Advances in multiple omics of natural-killer/T cell lymphoma

Abstract

Natural-killer/T cell lymphoma (NKTCL) represents the most common subtype of extranodal lymphoma with aggressive clinical behavior. Prevalent in Asians and South Americans, the pathogenesis of NKTCL remains to be fully elucidated. Using system biology techniques including genomics, transcriptomics, epigenomics, and metabolomics, novel biomarkers and therapeutic targets have been revealed in NKTCL. Whole-exome sequencing studies identify recurrent somatic gene mutations, involving RNA helicases, tumor suppressors, JAK-STAT pathway molecules, and epigenetic modifiers. Another genome-wide association study reports that single nucleotide polymorphisms mapping to the class II MHC region on chromosome 6 contribute to lymphomagenesis. Alterations of oncogenic signaling pathways janus kinase-signal transducer and activator of transcription (JAK-STAT), nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), WNT, and NOTCH, as well as epigenetic dysregulation of microRNA and long non-coding RNAs, are also frequently observed in NKTCL. As for metabolomic profiling, abnormal amino acids metabolism plays an important role on disease progression of NKTCL. Of note, through targeting multiple omics aberrations, clinical outcome of NKTCL patients has been significantly improved by asparaginase-based regimens, immune checkpoints inhibitors, and histone deacetylation inhibitors. Future investigations will be emphasized on molecular classification of NKTCL using integrated analysis of system biology, so as to optimize targeted therapeutic strategies of NKTCL in the era of precision medicine.

Genomic and Transcriptomic Characterization of Natural Killer T Cell Lymphoma

“…To examine the genome diversity of EBV, complete genomes of 126 EBV strains derived from populations of different regions (Asia, n = 42; Africa, n = 35; Europe, n = 18; North America, n = 9; Oceania, n = 21; and unclassified, n = 1) and disease types (NPC, n = 27; BL, n = 19; GC, n = 16; HL, n = 8; infectious mononucleosis, IM, n = 6; posttransplant lymphoproliferative disorders, PTLD, n = 19; spontaneous lymphoid cell lines, sLCL, n = 30; and unclassified, n = 1) were collected (Table S3). Phylogenetic analysis (Figure 3A) and comparison of EBV sequence coverage/ SNVs (Peng et al, 2019) (Figure S4B) revealed similarity (higher sequence coverage/less SNVs) between EBV sequences in NKTCL and those of Asia or NPC, providing genetic evidence for geographic prevalence of NKTCL in Asian populations and common involvement of nasal/paranasal area (Xiong and Zhao, 2018). SNVs of EBV genome were also strongly associated with disease pathogenesis (Peng et al, 2019;Xu et al, 2019).…”

Plasma circulating tumor DNA assessment reveals KMT2D as a potential poor prognostic factor in extranodal NK/T-cell lymphoma

“…In the present study, to decrease the bias caused by clonal hematopoiesis associated mutations, the age range of the included patients was narrow, matched ctDNA-PBMC sample was applied, and a sequencing panel was conducted according to a previous gene-expression profiling study on ENKTL. Zhao et al confirmed that the most frequently mutated genes in NKTCL were the RNA helicase gene DDX3X , tumor suppressors ( TP53 and MGA ), JAK-STAT pathway molecules ( STAT3 and STAT5b ) and epigenetic modifiers ( MLL2, ARID1A, EP300 and ASXL3 ) [ 36 , 37 ]. In addition to these recurrent mutations, JAK3, KMT2D, EZH2, NOTCH1 and TET2 were also identified by different groups [ 38 – 41 ].…”

EBV and the Pathogenesis of NK/T Cell Lymphoma

“…This has led to a better understanding of the molecular pathogenesis of this entity, the discovery of new targeted therapies, and more recently, to the proposal of a classification according to the molecular changes associated with clinical prognosis. In Table 3 , the main genetic features reported in ENKTCL so far are summarized [ 81 , 124 , 125 ].…”