Comparative analysis of Epstein-Barr virus gene polymorphisms in nasal T/NK-cell lymphomas and normal nasal tissues: Implications on virus strain selection in malignancy

Abstract

Whether particular Epstein-Barr virus (EBV) strains are preferentially selected in malignant diseases remains controversial. Assessment of the importance of strain variation in the pathogenicity of EBV has been hampered principally by the lack of accurate data on the prevalence of virus variants in the normal population. To clarify this issue, a detailed comparative analysis of the EBV genomes contained in normal nasal and nasopharyngeal mucosal tissues and in nasal T/NK-cell lymphoma, which originates at these anatomic sites, was carried out by PCR amplification across the 30-bp deletion and the 33-bp repeat loci in the LMPI gene and the typespecific polymorphic loci in the EBNA2 and EBNA3C genes and by sequence analysis of the 3' C-terminal region of the LMPI gene. Whilst the majority of EBV strains in either normal or tumour tissues were type I viruses with similar numbers of LMPI repeats, a marked predominance of LMPI deletion (del-LMP) over non- deleted/wild-type LMPI (wt-LMPI) variants was observed in nasal T/NK-cell lymphoma. Although del-LMPI variants were also prevalent in the normal carriers of our population, wt-LMPI was detected at a significantly higher frequency in normal vs. tumour tissues (p = 0.036). More critically, wt-LMPI variants were found frequently in mixed infection with del-LMPI variants in the normal carriers. Sequence analysis identified 2 major del-LMPI (and several wt-LMPI) variants containing signatory nucleotide changes in relation to the prototype B95-8 sequence in both normal and neoplastic nasal tissues. Together, our data provide strong evidence for a selection mechanism for del- LMPI over the wt-LMPI variants in tumours.