Gastric carcinoma: monoclonal epithelial malignant cells expressing Epstein-Barr virus latent infection protein.

Abstract

In 1000 primary gastric carcinomas, 70 (7.0%) contained Epstein-Barr virus (EBV) genomic sequences detected by PCR and Southern blots. The positive tumors comprised 8 of 9 (89%) undifferentiated lymphoepithelioma-like carcinomas, 27 of 476 (5.7%) poorly differentiated adenocarcinomas, and 35 of 515 (6.8%) moderately to well-differentiated adenocarcinomas. In situ EBV-encoded small RNA 1 hybridization and hematoxylin/eosin staining in adjacent sections showed that the EBV was present in every carcinoma cell but was not significantly present in lymphoid stroma and in normal mucosa. Two-color immunofuorescence and hematoxylin/eosin staining in parallel sections revealed that every keratin-positive epithelial maiant cell expressed EBV-determined nuclear antigen 1 (EBNA1) but did not significantly express CD45+ infiltrating leukocytes. A single fused terminal fragment was detected in each of the EBNA1-expressing tumors, thereby suggesting that the EBV-carrying gastric carcinomas represent clonal proliferation of cells infected with EBV. The carcinoma cells had exclusively EBNA1 but not EBNA2, -3A, -3B, and -3C; leader protein; and latent membrane protein 1 because of methylation. The patients with EBV-carrying gastric carcinoma had elevated serum EBVspecific antibodies. The EBV-specific cellular immunity was not signficantly reduced; however, the cytotoxic T-cell target antigens were not expressed. These findings strongly suggest a causal relation between a significant proportion of gastric carcinoma and EBV, and the virus-carrying carcinoma cells may evade immune surveillance.

Epstein‐Barr virus‐encoded latent membrane protein 1 promotes stress‐induced apoptosis upstream of caspase‐2‐dependent mitochondrial perturbation

“…EBV is a ubiquitous virus that infects more than 90% of the human population and has been linked to a number of malignant diseases, including nasopharyngeal carcinoma (NPC), 44 gastric cancer, 45 Burkitt's lymphoma 46 and B lymphomas in immunocompromised individuals. 47 The precise role of EBV in the malignant transformation of different cell types remains unclear.…”

Epigenetic changes in virus-associated human cancers

“…Intriguingly, EBV-associated GC does express latency genes (EBNA1, EBER1, BARF0 and LMP2A), but does not express LMP1 and EBNA2 [66], suggesting other viral gene(s) or alternative mechanism may be involved in the EBV-associated GC epigenetic alteration.…”

Molecular Diagnosis of Epstein-Barr Virus-Related Diseases

“…59 Analogous studies are underway in gastric carcinoma patients who likewise harbor high serological titers against EBV. 7 Immunosuppressed patients have inconsistent humoral responses against EBV; therefore, serology is not as reliable a marker of clinical status. In these patients, direct detection of viral nucleic acid or protein is more reliable for identifying clinically relevant EBV infection.…”

“…Nasopharyngeal carcinomas and posttransplant lymphoproliferative disorders are nearly always EBV-associated, whereas several other tumors, such as Hodgkin's disease, nonHodgkin's lymphoma, lymphoepithelioma-like carcinoma, gastric adenocarcinoma, and several types of sarcoma, are less uniformly EBV-associated. [2][3][4][5][6][7] EBV causes benign transient lymphoproliferative lesions at the time of primary infection, and it is found in a benign lesion of the tongue called oral hairy leukoplakia. 8,9 Patients affected by these benign or malignant diseases may benefit from laboratory detection of EBV to confirm their diagnosis or to monitor disease burden after the initiation of therapy.…”