We examined the prognosis of 64 EBV-associated gastric carcinoma (EBV-GC) cases and 128 EBV-negative gastric carcinoma cases. EBV-GCs were identified by detecting EBV-encoded small RNA (EBER) using in situ hybridization assay of paraffin-embedded tissue. For each EBV-GC case, 2 EBER-negative cases (EBV-negative cases) were selected, matching the EBV-GC case with respect to age, sex, tumor location, and depth of invasion. The average follow-up period was 70.9 months (SD=61.1) in EBV-GCs and 63.8 months (SD=59.7) in EBV-negative cases. Tumor-advanced stage determined by TNM classification of UICC, tumor location, and p53 over-expression were statistically significant prognostic factors. On the other hand, EBER expression was not related to the survival of patients. However, further analysis specific for intestinal and diffuse types of Lauren classification revealed that the association of EBER expression with prognosis was different in the two histological types. EBER expression was related to poor prognosis in intestinal-type carcinoma [hazard ratio (HR) =2.5, 95% confidence intervals (CI) =1.3-4.8] after adjusting for stage, p53 over-expression, and tumor location, whereas the diffuse-type EBV-GC had better prognosis (HR=0.4, 95% CI=0.2-0.9) even when lymphoepithelioma-like carcinomas were excluded. To examine the interactive prognostic effects between EBER expression and p53 over-expression, the study subjects were divided into 4 groups on the basis of EBER expression and p53 over-expression. In intestinal-type tumors, the cases having both EBER expression and p53 over-expression showed the poorest prognosis (HR=10.0, 95% CI=3.3-30.4), and the cases with either EBER expression or p53 over-expression had an intermediate prognosis. In diffuse-type tumor, only EBER was an important prognostic factor. These results give additional evidence implicating EBV in the natural history of EBV-GCs.

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