positive. DNA methylation of each of the 12 genes was observed more frequently in the high-methylation group than in the low-methylation group. Methylation of 6 specific genes occurred more frequently in CIMP-positive GC than in CIMP-negative GC. Methylation of the remaining 6 genes was not correlated with CIMP-status. High methylation was found more frequently in Stage III/IV GC (26 of 40 cases, 65.0%) than in Stage I/II GC (13 of 35 cases, 37.1%, P = 0.029).CONCLUSIONS.These findings indicate that GCs with higher numbers of methylated genes have more distinct DNA methylation profiles than the originally defined CIMP-positive GCs. DNA methylation of tumor-related genes accumulates in conjunction with tumor progression.

Oue N ，Mitani Y ，Motoshita J ，Matsumura S ，Yoshida K ，Kuniyasu H ，Nakayama H ，Yasui W ... -  《CANCER》

Epstein-barr virus-positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma.

Kang GH ，Lee S ，Kim WH ，Lee HW ，Kim JC ，Rhyu MG ，Ro JY ... -  《-》

Laterally spreading type of colorectal adenoma exhibits a unique methylation phenotype and K-ras mutations.

Hiraoka S ，Kato J ，Tatsukawa M ，Harada K ，Fujita H ，Morikawa T ，Shiraha H ，Shiratori Y ... -  《GASTROENTEROLOGY》