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Page 324 Jiang et al. J Transl Genet Genom 2021;5:323-40 https://dx.doi.org/10.20517/jtgg.2021.21

Keywords: Extranodal natural killer/T cell lymphoma, Epstein-Barr virus, genomics, genetics, therapeutic targets

INTRODUCTION
Extranodal natural killer/T cell lymphoma (NKTCL) commonly involves the upper aerodigestive tract such
[1,2]
as the nasal cavity and is prevalent in Asia, Mexico, and Latin America while rare in the United States and
Europe . NKTCL was previously called “lethal midline granuloma”, of which the pathological features are
[2,3]
pleomorphic and atypical cells ranging from medium to large, obvious necrosis, irregular nucleus and
cytoplasmic changes, and showing an angiocentric/angiodestructive growth pattern with infiltration of
immune inflammatory cells [1,4-7] . Neoplasm cells are positive for CD56, CD2, and CD3ε with the expression
of cytotoxic molecules, such as TIA1 and Granzyme B. Epstein-Barr virus (EBV) DNA and non-coding
EBV-encoded RNAs could be detected in tumor tissues [8-10] , which leads to the correlation of EBV infection
and the pathogenesis of NKTCL. In addition, NKTCL tumor cells express P-glycoprotein, which is related
to multidrug resistance, resulting in poor response to anthracyclines . Concurrent L-asparaginase-
[11]
containing regimens with or without radiotherapy are the current standard treatment. The International T-
cell Project’s report showed great improvement in the survival of NKTCL patients over the past decade .
[12]
The five-year overall survival rates for stage I, stage II, and stage III-IV are 55%, 42%, and 24%,
respectively . However, the treatment for advanced-stage, relapsed, or refractory patients is still
[12]
challenging . Therefore, there is an urgent need for more effective treatments to improve the survival of
[12]
NKTCL patients.

Identifying the unique gene expression profile, dysregulated molecules, and signaling pathways of NKTCL
provided a new perception for understanding pathogenic mechanisms and potential therapeutic targets [13,14] .
Genome-wide association study revealed susceptible genes significantly associated with the higher risk of
NKTCL [15,16] . EBV genome and transcriptomics analysis showed that EBV infection might contribute to the
pathogenesis of NKTCL by affecting the host cell genome . Exploring the genomics and genetic variations
[17]
in the tumorigenesis and development of NKTCL from the molecular aspects has vital biological
[18]
significance for the future clinical diagnosis, treatment, and prognosis of NKTCL. Xiong et al. integrated
the cell origin, EBV expression pattern, clinical significance and characteristics of alterations in the human
genome of NKTCL samples, and divided NKTCL into three molecular subtypes: TSIM subtype [based on
variants in the Janus kinase/signal transduction and activator of transcription (JAK/STAT) pathway and
TP53], MB subtype (based on MGA mutation and 1p22.1/BRDT loss of heterozygosity), and HEA subtype
(based on HDAC9, EP300, and ARID1A mutation) . Disease stratification bridges the pathogenesis of
[18]
NKTCL with clinical intervention from pathogenesis theory into clinical practice.

THE ALTERATION OF HUMAN GENETICS AND POTENTIAL TREATMENTS
The network of NKTCL pathogenesis has not been totally revealed. However, changes in a variety of genes
and signaling pathways have been reported. We try to excavate underlying signatures from reported genetic
variations and search the genetic hallmarks increasing the risk of NKTCL, which furnish guidance for
mechanism-based anti-tumor therapy.

Tumor suppressor genes and Somatic mutations
Dysfunction of tumor suppressor genes occupies a significant position in the development of hematological
malignancies, which has been discussed in leukemia and myeloma [19,20] . Many major candidate genes, such
as PRDM1, TP53, HACE1, FOXO3, and ATG5, are located in the deletion region of chromosome 6q21,
which is the most frequently discussed in NKTCL [13,14,21] . There are recurrent somatic mutations in NKTCL
as well.