Table 3.

Main genetic alterations in ENKTCL.

Genetic Alteration				Reference
Chromosomal abnormalities	Losses of 6q21–6q25 (40–50%)	POPDC3, PREP, PRDM1, ATG5, AIM1 and HACE1		[126,127]
	Other chromosomal alterations	Losses in 5p13, 11q22-q23,11q24-25, 12q3, 13q14, 14q21, 15q24, 17p13, 17p4 and 19q13 Gains in 1q21-q44, 2q13-14, 2q31-q32, 2q5, 3q26, 6p25-p11, 7q34, 7q35-q36, 8q24, 10q3, 13q14, 13q4 and 20q11.		[129,130,134]
Recurrent mutations	JAK-STAT signaling pathway	STAT3, STAT5b, JAK3,		[21,135,136]
	RNA helicase family	DDX3X		[22]
	Tumor suppressors	TP53, MGA		[22,23,50]
	RAS-MAPK signaling pathway	NOTCH3, EPHA1, PTPRQ, PTPRK, GNAQ		[81,137]
	Apoptosis	FAS		[138,139]
	Epigenetic modifiers	ARID1A, ASXL1, BCOR, KMT2D, MLL2, EP300		[23,124,125]
Epigenetic alterations	Hyper methylation	Cell cycle regulators: CDKN2A, CDKN2B, CDKN1A Tumor suppressors: BCL2L11 (BIM), DAPK1, PTPN6 (SHP1), TET2, SOCS6, and ASNS.		[140] [141]
	Histone modifications	EZH2: histone methyltransferase, aberrant overexpressed in ENKTCL, leading to activation of NF-kB signaling pathway.		[142,143,144]
	mi-RNAs	Downregulated	miR-26a, miR-26b, miR-28-5, miR-101 and miR-363. De-regulated miR-146a: leading to inhibition of TRAF6, downregulating NF-kB signaling.	[144,145]
		Upregulated	miR-155 and miR21	[137,146]
Gene Overexpression	Survivin:	Induced by LMP1, EBV latent viral proteins		[147]
	MYC:	Upregulation possibly through LMP1 latent viral protein.		[81,148,149]
	PD-L1:	Overexpression of the cell death ligand favoring immune evasion		[150,151,152]
	RUNX3:	Mediated by MYC, resulting in decreased apoptosis and increase cell proliferation		[148]
	AURKA:	Increased cell proliferation		[153]
	PDGFRA:	Overexpression of PDGFRα but absence of genomic alteration		[154]
Other	CD38	Transmembrane protein associated with poor outcome		[155]