title: Epstein-Barr virus (EBV) nuclear antigen (EBNA)-4 mutation in EBV-associated malignancies in three different populations.
abstract: Different ethnic groups with a high human leukocyte antigen (HLA)-A11 prevalence have been shown to experience a high rate of Epstein-Barr virus (EBV) infection, EBV-associated malignancies, and Epstein-Barr nuclear antigen (EBNA)-4 mutations. The epitopes 399-408 and 416-424 of EBNA-4 are major antigenic epitopes that elicit an HLA-A11 cytotoxic T lymphocyte (CTL) response to EBV infection. Mutations selectively involving one or more nucleotide residues in these epitopes affect the antigenicity of EBNA-4, because the mutant EBV strains are not recognized by the HLA-A11-restricted CTLs. To investigate these mutations in common EBV-associated malignancies occurring in different populations, we studied the mutation rate of epitopes 399-408 and 416-424 of EBNA-4 in 25 cases of EBV-associated Hodgkin's disease (HD), nine cases of AIDS-related non-Hodgkin's lymphoma, and 37 cases of EBV-associated gastric carcinoma (GC) from the United States, Brazil, and Japan. We found one or more mutations in these two epitopes in 50% (6/12) of United States HD, 15% (2/13) of Brazilian HD, 50% (6/12) United States GC and 28% (7/25) Japanese GC, and 22% (2/9) of United States AIDS-lymphoma. Similar mutations were found in 30% (3/10) of United States reactive, 0% (0/6) of Brazilian reactive, and 25% (2/8) Japanese reactive tissues. The most frequent amino acid substitutions were virtually identical to those seen in previously reported isolates from EBV-associated nasopharyngeal carcinomas and Burkitt's lymphomas occurring in high prevalence HLA-A11 regions. However, only 2/28 (7%) mutations occurred in HLA-A11-positive patients. Our studies suggest that: 1) EBNA-4 mutations are a common phenomenon in EBV-associated HD, GC, and AIDS-lymphoma; 2) the mutation rate does not vary in these geographic areas and ethnic groups; 3) EBNA-4 mutations in EBV-associated United States and Brazilian HD, United States and Japanese GC, and United States AIDS lymphomas are not related to patients' HLA-A11 status.
authors.affiliation: Division of Pathology, City of Hope National Medical Center, Duarte, California 91010-0269, USA.
authors.forename: P G
authors.initials: PG
authors.lastname: Chu
authors.forename: K L
authors.initials: KL
authors.lastname: Chang
authors.forename: W G
authors.initials: WG
authors.lastname: Chen
authors.forename: Y Y
authors.initials: YY
authors.lastname: Chen
authors.forename: D
authors.initials: D
authors.lastname: Shibata
authors.forename: K
authors.initials: K
authors.lastname: Hayashi
authors.forename: C
authors.initials: C
authors.lastname: Bacchi
authors.forename: M
authors.initials: M
authors.lastname: Bacchi
authors.forename: L M
authors.initials: LM
authors.lastname: Weiss
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D002277:Carcinoma / Q000821:virology; D004252:DNA Mutational Analysis; D004279:DNA, Viral / Q000032:analysis; D000939:Epitopes / Q000235:genetics; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics*; D015234:HLA-A Antigens / Q000235:genetics; D059870:HLA-A11 Antigen; D006689:Hodgkin Disease / Q000821:virology*; D006801:Humans; D016483:Lymphoma, AIDS-Related / Q000821:virology*; D008228:Lymphoma, Non-Hodgkin / Q000821:virology*; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000821:virology*
chemical_list: D004279:DNA, Viral; D000939:Epitopes; D019309:Epstein-Barr Virus Nuclear Antigens; D015234:HLA-A Antigens; D059870:HLA-A11 Antigen