Clonal deleted latent membrane protein 1 variants of Epstein‐Barr virus are predominant in European extranodal NK/T lymphomas and disappear during successful treatment

Abstract

Extranodal natural killer/T-cell lymphomas (NK/TL), rare in Europe, are Epstein-Barr virus (EBV) associated lymphomas with poor outcomes. Here, we determined the virus type and analyzed the EBV latent membrane protein-1 (LMP1) gene sequence in NK/TL from French patients. Six clones of viral LMP1 were sequenced by Sanger technology in blood from 13 patients before treatment with an L-asparaginase based regimen and, for 8 of them, throughout the treatment. Blood LMP1 sequences from 21 patients without any known malignancy were tested as controls. EBV Type A was identified for 11/13 patients and for all controls. Before treatment, a clonal LMP1 gene containing a 30 bp deletion (del30) was found in 46.1% of NK/TL and only in 4.8% of controls. Treatment was less effective in these patients who died more rapidly than the others. Patients with a deleted strain evolving toward a wild-type strain during treatment reached complete remission. The LMP1 gene was sequenced by highly sensitive next-generation sequencing technology in five NK/TL nasopharyngeal biopsies, two of them originating from the previous patients. Del30 was present in 100% of the biopsies; two viruses at least coexisted in three biopsies. These results suggest that del30 may be associated with poor prognosis NK/TL and that strain evolution could be used as a potential marker to monitor treatment.

Metagenomic analysis of DNA viruses from posttransplant lymphoproliferative disorders

“…Specific polymorphisms in two viral gene promoters Cp and Qp were found in nasopharyngeal carcinoma . A clonal LMP1 gene containing a 30 bp deletion (del30) was found in 46.1% of NK/T cell lymphomas and only in 4.8% of the controls, with much worse patient survival in those with this deletion . However, as shown in endemic Burkitt lymphoma, within a geographic region, different EBV genetic variations can coexist, such that specific gene variation associations with presentation or prognosis have been difficult.…”

EBV Genome Mutations and Malignant Proliferations

“…Given that del30 strains have been currently detected in normal carriers [89] or in various EBV-associated diseases [90], and, because of a low prevalence of del30 strains in samples from Africa, North America, and Europe [8,91], it is generally admitted that LMP1 del30 may represent a geographic polymorphism rather than a diseaseassociated polymorphism [92]. In a study, we carried out in France in patients with NK/T lymphoma, we found a del30 EBV in 4/4 biopsies studied and in 46.1% of total blood samples analyzed, while in a control population, the deletion was present in 4.8% of cases [93]. Other deletions were also described, such as the rare C terminal 69 bp deletion reported to weakly activate the AP1 transcription factor [94], or the 15 bp deletion (aa 275-279) frequently encountered in Western Europe [93].…”

MicroRNA-150 enhances radiosensitivity by inhibiting the AKT pathway in NK/T cell lymphoma

“…EBV plays an important role in the lymphomagenesis of NKTL [ 27 ]. Latent membrane protein 1 (LMP1) is a major oncoprotein that is encoded by one of the EBV genes [ 28 ]. This protein contributes to the activation of the AKT pathway in EBV-infected lymphomas, which, in turn, affects cell survival, apoptosis, proliferation, and genomic instability via its downstream target proteins to cause cancer [ 29 ].…”