Affiliations: Institute of Pathology, University Hospital of Düsseldorf, Düsseldorf, Germany | Institute of Pathology, University Hospital of Freiburg, Freiburg, Germany | Institute of Pathology, Technical University of Munich, Munich, Germany
Note: [] Corresponding author: Helene Geddert, Institute of Pathology, St. Vincentius Hospital, Südendstrasse 37, 76137 Karlsruhe, Germany. Tel.: +49 721 8108 3006; Fax: +49 721 8108 3700; E-mail: Helene.Geddert@vincentius-ka.de.
Note: [] Present address: Institute of Pathology, St. Vincentius Hospital, Karlsruhe, Germany.
Note: [] Present address: Department of Pathology, University Hospital Maastricht, Maastricht, The Netherlands.
Note: [] Present address: Institute of Pathology, Munich-Nymphenburg, Germany.
Abstract: Background: Epstein–Barr virus (EBV)-associated gastric carcinomas (GC) constitute a distinct clinicopathological entity of gastric cancer. In order to determine underlying distinct aberrant promoter methylation we tested cardiac and non-cardiac GC with regard to the presence of EBV. Methods: One hundred GC were tested by RNA-in situ hybridization for the presence of EBV by EBV-encoded small RNA (EBER). Aberrant promoter methylation was investigated by methylation-specific real-time PCR for p16, p14, APC and hMLH1. P16 protein expression was assessed by immunohistochemistry. Results: In our selected study cohort, EBER-transcripts were detected in 19.6% (18/92) of GC. EBV-positive GC revealed significantly more often gene hypermethylation of p16, p14 and APC (p<0.0001, p<0.0001 and p=0.02, respectively) than EBV-negative GC. The majority of GC with p16 hypermethylation showed a p16 protein loss (22/28). In contrast, no correlation between the presence of EBV and hMLH1 hypermethylation was found (p=0.7). EBV-positive GC showed a trend towards non-cardiac location (p=0.06) and lower stages (I/II) according to the WHO (p=0.05). Conclusions: Hypermethylation of tumor suppressor genes is significantly more frequent in EBV-associated GC compared to EBV-negative GC. Our data add new insights to the role of EBV in gastric carcinogenesis and underline that EBV-associated GC comprise a distinct molecular-pathologic as well as a distinct clinicopathological entity of GC.
