Table 3.

Main mechanisms associated with ENKTCL pathogenesis.

Pathogenic mechanism	Details
Chromosomal aberrations	Gains at chromosomes 1p, 6p, 11p, 12q, 17q, 20q, and Xp Losses at chromosomes 6q, 11q, 13q, and 17p Del(6q-) are associated with losses of tumor suppressor genes FOXO3, HACE1, PRDM1, ATG5, and AIM1 Del(17p-) is associated with loss of the tumor suppressor gene TP53
EBV-mediated oncogenesis	Viral oncoproteins LMP-1 and EBNAs Intragenic EBV deletions More pathogenic EBV strains—prevalent in Latin America and Asia Activation of proliferative signaling pathways: JAK/STAT, AKT, MAPK, and NF-κB; apoptosis inhibition and immune modulation via PD-1/PD-L1 axis
Deregulated molecular signaling pathways and mutational landscape	Pro-proliferative effect and cell-cycle regulation: JAK/STAT, NF-κB, C-MYC, RUNX3, NOTCH1, and Aurora kinase pathways Apoptosis inhibition: surviving overexpression, deregulation of TP53 pathway, and reprogramming of cellular metabolism and autophagy Immune evasion: PD-1/PD-L1 axis Dysregulation of DNA repair: ATM/ATR axis Pro-angiogenic activity: VEGFA, VEGFR2, HGF, and MET Epigenetic dysregulation: BCOR, MLL2, ASXL3, ARID1A, and EP300 Mutational landscape: STAT3, JAK3, STAT5B, SOCS1, and PTPRK (JAK/STAT pathway ~40%) MAP3K5, BRAF, and EPH1A (RAS/MAPK pathway ~15%) ECSIT, IKBkB, and BIRC2 (NF-κB pathway ~15%) DDX3X (RNA helicases, ~40%–50%), TP53 (~10%) BCOR, EP300, TET2, and ARID1A (epigenetic machinery, ~5%–10%)

ENKTCL, extranodal NK-/T-cell lymphoma; EBV, Epstein–Barr virus.