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Structural variability of the carboxy‐terminus of Epstein–Barr virus encoded latent membrane protein 1 gene in Hodgkin's lymphomas
Author(s) -
Guiretti Deisy M.,
Chabay Paola A.,
Valva Pamela,
Stefanoff Claudio G.,
Barros Mário H.M.,
De Matteo Elena,
Renault Ilana Zalcberg,
Preciado Maria Victoria,
Hassan Rocio
Publication year - 2007
Publication title -
journal of medical virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.782
H-Index - 121
eISSN - 1096-9071
pISSN - 0146-6615
DOI - 10.1002/jmv.21020
Subject(s) - virus , lymphoma , biology , epstein–barr virus , virology , gammaherpesvirinae , exact test , pathogenesis , gene , oncogene , direct repeat , herpesviridae , microbiology and biotechnology , genetics , viral disease , immunology , medicine , genome , cell cycle
Epstein–Barr virus (EBV) is implicated in the pathogenesis of several lymphoid and epithelial neoplasms. Latent membrane protein 1 (LMP1) is the major viral oncogene and it is controversial whether tumor LMP1 variants reflect their geographical predominance or are associated with enhanced oncogenic properties. This study aimed to analyze LMP1 molecular variability of 62 EBV+ Hodgkin's lymphomas and 22 non‐neoplastic controls from Brazil and Argentina. EBV association was characterized by EBER‐ISH, LMP1 immunohistochemistry and PCR assays for EBNA2 and 3C (typing), LMP1 30 bp deletion (del30) and number of 33 bp tandem repeats. LMP1 C‐terminal sequencing was performed in 42 cases. EBV1 was the predominant strain in both geographical Hodgkin's lymphoma groups (average 82%). A higher frequency of del30 variant was observed in lymphomas (41/63) than in non‐neoplastic controls (6/22) (OR 4.97, CI 95% 1.53–16.79; P = 0.005, χ 2 test). A large number (5–7) of 33 bp repeat units was characteristic of del30 LMP1 variants ( P < 0.0001, Fisher's exact test). Sequence analysis showed a similar mutation spectrum to that described worldwide but none of the current classification schemes could be applied completely. A distinct structural pattern was observed in del30 variants, characterized by a large number of 33 bp repeat units and the presence of a 15 bp insertion encoding the JAK3 Box‐1a motif (3/15 wt vs. 16/20 del30; P = 0.001, χ 2 test). The results suggest a pathogenic role for LMP1 del30 variants in Hodgkin's lymphoma from South America and point to particular virus‐host molecular mechanisms, such as genomic instability in LMP1 carboxy‐terminus, leading to enhanced production and selection of these deletion variants. J. Med. Virol. 79:1722–1730, 2007. © 2007 Wiley‐Liss, Inc.