Molecular analysis of the Epstein-Barr virus LMP1 in Hodgkin lymphoma from Argentina and Brazil: Identification of a distinct LMP1 deleted variant

CHABAY P; HASSAN R; GUIRETTI D; VALVA P; BARROS M; LORENZETTI M; DE MATTEO E; ZALCBERG I; REY G; PRECIADO MV

Chicago, Illinois, Estados Unidos

Congreso; Annual Meeting of the American Society of Clinical Oncology 2007; 2007

American Society of Clinical Oncology

Background:Epstein Barr virus (EBV), a human oncogenic virus, has two types, EBV1 and 2, and several polymorphic markers allow individual variants to be distinguished. Variations in EBV latent membrane protein 1 (LMP1) gene could define a more oncogenic strain or reflect geographic EBV origin. By sequence analysis of C-ter, N-ter and promoter (prom) regions, 4 distinct EBVgroups (A to D) have been defined. Aim: To analyze LMP1 molecular variability of two different groups of Hodgkin´s lymphoma (HL) from the same geographic area. Methods: EBV association by EBERs in situhibridization and LMP1 immunohistochemistry was analyzed in 27 HL from Argentina(Arg) and 36 HL from Brazil(Br). EBV type was assessed by EBNA PCR. C-ter LMP1 PCR was done in all cases. Sequencing of Cter, N-ter and prom regions was done in 16 patients. Results:21/27 (78%) Arg HL and 31/36 (86%) Br HL were EBV1, while 6/27 (22%) and 4/36 (11%) were EBV2, respectively (p= 0.29). Coinfection was observed in 1 (3%) Br HL. LMP1 deleted del variant was observed in 20/27 (74%) Arg HL and 20/36 (55%) Br HL (p= 0.18), as well as in non-neoplastic controls, 4/11 and 3/10 (36 and 30%) from Arg and Br respectively. Most LMP1 del displayed high number (5-7) of 33bp repeats (86% LMP1 del Br HL and 77% LMP1 del Arg HL) compared with LMP1 wt that exhibited low number (3-4) 33bp repeats (68% LMP1 wt Br HL and 100% LMP1 wt Arg HL). Analysis of LMP1 sequences showed that: LMP1 wt C-ter regions had unmutated N-ter and prom as B95.8, A and B groups (31%), except for a case showing new mutations. LMP1 del C-ter regions showed molecular identity with C group, but they showed new, undescribed mutations in prom and N-ter (63%). Conclusions: We found high frequency of LMP1 del variants in HL from Argentina and Brazil, which was associated with high number of 33bp repeats in C-ter region. This suggests a role for this variant in lymphomagenesis. A new molecular variant with characteristic promoter and N-ter mutations was identified in LMP1 del cases, which could be proposed as a regional South American variant.