Polymorphism analysis of Epstein-Barr virus isolates from patients with cutaneous natural killer/T-cell lymphoproliferative disorders: A possible relation to the endemic occurrence of these diseases in Japan

Certain forms of cutaneous lymphomas in Asia are associated frequently with Epstein-Barr virus (EBV) infection, whereas such cases are less common in western countries. The virus-related peptides, EBV-determined nuclear antigen (EBNA)-2 and the latent membrane protein (LMP)-1, play an essential role in cell transformation. The polymorphisms of these EBV genes may be related to their transforming abilities. In order to clarify the viral subtype that may be involved in the incidence of EBV-associated lymphomas, we analyzed the EBNA-2 and LMP-1 gene polymorphisms and mutations in healthy adults and in patients with EBV-associated cutaneous natural killer(NK)/T-cell lymphoproliferative disorders in Japan. In EBV-related cutaneous lymphoproliferative disorders, EBV subtype 1 was found in all 15 cases, and 1 sample contained a dual infection with subtypes 1 and 2. All EBV isolates from our patients lost a Xho-1 site in exon 1 of the LMP-1 gene, and 7 of 13 cases had a Nco-1 site within the promoter region. All isolates without the LMP-1-Xho-1 site had a 30 bp deletion in the carboxy terminus of the LMP-1 gene, except for the isolate from a patient with angioimmunoblastic lymphadenophathy-like T-cell lymphoma in which a novel Nco-1 site was present in exon 1. Eleven of fourteen throat washings from healthy adults which contained EBV-DNA harbored EBV subtype 1, and the EBNA2 region was not amplified in the other 3 samples. The Xho-1 site was lost in 12 (86%) of 14 isolates and the 30 bp deletion was present in 11 (78%) of 14 isolates from the throat washings. The findings indicate that the predominant EBV isolate from Japanese healthy adults and patients with cutaneous NK/T-cell lymphoproliferative disorders is subtype 1 with a 30 bp deletion and loss of a Xho-1 site in the LMP-1 gene. Since previous data indicated that either subtype 1 or the 30 bp deletion variant possesses high tumorigenic activity, the prevalence of subtype 1 containing these mutations might be responsible for the high incidence of EBV-associated lymphoproliferative disorders in Japan.