Background
Epstein-Barr virus (EBV) is a member of gamma herpes virus family and persistently infects B lymphocytes in more than 90 % population of adults [
1]. EBV is related to the tumorigenesis of various malignancies, which include some epithelial cell malignancies, such as nasopharyngeal carcinoma (NPC) and EBV-associated gastric carcinoma (EBVaGC), and a variety of lymphocytic cell malignancies, including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and post-transplant and AIDS associated lymphoproliferative disorders [
2,
3].
Although being a B-lymphotropic virus, EBV can also infect NK/T cells [
4] and is highly associated with natural killer (NK)/T cell lymphoma [
5]. NK/T cell lymphoma derives from natural killer (NK) cells or activated γδ or αβ cytotoxic T cells (CTLs) and expresses granzyme B, TIA-1 and perforin [
6]. Unlike B-cell lymphomas, EBV-associated NK/T cell lymphoma seems to be site-restricted. EBV is found in nearly 100 % nasal NK/T cell lymphoma but rarely in primary cutaneous NK/T cell lymphoma [
6].
Despite the ubiquity of the EBV infection, the frequencies of EBV-associated malignancies differ in different geographic regions, which may suggest that particularly tumorigenic EBV strains might exist. Studies have been carried out to determine variations in EBV genome and explore their relationship with NPC, EBVaGC or other EBV-associated disorders. Just like other EBV-associated malignancies, the frequency of NK/T lymphoma varies in different geographic regions [
7]. But only a few studies have investigated EBV gene variations in NK/T cell lymphoma.
BamHI-A rightward open reading frame 1 (BARF1) and BamHI-H rightward open reading frame 1 (BHRF1) are two EBV early genes critical to replication of the virus, encoding proteins homologous to important human proteins c-fms and Bcl-2 respectively. Recently, the role of BARF1 and BHRF1 in the development of EBV associated tumors has drawn great interest. Both transcripts of them were detected in NK/T cell lymphoma [
8,
9].
BARF1 gene is a multifunctional gene. It could induce malignant transformation in rodent fibroblasts [
10] and enhance the tumorigenicity of EBV-negative Louckes and Akata cells [
11,
12]. The first 54 amino acids at the N-terminus may be responsible for the malignant transformation of BARF1 [
10]. In addition, this region could also upregulate the cellular anti-apoptotic protein Bcl-2. The secreted hexameric BARF1-encoded protein has immune modulation properties. It is a homologue of c-fms, the human colony stimulating factor 1 (hCSF-1) receptor and has the ability to bind CSF-1 [
13] therefore inhibiting interferon-alpha secretion from mononuclear cells. The immune modulation ability of BARF1 allowing EBV-infected tumor cells to escape elimination of host. Despite its immune-modulating properties, BARF1 protein may trigger an immune response as a target for antibody-dependent cytotoxicity [
14]. Several HLA-A*0201-restricted cytotoxic T lymphocyte (CTL) epitopes of BARF1 have been identified [
15].
Though it was widely believed that BARF1 expressed frequently in latently infected carcinomas and rarely in lymphomas [
16,
17], some studies detected the expression of BARF1 in latently infected B cells [
18] and B lymphoma in Malawi [
19]. Zhang et al. [
8] detected BARF1 expression in nasal NK/T lymphoma and postulated that BARF1 expression might be associated with the pathogenesis in NK/T cell lymphoproliferative disorders [
8].
BHRF1 is structurally and functionally homologous to the pro-survival protein Bcl-2. It could protect T and B lymphocytes from apoptosis induced by growth factor withdrawal, chemotherapeutic drug or granzyme B [
20‐
22]. BHRF1 protein shares 38 % primary sequence homology with human Bcl-2 and has three conserved Bcl-2 homology (BH) domains, BH1–BH3 [
23]. Helices α2-α5 of BHRF1 protein form a hydrophobic surface groove which can bind BH3 domains of pro-apoptotic Bcl-2 family members such as Bim to block their pro-apoptotic ability [
21,
24]. Though not expressed consistently in all EBV-associated tumors, BHRF1 transcripts can be detected in EBV-associated carcinomas [
25], B cell lymphoma, T cell lymphoma [
17], as well as in NK/T cell lymphoma [
9]. Recent study linked BHRF1 to the transformation of B lymphocytes and lymphomagenesis [
26].
In our previous study, the sequences of BARF1 and BHRF1 genes in Northern Chinese nasopharyngeal carcinoma (NPC), EBV-associated gastric carcinoma (EBVaGC) and throat washings (TWs) from healthy donors were analyzed [
27,
28]. Sequences of these two genes were highly conserved. V29A strains, a BARF1 mutant subtype, showed higher prevalence in NPC, which may suggest the association between this variation and NPC [
28]. As to BHRF1, there were no significantly different variations among different samples [
27].
In order to clarify the sequence variation patterns of BARF1 and BHRF1 in NK/T cell lymphoma and explore whether the polymorphisms of the two early genes were associated with oncogenesis of NK/T cell lymphoma, we analyzed their sequences and compared the results with the data from our previous study and other studies involved different populations and regions.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
LLS and BL designed the study. LLS collected the samples. KC, SL and ZZ performed the tests and analyzed the data. LLS drafted the manuscript. XMX and BL revised the manuscript. All authors read and approved the final manuscript.