Paediatric Hodgkin's disease in Spain: association with Epstein‐Barr virus strains carrying latent membrane protein‐1 oncogene deletions and high frequency of dual infections

Abstract

Summary. The present report analyses the distribution of 30-base pair (bp) latent membrane protein-1 (LMP-1) oncogene deletions in 24 cases of Epstein-Barr virus (EBV)-positive paediatric Hodgkin's disease (HD) and 39 normal controls.The 30 bp deletion was identified in 19/24 paediatric HD cases (79·2%), of which seven (29·2%) showed the deleted fragment alone, whereas in the remaining 12 (50%) it was accompanied by the nondeleted fragment. Conversely, the deletion was found in 8/22 (36·4%) EBV-positive healthy children, in two (9·1%) of whom the deleted fragment was alone, and was coinfecting with the nondeleted fragment in the other six (27·3%). The LMP-1 deletion was significantly associated with paediatric HD, both including dual infections (P ¼ 0·006) or excluding them (P ¼ 0·01).Type 2 EBV was carried by 25% of HD children, whereas all controls harboured type 1 EBV. The 30 bp deletion was present in all the paediatric HD specimens that contained type 2 EBV, suggesting that a deleted type 2 EBV strain may be more tumourigenic than a nondeleted type 2 EBV strain.These findings indicate that EBV strains carrying a 30 bp deletion in the third exon of the LMP-1 oncogene may have a more important role in the pathogenesis of paediatric HD than full-length EBV strains. Dual infection by LMP-1 deleted and nondeleted EBV strains is a frequent event both in healthy children and in the paediatric HD population.

Epstein Barr virus genotypes and LMP‐1 variants in HIV‐infected patients

“…On the other hand, the sequencing proved nine nucleotidic changes in the analyzed fragments (Table V), two of which were repeated in most of the samples (nt: 168295 A!T and nt: 168225 T!A). The last mutation involves a conservative aminoacid change in codon 366 (Ser!Thr), described both in benign (infectious mononucleosis and plasmocytic hyperplasias [Berger et al, 1997]), and malignant pathologies (Hodgkin's disease [Santon et al, 1998]), LnH and nasopharyngeal carcinomas [Knecht et al, 1996;Chabay et al, 2004]). Different EBV strains have been previously distinguished by sequence variation in both amino and carboxi terminus of LMP-1 gene; these strains were termed China 1, China 2, China 3, Alaskan, Mediterranean, and North Carolina and have been isolated from different clinical specimens [Edwards et al, 1999].…”

Hodgkin's disease and the Epstein-Barr virus

“…100 However, some studies have shown an increased incidence of this deletion variant in HIV positive Hodgkin's disease compared with HIV negative Hodgkin's disease, 101 and also in paediatric Hodgkin's disease compared with normal controls. 102 LMP2 is also expressed by HRS cells in EBV associated Hodgkin's disease (fig 3). LMP2A aVects signal transduction by obstructing those pathways that are triggered by ligation of the B cell antigen receptor complex (see L S Young et al, this issue).…”

Contribution of the Epstein–Barr virus to the molecular pathogenesis of Hodgkin lymphoma

“…In general, virus strains carrying this 30 bp deletion occur with a similar frequency in virus-positive tumour patients and in healthy donors from the same geographical region 107. The exception to this is HL,108 where some studies have shown an increased incidence of this deletion variant in HIV-positive HL compared to HIV-negative HL,109 and in paediatric HL compared to normal controls 110…”