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
Molecular Biology Laboratory, Bone Marrow Transplantation Centre (CEMO), Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brazil.
J Med Virol. 2007 Nov;79(11):1730-22. doi: 10.1002/jmv.21020.
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, chi(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, chi(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.
爱泼斯坦-巴尔病毒（EBV）与多种淋巴样和上皮性肿瘤的发病机制有关。潜伏膜蛋白1（LMP1）是主要的病毒癌基因，肿瘤LMP1变体是否反映其地理优势或与增强的致癌特性相关仍存在争议。本研究旨在分析来自巴西和阿根廷的62例EBV阳性霍奇金淋巴瘤和22例非肿瘤对照的LMP1分子变异性。通过EBER原位杂交、LMP1免疫组织化学以及针对EBNA2和3C（分型）、LMP1 30 bp缺失（del30）和33 bp串联重复序列数量的PCR检测来表征EBV关联。对42例病例进行了LMP1 C末端测序。EBV1是两个地理区域霍奇金淋巴瘤组中的主要毒株（平均82%）。与非肿瘤对照（6/22）相比，淋巴瘤（41/63）中del30变体的频率更高（OR 4.97，95%CI 1.53 - 16.79；P = 0.005，卡方检验）。大量（5 - 7个）33 bp重复单元是del30 LMP1变体的特征（P < 0.0001，Fisher精确检验）。序列分析显示出与全球描述相似的突变谱，但目前的分类方案均无法完全适用。在del30变体中观察到一种独特的结构模式，其特征是大量33 bp重复单元以及存在一个编码JAK3 Box-1a基序的15 bp插入序列（野生型3/15 vs. del30 16/20；P = 0.001，卡方检验）。结果表明LMP1 del3变体在南美洲霍奇金淋巴瘤中具有致病作用，并指出了特定的病毒-宿主分子机制，如LMP1羧基末端的基因组不稳定性，导致这些缺失变体的产生和选择增加。
