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Page 326 Jiang et al. J Transl Genet Genom 2021;5:323-40 https://dx.doi.org/10.20517/jtgg.2021.21

results from a phase I clinical trial demonstrated that tazemetostat had a favorable safety profile and anti-
[38]
tumor activity in refractory NHL and advanced solid tumors, including epithelioid sarcoma . Analogously,
EZH2 inhibitors might be worth exploring in NKTCL treatment.

DDX3X
DDX3X belongs to the RNA helicase family, and its gene mutation is involved in the formation of a variety
[42]
of human tumors [39-41] . According to Jiang et al. , DDX3X is the most common somatic mutation gene
(20%, 21/105) in NKTCL. Notably, tumors with DDX3X mutation show activation and upregulation of NF-
κB and mitogen-activated protein kinase (MAPK) pathways, which also reflects that DDX3X mutation has
biological significance in NKTCL pathogenic process. However, the actual significance in clinical treatment
of NKTCL still needs more studies and trials to confirm.

Other TSGs and Somatic mutations
The tumor suppressor gene TP53 is considered to be dysfunctional due to somatic mutations [41,43] . Genes
normally suppressed by TP53 are upregulated in tumor tissues, which may lead to the progression of
NKTCL . FOXO3 is lowly expressed in NKTCL and induces apoptosis and cell cycle arrest of NK cell
[29]
[23]
lines, which is recognized to be of great significance in the pathogenesis of NKTCL . Hexokinase domain
component 1 has been proven to be transcriptionally upregulated in the NKTCL cell line. It not only
promotes the proliferation of tumor cells but also inhibits EBV replication and P-glycoprotein expression
through promoting the overproduction of ROS and DNA damage . Besides, survivin is overexpressed in
[44]
NKTCL. In vitro, terameprocol, a survivin inhibitor, can significantly inhibit the growth of NKTCL cell
[29]
lines .
The alterations of these genes further enrich the molecular network of NKTCL pathogenesis and provide
potent targets for anti-tumor therapy. The relevant content is summarized in Table 1. Whether they could
be used as valuable clinical factors for diagnosis and treatment needs to be verified in larger-scale
experiments.

Oncogenic signaling pathways
JAK/STAT signaling pathway
Targeted capture sequencing observed somatic alteration of the JAK/STAT pathway in 78% (85/109) of
NKTCL samples. STAT3 and TP53 genes (21%, 23/109) were mutated most frequently, followed by JAK3,
JAK1, and suppressor of cytokine signaling 1 mutations. Furthermore, STAT3 activation resulting from
mutations or abnormal phosphorylation may drive the high expression of programmed death ligand-1 (PD-
L1), which may have an influence on immune escape of NKTCL . In another study, STAT3 is the most
[45]
common mutant gene of NKTCL (9/34, 26.5%), and all mutations are located in the SRC homology 2
[46]
domain that seems to be an underlying effective target region . Apart from mutations, abnormal
expression of phosphorylated STAT3 (pSTAT3) at Tyr705 is also recognized as aberrant activation
[13]
signature . Dysregulated JAK2 mediates the constitutive phosphorylation of STAT3 (Tyr705) facilitating
the growth of NKTCL MEC04 cells and Ser727 phosphorylation of activated MAP-Kinase/Erk pathway,
[47]
both of which have similar oncogenic significance . In addition, receptor-type tyrosine-protein
phosphatase κ (PTPRK) binding to pSTAT3 led to the dephosphorylation of pSTAT3, and some NKTCL
patients suffer from function deficiency of PTPRK according to the previous formulation . The above
[48]
suggests that STAT3 is activated through different mechanisms in NKTCL.

STAT3 obtained phosphorylated activation following JAK3 constitutive phosphorylation on tyrosine
[49]
Tyr980 . Whole-exome sequencing detected JAK3 mutations (A572V and A573V) that exceptionally