Structural variability of the carboxy-terminus of Epstein-Barr virus encoded latent membrane protein 1 gene in Hodgkin lymphomas

GUIRETTI, D.; PAOLA ANDREA CHABAY; VALVA, P.; STEFANOFF CG; DE MATTEO E; ZALCBERG, I.; PRECIADO MV; HASSAN, R.

JOURNAL OF MEDICAL VIROLOGY

Wiley Interscience

Año: 2007 vol. 79 p. 1722 - 1730

0146-6615

Epstein–Barr virus (EBV) is a Gamma-Herpesvirus implicated in the pathogenesis of several lymphoid and epithelial neoplasms. LMP1 is the major viral oncogene and it is not clear whether tumor LMP1 genetic variants reflects their geographic predominance or are rather associated to enhanced oncogenic proprieties. We analyzed LMP1 molecular variability of 35 and 27 EBV+ Hodgkin lymphomas (HL) and a group of 22 non-neoplastic (NN) controls from South East Brazil and Argentina. EBV association was determined by EBER-ISH and immunohistochemistry for LMP1 protein. All 62 EBV+ cases were characterized by PCR for EBNA2 and 3C (typing), and LMP1 30 bp deletion (del30) and number of 33bp tandem repeats. LMP1 C-terminal sequencing was performed in 41 cases. EBV1 was the predominant strain in both geographic groups (78% Argentine HL and 86% Brazilian HL) and did not differ from the NN samples. A higher frequency of del30 variant was observed in HL (41/63, 65%) than in NN tissue (6/22, 27%) (P= 0.005; OR 4.97, CI 95% 1.53 – 16.79). A high number (5-7) of 33bp repeat units was characteristic of del30 LMP1 variants (P<0.0001). Sequence analysis showed a similar mutation spectrum than the described worldwide but none of the current classification schemes could be entirely applied. A distinct structural pattern was observed in del30 variants, characterized by a significant high number of 33 bp repeat units and the presence of a 15 bp insertion encoding the JAK3 Box 1a signaling motif (wt 3/14 vs del30 16/20; P=0.002). Our results suggest a pathogenic role for LMP1 del30 variants in HL from South America and point to particular virus-host molecular mechanisms, like genomic instability in LMP1 C-ter region, leading to enhanced production and selection of these deletion variants.