title: Epstein-barr virus-positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma.
abstract: CpG island methylation is an important mechanism for inactivating the genes involved in tumorigenesis. Gastric carcinoma (GC) is one of the tumors that exhibits a high frequency of aberrant CpG island methylation. There have been many reports suggesting a close link between Epstein-Barr virus (EBV) and the development of GC. However, little is known about the oncogenic mechanism of EBV in gastric carcinogenesis. Twenty-one cases of EBV-positive GC and 56 cases of EBV-negative GC were examined for aberrant DNA methylation of the CpG islands of 19 genes or loci and the differences in the methylation frequency between EBV-positive and -negative GCs were investigated to determine a role of aberrant methylation in EBV-related gastric carcinogenesis. The average number of methylated genes or loci was higher in EBV-positive GCs than in EBV-negative GCs (13.4 versus 7.8, respectively, P < 0.001). EBV-positive GCs showed methylation in at least 10 CpG islands (52.6% of the tested genes), whereas 62.5% of EBV-negative GCs showed methylation in <10 CpG islands. THBS1, APC, p16, 14-3-3 sigma, MINT1, and MINT25 were methylated at a frequency >90% in EBV-positive GCs. The methylation frequency difference in the respective CpG islands between EBV-positive and -negative GCs was statistically significant (P < 0.05). Among these genes or loci, the methylation frequency of p16 in the EBV-positive GCs was more than three times higher than in the EBV-negative GCs. The PTEN, RASSF1A, GSTP1, MGMT, and MINT2 were methylated in EBV-positive GCs at a frequency of more than three times that of the EBV-negative GCs. These results demonstrate a relationship between EBV and aberrant methylation in GC and suggest that aberrant methylation may be an important mechanism of EBV-related gastric carcinogenesis.
authors.affiliation: Department of Pathology, Seoul NationalUniversity College of Medicine and Cancer Research Institute, Seoul, Korea. ghkang@snu.ac.kr
authors.forename: Gyeong Hoon
authors.initials: GH
authors.lastname: Kang
authors.forename: Sun
authors.initials: S
authors.lastname: Lee
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Lee
authors.forename: Jin Cheon
authors.initials: JC
authors.lastname: Kim
authors.forename: Mun-Gan
authors.initials: MG
authors.lastname: Rhyu
authors.forename: Jae Y
authors.initials: JY
authors.lastname: Ro
mesh_terms: D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D020031:Epstein-Barr Virus Infections / Q000235:genetics*; D005260:Female; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000235:genetics* / Q000821:virology*
chemical_list: D004273:DNA, Neoplasm