In nasopharyngeal carcinoma-bearing patients, tumors and lymphocytes are infected by different epstein-barr virus strains

Henry, Sabine; Sacaze, Céline; Berrajah, Lamia; Karray, H.; Drira, M.; Hammami, Adnane; Icart, J.; Mariamé, Bernard

doi:10.1002/1097-0215(200002)9999:9999<::aid-ijc1110>3.0.co;2-2

Cited by 34 publications

(25 citation statements)

References 44 publications

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“…Similarly, some studies examined the EBV termini and reported monoclonal expansion of EBV in several kinds of lymphoma (14,29). However, in contrast to the pattern in tumor cells, multiple EBV strains were observed in peripheral blood from patients with NPC and from asymptomatic EBV carriers (11,19,39,42), as determined based on variations in LMP1 genes. These findings suggest that EBV might infect the progenitor cell before cell proliferation and then undergo monoclonal expansion in tumor cells, thereby contributing to pathogenesis.…”

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confidence: 85%

Direct Sequencing and Characterization of a Clinical Isolate of Epstein-Barr Virus from Nasopharyngeal Carcinoma Tissue by Using Next-Generation Sequencing Technology

Liu

Fang

Feng

et al. 2011

J Virol

103

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Epstein-Barr virus (EBV)-encoded molecules have been detected in the tumor tissues of several cancers, including nasopharyngeal carcinoma (NPC), suggesting that EBV plays an important role in tumorigenesis.However, the nature of EBV with respect to genome width in vivo and whether EBV undergoes clonal expansion in the tumor tissues are still poorly understood. In this study, next-generation sequencing (NGS) was used to sequence DNA extracted directly from the tumor tissue of a patient with NPC. Apart from the human sequences, a clinically isolated EBV genome 164.7 kb in size was successfully assembled and named GD2 (GenBank accession number HQ020558). Sequence and phylogenetic analyses showed that GD2 was closely related to GD1, a previously assembled variant derived from a patient with NPC. GD2 contains the most prevalent EBV variants reported in Cantonese patients with NPC, suggesting that it might be the prevalent strain in this population. Furthermore, GD2 could be grouped into a single subtype according to common classification criteria and contains only 6 heterozygous point mutations, suggesting the monoclonal expansion of GD2 in NPC. This study represents the first genome-wide analysis of a clinical isolate of EBV directly extracted from NPC tissue. Our study reveals that NGS allows the characterization of genome-wide variations of EBV in clinical tumors and provides evidence of monoclonal expansion of EBV in vivo. The pipeline could also be applied to the study of other pathogen-related malignancies. With additional NGS studies of NPC, it might be possible to uncover the potential causative EBV variant involved in NPC.Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that infects more than 90% of the worldwide human population. Following the first discovery of EBV particles in cultured lymphoma cells from patients with Burkitt's lymphoma (BL) (12, 13), EBV and its encoded molecules were also detected in cases of nasopharyngeal carcinoma (NPC) (52) and several other malignancies, such as non-Hodgkin lymphoma (NHL) (51) and T-cell and Hodgkin lymphomas (22,43,44). Both the presence of virus sequences in tumor cells and the virus's oncogenic potency (24, 46) strongly associate EBV with NPC. However, the genome-wide nature of the EBV in NPC tissue is still poorly understood.EBV harbors different genetic variations in different geographic populations (4,10,18,21,40,(48)(49)(50). Likewise, the prevalence characteristics of NPC show remarkable geographical and ethnic differences, with a high prevalence rate in southern China, especially in the Guangdong province (5). Several EBV genes, including EBNA2, LMP1, and EBNA1, have been implicated in the development of NPC (10,17,28,34). Certain EBV subtypes such as China 1 and V-val, as classified by the sequence variations of these genes, were found more frequently in patients with NPC than in controls and thus have been associated with NPC (26, 50). However, an NPCspecific EBV subtype has not yet been identified, suggesting that EBV subtypes cannot be classi...

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confidence: 85%

Direct Sequencing and Characterization of a Clinical Isolate of Epstein-Barr Virus from Nasopharyngeal Carcinoma Tissue by Using Next-Generation Sequencing Technology

Liu

Fang

Feng

et al. 2011

J Virol

103

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“…Expressed early in the EBV infection of a B lymphocyte (13,14), lyLMP-1 may act to modulate the inhibition of productive EBV replication by LMP-1 (1, 39). The finding that lyLMP-1 expression decreases the LMP-1 half-life in epithelial cells may explain the observation that the lyLMP-1 ORF is consistently absent from the LMP-1 genes of EBV strains found in patients with NPC (12,21), despite the apparent transcriptional activity of the ED-L1A promoter in NPC (30). Differences between NPC and B958 LMP-1 signal activation and oncogenicity in vitro (5,7,8,15,16,24,27,28,33,34,52) may be explained by the absence of the lyLMP-1 ORF in the NPC LMP-1 genes and the consequently longer half-lives of the NPC LMP-1s, although this hypothesis remains to be tested.…”

Section: Lmp-1 Amino Acid 129 and The Lytic Lmp-1 (Lylmp-1) Open Readmentioning

confidence: 99%

Epstein-Barr Virus Latent Membrane Protein 1 (LMP-1) Half-Life in Epithelial Cells Is Down-Regulated by Lytic LMP-1

Pandya¹,

Walling

2004

J Virol

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This study examined the effect of naturally occurring Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1) gene sequence variation on the LMP-1 half-life in epithelial cells. The LMP-1 half-life was not influenced by sequence variation in amino acids 250 to 307 or amino acids 343 to 352. The LMP-1 half-life was short when the amino acid encoded at position 129 was methionine, the initiation codon product of lytic LMP-1 (lyLMP-1). The mutation of amino acid 129 to isoleucine greatly increased the LMP-1 half-life. Expression of lyLMP-1 in trans down-regulated the LMP-1 half-life in a dose-dependent manner and restored a short-half-life phenotype to the mutated LMP-1 construct lacking the cis ability to express lyLMP-1. This observed dominant negative effect of lyLMP-1 expression on the LMP-1 half-life in epithelial cells in vitro may have implications for EBV epithelial oncogenesis in vivo.Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that is associated with numerous malignancies, especially nasopharyngeal carcinoma (NPC). Oncogenic EBV latent membrane protein 1 (LMP-1) is a 63-kDa protein of 386 amino acids (strain B958) encoded by the BNLF1 gene ( Fig. 1). LMP-1 inserts into the plasma membrane and functions as a ligand-independent, constitutively active growth factor receptor, similar to CD40 of the tumor necrosis factor receptor (TNFR) family. After oligomerization, LMP-1 binds TNFRassociated factors (TRAFs) and the TNFR-associated death domain protein (26, 38) to activate intracellular signaling through the NF-B, cJun N-terminal kinase, and p38 mitogenactivated protein kinase pathways (10,11,42). LMP-1 also activates the JAK-STAT signaling pathway, possibly through interaction with Janus kinase 3 (JAK3) (19,22). Cumulatively, these signals generate many effects on host cell growth, differentiation, apoptosis, and immune response.The LMP-1 gene manifests remarkable natural sequence heterogeneity (9,35,48). Although a specific LMP-1 genotypedisease phenotype relationship has not yet been identified (48), NPC-derived LMP-1 is both structurally and functionally different from the LMP-1 derived from the laboratory EBV strain B958 in the following ways: (i) NPC LMP-1 activates NF-B signaling and AP-1 transactivation better than B958 LMP-1 (5,7,15,16,27,33,34), (ii) NPC LMP-1 down-regulates cell immune markers, blocks cell apoptosis, and up-regulates the epidermal growth factor receptor (EGFR) better than B958 LMP-1 (7,8,15,27,33,34,52), and (iii) NPC LMP-1 transforms cells and forms tumors in mice more efficiently than B958 LMP-1 (8,24,28,33,52). Chimeric studies of LMP-1 have mapped some of these functional differences to the carboxy-terminal 30-nucleotide domain encoding amino acids 343 to 352 (28) and transmembrane domain amino acids 85 to 129 (5, 34).The intracellular quantity of expressed LMP-1 and the cell type background together influence the strength of LMP-1 signaling and its ultimate phenotypic effect on the cell (4,16,17,20,24,28,49,50). The intracellular half-life of LMP-1 is g...

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“…Previous studies have shown that different EBV genotypes are harbored by latently EBV-infected lymphoid tissues and blood cells (7)(8)(9)(10) in healthy persons and patients with malignancies. On the other hand, it is well established that the EBV is monoclonal in NPC tumor tissues and other EBV-associated cancers (11)(12)(13)(14).…”

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Investigation into the Origin and Tumoral Mass Correlation of Plasma Epstein–Barr Virus DNA in Nasopharyngeal Carcinoma

Chan¹,

Chan²,

Leung³

et al. 2005

Clinical Chemistry

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In nasopharyngeal carcinoma-bearing patients, tumors and lymphocytes are infected by different epstein-barr virus strains

Cited by 34 publications

References 44 publications

Direct Sequencing and Characterization of a Clinical Isolate of Epstein-Barr Virus from Nasopharyngeal Carcinoma Tissue by Using Next-Generation Sequencing Technology

Direct Sequencing and Characterization of a Clinical Isolate of Epstein-Barr Virus from Nasopharyngeal Carcinoma Tissue by Using Next-Generation Sequencing Technology

Epstein-Barr Virus Latent Membrane Protein 1 (LMP-1) Half-Life in Epithelial Cells Is Down-Regulated by Lytic LMP-1

Investigation into the Origin and Tumoral Mass Correlation of Plasma Epstein–Barr Virus DNA in Nasopharyngeal Carcinoma

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