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Page 334 Jiang et al. J Transl Genet Genom 2021;5:323-40 https://dx.doi.org/10.20517/jtgg.2021.21

All the above research provides new insights for the tumorigenesis and development of NKTCL and reveals
the significance of inflammation and immune regulation through the IL18/IL-18RAP axis and antigen
presentation involving HLA-DRB1. The relevant content is summarized in Table 5. The above implicated
guiding significance for the risk stratification of NKTCL patients and clinical intervention. It could be
combined with other genetic risk factors or prognostic models to help identify high-risk populations for
targeted prevention.

THE VARIATIONS OF EBV GENOME
Epstein-Barr virus (EBV) is a widespread human herpes virus that has infected more than 90% of
population in a lifetime . EBV infection is believed to be associated with various human cancers such as
[92]
nasopharyngeal carcinoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, gastric cancer, DLBCL, NKTCL,
etc. . The virus expresses six Epstein-Barr nuclear antigens (EBNAs 1, 2, 3A, 3B, and 3C and EBNA leader
[92]
protein), latent membrane proteins (LMP1 and LMP2), non-coding EBV-encoded RNAs (EBER1 and
EBER2), and viral microRNA . The virus presents a type II latent pattern with the episomal form
[93]
(EBNA1+/LMP-1+ and EBNA-2) in the host body [94,95] . LMP1 is one of the main oncogenes encoded by EBV
that is of significance for EBV-mediated B-cell immortalization . EBNA1 makes a difference in virus
[96]
replication and the maintenance of episomal form in the latent state and promotes the malignant
transformation of B cells .
[97]

Structural variation of EBV genome
There are common intragenic EBV deletions (73-49,847 bp) detected in NKTCL (10/23), EBV-positive
DLBCL (10/14), and other malignancies (2/7) . Sanger sequencing revealed that LMP1 gene contained a 30
[98]
[99]
bp deletion, which may be related to the poor prognosis of NKTCL patients . Analyzing the EBV genome
and transcriptome derived from NKTCL, in addition to the 30 bp deletion in LMP1, small deletions in
BARTs, EBNA2, EBNA3s, BLLF1/2, and other regions were also detected, which disclosed the heterogeneity
in EBV cloning in NKTCL patients . Interestingly, this study also clarified an insertion of EBV fragments
[17]
into the human nonhomologous end-joining 1 (NHEJ1) gene region, which may lead to changes in the
expression and function of NHEJ1. The NHEJ1 gene is vital in repairing DNA damage and maintaining
genome stability . Thus, integration of the EBV genome and human genome might have crucial impact
[100]
on the pathogenesis and development of NKTCL. The molecular mechanism of this integration affecting
NKTCL tumorigenesis and whether the integration indeed contributes to clinical treatment of NKTCL need
to be explored in further research.

Lytic genes
There are two infection routes of EBV-infected cells: latent infection and lytic infection . Similar to latent
[101]
genes, lytic genes also play a crucial role in the promotion of EBV infection and tumorigenesis of NKTCL.
Previous studies demonstrated that the lytic genes BNLF2a and BNLF2b were highly expressed in NKTCL
[17]
tissues , and the expressions of BARF1, BHRF1, and BZLF1 were detected in the NKTCL cell line .
[102]
Besides, the single-nucleotide variations of lytic gene BALF3 frequently were detected, and overexpression
of BALF3 might drive DNA damage and bring about genomic instability in NKTCL. Intragenic EBV
deletions often affect BamHI A rightward transcript (BART) microRNA clusters, core genes necessary for
lytic DNA replication (BMRF1, BSLF1, BALF2, BALF5, BBLF2/BBLF3, and BBLF4) and some genes related
to the lytic cycle and latent infection . High-throughput sequence identified that EBV noncoding BART
[98]
lncRNAs RPMS1 and A73 were strongly expressed in NKTCL and delivered regulatory signals to host cells
without triggering specific immunity, which is helpful to retain the latent state of EBV in the host .
[103]
However, deletions located on (BART) microRNA clusters often have an unfavorable effect on EBV-miR-
BART6-5p, EBV-miR-BART6-3p, EBV-miR-BART18-5p, and EBV-miR-BART20-5p, which negatively
regulated early genes BZLF1 and BRLF1 that are thought to upregulate the lysis cycle and promote