Promoter hypermethylation of E‐cadherin and its abnormal expression in Epstein‐Barr virus‐associated gastric carcinoma

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Abstract
Promoter hypermethylation of various tumor‐related genes is extremely frequent in Epstein‐Barr virus (EBV)‐associated gastric carcinoma (EBVaGC). To investigate the significance of the promoter methylation in EBVaGC, we focused on one of the important proteins in the carcinogenesis of the stomach, E‐cadherin. Methylation‐specific PCR analysis (MSP) was applied to surgically resected gastric carcinomas, together with immunohistochemistry, PCR‐based analysis of mutations and allelic loss, and site‐specific MSP of E‐cadherin gene. By MSP, nearly all of the carcinomas showed aberrant methylation of E‐cadherin promoter in EBVaGC (21/22), and the frequency of this aberration was significantly higher than that in EBV‐negative gastric carcinoma (GC; 45/81; p = 0.0003). According to immunohistochemistry of E‐cadherin, the frequency of abnormal staining pattern in EBVaGC (87%) was comparable to that in the diffuse type (80%), but higher than that in the intestinal type of EBV‐negative GC (47%). Promoter methylation was well correlated with abnormal staining pattern in EBVaGC, but not in EBV‐negative GC. Neither mutation nor allelic loss of E‐cadherin was observed in EBVaGC. Methylation status of E‐cadherin within each carcinoma was heterogeneous as far as examined. Thus, in addition to the known association involving p16, we determined that promoter methylation‐mediated silencing of E‐cadherin gene was also closely associated with the development of EBVaGC, although it becomes heterogeneous within a given tumor along its progression.