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Epstein-Barr virus in gastric adenocarcinomas: association with ethnicity and CDKN2A promoter methylation

¹ Department of Pathology, Louisiana State University Health Sciences Center and Stanley Scott Cancer Center, New Orleans, LA 70112, USA
² Roswell Park Cancer Institute, Buffalo, NY 14263, USA
³ Universidad Del Valle, Cali, Colombia
⁴ Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27514, USA

Correspondence to:
Dr B Schneider, Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA;
bschne{at}lsuhsc.edu Aims: It has been shown previously (by immunohistochemistry) that gastric adenocarcinomas harbouring Epstein-Barr virus (EBV) frequently lose p16 protein. This study aimed to examine the mechanisms of inactivation of the CDKN2A gene and correlate the results with clinicopathological features.

Methods: Methylation specific polymerase chain reaction was used to detect CDKN2A promoter methylation in gastric adenocarcinomas from American patients. In addition, immunohistochemistry was used to detect the loss of the p16 protein and in situ hybridisation was used to detect the presence of EBV. The tumours were also analysed for the presence of microsatellite instability.

Results: Eleven (10%) of 107 tumours harboured EBV in the malignant cells. In gastric cancers without EBV, 32% exhibited CDKN2A promoter methylation and 26% had p16 protein loss. In contrast, 91% of the tumours containing EBV had CDKN2A promoter methylation (p = 0.0003) and 90% showed p16 protein loss (p = 0.0001). The presence of EBV was also associated with male sex (p = 0.03) and was more common in tumours from Texas Hispanics than from non-Hispanic whites or African–Americans (p = 0.01). EBV was not associated with microsatellite instability, histological subtype, stage, or grade of the tumour, or age or survival time of the patient.

Conclusions: The presence of EBV in gastric adenocarcinomas is strongly associated with CDKN2A inactivation by promoter methylation. In addition, these findings suggest that there are ethnic differences in tumour virology and pathogenesis.

Keywords: CDK2A; Epstein-Barr virus; methylation

Abbreviations: CDKN2A, cyclin dependent kinase inhibitor 2A; EBER1, Epstein-Barr virus encoded RNA 1; EBNA, Epstein-Barr virus encoded nuclear antigen; EBV, Epstein-Barr virus; IHC, immunohistochemistry; LCM, laser capture microdissection; LEL, lymphoepithelioma-like; LMP1, latent membrane protein 1; MSI, microsatellite instability; MSI-L, low frequency microsatellite instability; MSI-H, high frequency microsatellite instability; MS-PCR, methylation specific polymerase chain reaction; MSS, microsatellite stable; NCI, National Cancer Institute

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