Reduced expression and promoter methylation of p16 gene in Epstein-Barr virus-associated gastric carcinoma.
Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a unique type of gastric carcinoma (GC), which is considered to develop in a different pathway from EBV-negative GC. To evaluate a possible role of p16, an inhibitor of G1/S transition of the cell cycle, in the carcinogenesis of EBVaGC, p16-immunohistochemistry and methylation-specific PCR analysis (MSP) were applied to surgically resected gastric carcinomas. When the percentage of p16-positive cells in more than 1000 carcinoma cells was expressed as p16 labeling index (p16-LI), it ranged from 2.5 to 88.1 (mean 42.9+/-24.4) in 70 gastric carcinomas. EBVaGC showed significantly lower values (n=15, 26.1+/ -22.1) than EBV-negative GC (n=55, 47.5+/-23.2) (P=0.0036). Fresh frozen tissues of 55 gastric carcinomas (16 EBVaGC and 39 EBV-negative GC) were further subjected to MSP, to evaluate abnormal methylation of the promoter region of the p16 gene. The frequency of methylation was significantly higher in EBVaGC (14/16) than in EBV-negative GC (9/39) (<0.0001). The methylation-positive carcinomas showed significantly lower p16-LI (35.9+/-21.6) than the unmethylated ones (55.2+/-22.7) (P=0.0014). Thus, a marked decrease of p16 expression, caused by the aberrant methylation of the p16 gene promoter, is closely associated with the development of EBVaGC.
Osawa
Toshiya
T
Department of Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Chong
Ja-Mun
JM
Sudo
Makoto
M
Sakuma
Kazuya
K
Uozaki
Hiroshi
H
Shibahara
Junji
J
Nagai
Hideo
H
Funata
Nobuaki
N
Fukayama
Masashi
M
D000328:Adult; D000368:Aged; D018899:CpG Islands; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D019175:DNA Methylation; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000235:genetics; D005260:Female; D019942:Genes, p16; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000821:virology*
D019941:Cyclin-Dependent Kinase Inhibitor p16