Reduced Expression and Promoter Methylation of p16 Gene in Epstein-Barr Virus-associated Gastric Carcinoma.

摘要

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.