Reduced Expression and Promoter Methylation p16 Gene in Epstein‐Barr Virus‐associated Gastric Carcinoma

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Abstract
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, pl6‐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.