EBNA-1 Gene Sequences in Brazilian and American Patients With Hodgkin’s Disease

Abstract

We examined the types of Epstein-Barr virus–associated nuclear antigen-1 (EBNA-1) gene carboxy (C)-terminal mutations occurring in Hodgkin’s disease (HD) and reactive tissues from two different geographic regions. Previously reported EBNA-1 C-terminal region amino acid sequence variants, based on the amino acid at codon 487, include Prototype (P)-ala, which is found in the B95.8-derived prototype virus, P-thr, Variant (V)-leu, V-val, and V-pro. Using polymerase chain reaction (PCR) to amplify portions of the EBNA-1 gene, followed by DNA sequencing, we found a single EBNA-1 gene sequence variant in each tissue, whether reactive or neoplastic and whether from Brazil or the United States. Variant EBNA-1 gene sequences were more common in both neoplastic and non-neoplastic tissues from different geographic areas than the so-called prototype sequence. In the 17 Brazilian HD cases, 4 cases had P-thr variants and 13 had V-leu variants. In the six reactive tissues from Brazil, one had a P-ala variant, two had P-thr variants, and three had V-leu variants. In the 12 American HD cases, 2 had P-ala variants, 6 had P-thr variants, and 4 had V-leu variants. The 11 American reactive tissues included 2 P-ala variants, 5 P-thr variants, and 4 V-leu variants. In both countries, there were similar variant EBNA-1 sequences present in normal tissues and HD cases. Compared with the P-ala and P-thr cases, the V-leu cases were more likely to have the 30-bp latent membrane protein 1 (LMP1) gene deletion (P = 0.0075). In addition, cases of HD with the V-leu were statistically associated with a substitution of asparagine for glutamine at codon 322 of the C-terminal portion of the LMP1 gene. Our results suggest that any variation in EBNA-1 gene sequence is caused by a polymorphism present in pre-existing viral strains in the underlying population, and not a mutation occurring during oncogenesis.

Genome-wide analysis of Epstein-Barr virus (EBV) isolated from EBV-associated gastric carcinoma (EBVaGC)

“…V-val was the most common subtype, accounting for 77.7% of all 9 GC-EBV strains, followed by P-thrV, accounting for 22.3%. These findings are similar to those of previous studies on Asia populations, but different from those on western cases [ 18 , 19 , 36 – 44 ]. Multiple results showed that V-val is the dominant subtype in Asian regions studies, not only in EBVaGC but also in NPC and healthy donors, while V-val subtype was rarely found in Africa, Europe, and America irrespective of source (lymphoma, NPC, EBVaGC, or healthy donors) [ 18 , 19 , 36 – 44 ], indicating that polymorphism of EBNA1 subtypes has geographic differences but is not tumor-specific.…”

Sequence Variation Analysis of Epstein-Barr Virus Nuclear Antigen 1 Gene in the Virus Associated Lymphomas of Northern China

“…MacKenzie et al [ 21 ] found V-leu preferentially in 12/20 lymphomas from Brazil and P-thr in 9/14 lymphomas from the United Kingdom. Chang et al [ 22 ] reported 13/17 HL from Brazil present V-leu and 6/12 from the USA contained P-thr. Two other studies reported that 9/10 HL from Danish carried P-thr subtype and 9/19 lymphoma samples from Brazil showed V-leu variant respectively [ 15 , 23 ].…”

“…This may attribute to the fact that EBNA1 subtypes are discordant with EBNA3C typing data, which was demonstrated in this study. Many investigations have been focused on relations of different EBV gene variations with EBV associated diseases [ 9 , 21 , 22 , 31 ]. In the present study, we found no significant association between EBV subtypes and EBNA1 subtypes in lymphoma, which was different from our previous report in other tumor types [ 18 ].…”

Genome-Wide Profiling of Epstein-Barr Virus (EBV) Isolated from EBV-Related Malignancies

“…Based on the amino acid changes at position 487 in the COOH-terminal region in EBNA1 relative to B95-8 (P-ala), V-val was the most common subtype, accounting for 77.7% of nine GC-EBV strains, followed by P-thrV, accounting for 22.3%. Multiple results showed that V-val is the dominant subtype in Asian regions studies, not only in EBVaGC but also in NPC and healthy donors, while V-val subtype was rarely found in Africa, Europe, and America irrespective of source (lymphoma, NPC, EBVaGC, or healthy donors) [37][38][39], indicating that polymorphism of EBNA1 subtypes has geographic differences but is not tumor-specific. Apart from changes in the C-terminus, EBNA1 has variations in the N-terminus.…”