title: Genetic, epigenetic, and clinicopathologic features of gastric carcinomas with the CpG island methylator phenotype and an association with Epstein-Barr virus.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: First Department of Internal Medicine, Cancer Research Institute, Sapporo Medical University, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kusano
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Kimishige
authors.initials: K
authors.lastname: Akino
authors.forename: Fumio
authors.initials: F
authors.lastname: Aoki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujita
authors.forename: Masao
authors.initials: M
authors.lastname: Hosokawa
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokino
mesh_terms: D000368:Aged; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D005260:Female; D052138:Genes, Neoplasm; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D014407:Tumor Cells, Cultured