Gastric carcinoma: monoclonal epithelial malignant cells expressing Epstein-Barr virus latent infection protein.
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 immunofluorescence and hematoxylin/eosin staining in parallel sections revealed that every keratin-positive epithelial malignant 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 EBV-specific antibodies. The EBV-specific cellular immunity was not significantly 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.
Imai
S
S
Department of Virology, Hokkaido University School of Medicine, Sapporo, Japan.
Koizumi
S
S
Sugiura
M
M
Tokunaga
M
M
Uemura
Y
Y
Yamamoto
N
N
Tanaka
S
S
Sato
E
E
Osato
T
T
D000914:Antibodies, Viral / Q000276:immunology; D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D002999:Clone Cells; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019309:Epstein-Barr Virus Nuclear Antigens; D005260:Female; D005814:Genes, Viral; D004854:Herpesvirus 4, Human / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D007111:Immunity, Cellular; D007564:Japan; D008297:Male; D008745:Methylation; D013274:Stomach Neoplasms / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D014412:Tumor Virus Infections / Q000276:immunology / Q000382:microbiology*; D015678:Viral Structural Proteins / Q000235:genetics
D000914:Antibodies, Viral; D000956:Antigens, Viral; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D019309:Epstein-Barr Virus Nuclear Antigens; D015678:Viral Structural Proteins