Role of DNA methylation in the development of Epstein-Barr virus-associated gastric carcinoma.
The frequencies of DNA methylation of certain tumor-related genes are higher in Epstein-Barr virus (EBV)-associated gastric carcinomas than in EBV-negative gastric carcinomas. EBV-associated gastric carcinomas have distinct clinicopathological features; however, there are no case-control studies comparing methylation frequency between EBV-associated gastric carcinomas and controls that have been adjusted according to the clinicopathological features of EBV-associated gastric carcinomas. This study evaluated 25 EBV-associated gastric carcinomas that were positive for EBV-encoded small RNA 1 (EBER-1) by in situ hybridization and 50 EBV-negative gastric carcinomas that were matched with the EBV-associated gastric carcinomas by age, sex, histology, depth of tumor invasion, and stage. Methylation status of 16 loci associated with tumor-related genes was analyzed by methylation-specific polymerase chain reaction (PCR) to identify genes in which DNA methylation specifically occurred in EBV-associated gastric carcinomas. Methylation frequencies of 12 of the 16 genes were higher in EBV-associated gastric carcinomas than in EBV-negative controls, and the frequency of methylation of 6 specific loci (MINT2, MINT31, p14, p16, p73, and RUNX3) was significantly higher in EBV-associated gastric carcinomas than in EBV-negative controls. There were no significant differences in the methylation frequencies of the other genes. The mean methylation index in EBV-associated gastric carcinomas was significantly higher than that in EBV-negative controls. DNA methylation of tumor suppressor genes that regulate the cell cycle and apoptosis specifically occurred in EBV-associated gastric carcinomas. Aberrant DNA methylation might lead to the development and progression of EBV-associated gastric carcinoma.
Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
Mari
M
Saito
Jun
J
Nishikawa
Toshiyuki
T
Okada
Akihiro
A
Morishige
Kouhei
K
Sakai
Munetaka
M
Nakamura
Shu
S
Kiyotoki
Kouichi
K
Hamabe
Takeshi
T
Okamoto
Atsunori
A
Oga
Kohsuke
K
Sasaki
Yutaka
Y
Suehiro
Yuji
Y
Hinoda
Isao
I
Sakaida
D000368:Aged; D002277:Carcinoma / Q000821:virology*; D019175:DNA Methylation; D005260:Female; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000235:genetics / Q000302:isolation & purification; D013274:Stomach Neoplasms / Q000821:virology*
C099537:Epstein-Barr virus encoded RNA 1; D012367:RNA, Viral