extranodal nasal NK/T cell lymphoma

Summary

extranodal nasal NK/T cell lymphoma (MONDO:0019472) is a cancer with 3 cohort genes (3 GWAS associations across 2 studies) and 43 clinical trials. Molecularly, ALK R214H confers sensitivity to Crizotinib in Nasal Type Extranodal NK/T-cell Lymphoma (CIViC Level C). Top therapeutic interventions include pegaspargase, etoposide, and tislelizumab.

At a glance

• Classification: Cancer
• Prevalence: 1-9 / 100 000 (France) [Orphanet-validated]
• Cohort genes: 3
• GWAS associations: 3
• Clinical trials: 43
• Precision-medicine evidence (CIViC): 1 subtype–drug association

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	2.25	France	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	extranodal nasal NK/T cell lymphoma
Mondo ID	MONDO:0019472
Orphanet	86879
DOID	DOID:0080797
ICD-10-CM	C86.0
ICD-11	684005900
NCIT	C4684
UMLS	C0392788
MedGen	140278
GARD	0007041
MedDRA	10065855
Is cancer (heuristic)	yes

Also known as: angiocentric T-cell lymphoma · Extranodal NK/T lymphoma-nasal · Extranodal NK/T-cell lymphoma, nasal type · lethal midline granuloma · nasal T/natural killer-cell lymphoma · nasal type Extranodal NK/T-cell lymphoma · NK/T-cell lymphoma · NKTCL · reticulosis, malignant

Data availability: 3 GWAS associations (2 studies) · 10 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › hematopoietic and lymphoid system neoplasm › hematopoietic and lymphoid cell neoplasm › lymphoid neoplasm › lymphoma › extranodal nasal NK/T cell lymphoma

Related subtypes (26): prostate lymphoma, nasal cavity lymphoma, bladder lymphoma, tracheal lymphoma, retroperitoneal lymphoma, ureteral lymphoma, ovarian lymphoma, B-cell lymphoma, unclassifiable, with features intermediate between diffuse large b-cell lymphoma and classical Hodgkin lymphoma, pediatric lymphoma, adult lymphoma, breast lymphoma, heart lymphoma, chest wall lymphoma, lung lymphoma, mediastinal malignant lymphoma, eye lymphoma, B-cell neoplasm, gastrointestinal lymphoma, Hodgkins lymphoma, peripheral T-cell lymphoma, not otherwise specified, composite lymphoma, AIDS-related primary central nervous system lymphoma, primary organ-specific lymphoma, non-Hodgkin lymphoma, methotrexate-associated lymphoproliferative disorders, progressive transformation of germinal centers

Genetics & variants

GWAS landscape

3 GWAS associations across 2 studies. Top hits map to 2 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs9271588	9e-26	HLA-DRB1 - HLA-DQA1	C	1.53
rs9277378	4e-19	HLA-DPB1	A	1.84
rs13015714	3e-16	IL18R1	G	1.39

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST009759	Lin GW	2019	700	7,752	Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations.
GCST010657	Li Z	2016	189	0	Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	1
Tier 4: intronic/intergenic	2

MAF distribution

Bucket	Variants
common (>=0.05)	3
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
regulatory_region_variant	1
intron_variant	1
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs9271588	6	32623176	T>C	0.4	regulatory_region_variant	HLA-DRB1 - HLA-DQA1	9e-26	Tier 3: regulatory
rs9277378	6	33082502	A>C,G,T	0.29	intron_variant	HLA-DPB1	4e-19	Tier 4: intronic/intergenic
rs13015714	2	102355405	G>A,T	0.42	intergenic_variant	IL18R1	3e-16	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 16 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 1

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
HLA-DRB1	HLA-DRB1	GWAS, Orphanet

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HLA-DPB1	Orphanet:133	Chronic beryllium disease
HLA-DPB1	Orphanet:900	Granulomatosis with polyangiitis
HLA-DRB1	Orphanet:2073	Narcolepsy type 1
HLA-DRB1	Orphanet:220393	Diffuse cutaneous systemic sclerosis
HLA-DRB1	Orphanet:220402	Limited cutaneous systemic sclerosis
HLA-DRB1	Orphanet:220407	Limited systemic sclerosis
HLA-DRB1	Orphanet:3437	Vogt-Koyanagi-Harada disease
HLA-DRB1	Orphanet:397	Giant cell arteritis
HLA-DRB1	Orphanet:477738	Pediatric multiple sclerosis
HLA-DRB1	Orphanet:536	Systemic lupus erythematosus
HLA-DRB1	Orphanet:545	Follicular lymphoma
HLA-DRB1	Orphanet:703	Bullous pemphigoid
HLA-DRB1	Orphanet:747	Autoimmune pulmonary alveolar proteinosis
HLA-DRB1	Orphanet:797	Sarcoidosis
HLA-DRB1	Orphanet:83465	Narcolepsy type 2
HLA-DRB1	Orphanet:85414	Systemic-onset juvenile idiopathic arthritis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HLA-DPB1	HGNC:4940	ENSG00000223865	P04440	HLA class II histocompatibility antigen, DP beta 1 chain	gwas
HLA-DRB1	HGNC:4948	ENSG00000196126	P01911	HLA class II histocompatibility antigen, DRB1 beta chain	gwas
IL18RAP	HGNC:5989	ENSG00000115607	O95256	Interleukin-18 receptor accessory protein	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HLA-DPB1	HLA class II histocompatibility antigen, DP beta 1 chain	Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells.
HLA-DRB1	HLA class II histocompatibility antigen, DRB1 beta chain	A beta chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule.
IL18RAP	Interleukin-18 receptor accessory protein	Within the IL18 receptor complex, does not mediate IL18-binding, but involved in IL18-dependent signal transduction, leading to NF-kappa-B and JNK activation.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	3	29.2×	4e-05

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HLA-DPB1	Antibody/Immunoglobulin	yes		MHC_II_b_N, Ig/MHC_CS, Ig_C1-set
HLA-DRB1	Antibody/Immunoglobulin	yes		MHC_II_b_N, Ig/MHC_CS, Ig_C1-set
IL18RAP	Antibody/Immunoglobulin	yes		TIR_dom, Ig_sub, Ig-like_dom

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	3
vermiform appendix	2
lymph node	1
right lung	1
blood	1
bone marrow	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HLA-DPB1	135	ubiquitous	marker	granulocyte, lymph node, vermiform appendix
HLA-DRB1	131	tissue_specific	marker	vermiform appendix, granulocyte, right lung
IL18RAP	172	broad	marker	granulocyte, blood, bone marrow

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HLA-DRB1	3,448
IL18RAP	1,682
HLA-DPB1	160

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HLA-DRB1	P01911	108
HLA-DPB1	P04440	10
IL18RAP	O95256	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Translocation of ZAP-70 to Immunological synapse	2	423.0×	3e-05	HLA-DPB1, HLA-DRB1
Phosphorylation of CD3 and TCR zeta chains	2	362.5×	3e-05	HLA-DPB1, HLA-DRB1
Co-inhibition by PD-1	2	346.1×	3e-05	HLA-DPB1, HLA-DRB1
Generation of second messenger molecules	2	230.7×	5e-05	HLA-DPB1, HLA-DRB1
Downstream TCR signaling	2	85.5×	2e-04	HLA-DPB1, HLA-DRB1
Interferon gamma signaling	2	83.7×	2e-04	HLA-DPB1, HLA-DRB1
MHC class II antigen presentation	2	59.5×	4e-04	HLA-DPB1, HLA-DRB1
Interleukin-18 signaling	1	475.8×	0.002	IL18RAP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
peptide antigen assembly with MHC class II protein complex	2	702.2×	1e-04	HLA-DPB1, HLA-DRB1
antigen processing and presentation of exogenous peptide antigen via MHC class II	2	362.4×	1e-04	HLA-DPB1, HLA-DRB1
positive regulation of immune response	2	321.0×	1e-04	HLA-DPB1, HLA-DRB1
positive regulation of T cell activation	2	295.6×	1e-04	HLA-DPB1, HLA-DRB1
T cell receptor signaling pathway	2	101.2×	0.001	HLA-DPB1, HLA-DRB1
regulation of interleukin-4 production	1	5617.3×	0.001	HLA-DRB1
antigen processing and presentation of endogenous peptide antigen via MHC class II	1	2808.7×	0.002	HLA-DRB1
regulation of interleukin-10 production	1	2808.7×	0.002	HLA-DRB1
adaptive immune response	2	56.2×	0.002	HLA-DPB1, IL18RAP
myeloid dendritic cell antigen processing and presentation	1	1872.4×	0.002	HLA-DRB1
regulation of T-helper cell differentiation	1	1404.3×	0.002	HLA-DRB1
positive regulation of CD4-positive, alpha-beta T cell activation	1	1404.3×	0.002	HLA-DRB1
positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation	1	1123.5×	0.003	HLA-DRB1
interleukin-18-mediated signaling pathway	1	936.2×	0.003	IL18RAP
positive regulation of T cell mediated immune response to tumor cell	1	802.5×	0.003	HLA-DRB1
immune response	2	31.4×	0.003	HLA-DRB1, IL18RAP
T-helper 1 type immune response	1	624.1×	0.003	HLA-DRB1
positive regulation of memory T cell differentiation	1	624.1×	0.003	HLA-DRB1
positive regulation of monocyte differentiation	1	510.7×	0.004	HLA-DRB1
detection of bacterium	1	468.1×	0.004	HLA-DRB1
neutrophil activation	1	330.4×	0.006	IL18RAP
inflammatory response to antigenic stimulus	1	312.1×	0.006	HLA-DRB1
protein tetramerization	1	208.1×	0.008	HLA-DRB1
negative regulation of inflammatory response to antigenic stimulus	1	200.6×	0.008	HLA-DRB1
positive regulation of natural killer cell mediated cytotoxicity	1	187.2×	0.008	IL18RAP
positive regulation of T cell mediated cytotoxicity	1	170.2×	0.009	HLA-DRB1
macrophage differentiation	1	156.0×	0.009	HLA-DRB1
negative regulation of type II interferon production	1	127.7×	0.011	HLA-DRB1
positive regulation of insulin secretion involved in cellular response to glucose stimulus	1	124.8×	0.011	HLA-DRB1
negative regulation of T cell proliferation	1	110.1×	0.012	HLA-DRB1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HLA-DPB1	0	0
HLA-DRB1	0	0
IL18RAP	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
HLA-DRB1	17	Binding:17

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Drug repurposing candidates

0 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	HLA-DPB1, HLA-DRB1, IL18RAP
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
HLA-DPB1	0	—
HLA-DRB1	17	—
IL18RAP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 43.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	19
PHASE1/PHASE2	9
Not specified	7
PHASE1	3
PHASE4	2
EARLY_PHASE1	2
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04038411	PHASE4	UNKNOWN	PD-1 Antibody, Chidamide, Lenalidomide and Etoposide for Relapsed or Refractory NK/T Cell Lymphoma
NCT04490590	PHASE4	UNKNOWN	A Clinical Trial of Chidamide Combined With Etoposide in Relapsed or Refractory NK/T-cell Lymphoma
NCT02631239	PHASE3	UNKNOWN	MESA Versus ESA in the Treatment of Early Stage NK/T-cell Lymphoma
NCT04414163	PHASE2	ACTIVE_NOT_RECRUITING	A Study of IMC-001 in Subjects With Relapsed or Refractory Extranodal NK/T Cell Lymphoma, Nasal Type
NCT05475925	PHASE1/PHASE2	RECRUITING	A Study of DR-01 in Subjects With Large Granular Lymphocytic Leukemia or Cytotoxic Lymphomas
NCT05627856	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study of GNC-038 Injection in Patients With Relapsed or Refractory NK/ T-cell Lymphoma, AITL, and Other NHL
NCT05833893	PHASE2	RECRUITING	Clinical Study of XPO1 Inhibitor Selinexor Combined With COPL in Newly Diagnosed Advanced NK/T-cell Lymphoma
NCT06559553	PHASE1/PHASE2	RECRUITING	Selinexor+Pegaspargase+Dexamethasonein Ⅰ/Ⅱ NKTCL
NCT07000617	PHASE2	RECRUITING	A Phase II Study of Dexamethasone, Azacitidine, Pegaspargase and Tislelizumab Plus Radiotherapy for Patients With Stage I/II Extranodal NK/T-cell Lymphoma
NCT07502768	PHASE1/PHASE2	NOT_YET_RECRUITING	Tislelizumab Plus Zeprumetostat for Relapsed or Refractory NK/T-Cell Lymphoma
NCT07574528	PHASE2	NOT_YET_RECRUITING	A Phase II Study of Sintilimab, Pegaspargase and Selinexor Followed by Radiotherapy in Newly Diagnosed Stage I/II Extranodal NK/T-Cell Lymphoma
NCT07615283	PHASE1/PHASE2	NOT_YET_RECRUITING	Adebrelimab Combined With SHR2554 in Relapsed/Refractory PTCL and NK/T-Cell Lymphoma
NCT01667289	PHASE2	TERMINATED	Radiotherapy Alone Versus Concurrent Chemoradiation in Low Risk NK/T-cell Lymphoma
NCT01667302	PHASE2	UNKNOWN	Radiotherapy Followed by Adjuvant Chemotherapy in NK/T-cell Lymphoma
NCT01921790	PHASE2	UNKNOWN	Avastin+ GemAOD As First-Line Treatment in NK/T Cell Lymphoma
NCT01991158	PHASE2	UNKNOWN	GAD-M Regimen As First-Line Treatment in Untreated Extranodal NK/T Cell Lymphoma
NCT02742727	PHASE1/PHASE2	UNKNOWN	CAR-pNK Cell Immunotherapy in CD7 Positive Leukemia and Lymphoma
NCT02825147	PHASE2	COMPLETED	Pegaspargase and Methotrexate Based Regimens for Newly Diagnosed Extranodal NK/T Cell Lymphoma
NCT03012620	PHASE2	COMPLETED	Secured Access to Pembrolizumab for Patients With Selected Rare Cancer Types
NCT03075553	PHASE2	TERMINATED	Nivolumab in Treating Patients With Relapsed or Refractory Peripheral T-cell Lymphoma
NCT03363555	PHASE2	UNKNOWN	SHR-1210 in Patients With Relapsed or Refractory Extranodal NK/T Cell Lymphoma
NCT03493451	PHASE2	COMPLETED	Study of BGB-A317 in Participants With Relapsed or Refractory Mature T- and NK-cell Neoplasms
NCT03701022	PHASE2	UNKNOWN	PD1 Combined With Apatinib in Patients With Relapsed or Refractory NK/T Cell Lymphoma
NCT04096690	PHASE2	UNKNOWN	Anti-PD-1 Antibody Combined With Pegaspargase in the Treatment of Advanced Stage NK/T-cell Lymphoma
NCT04338282	PHASE2	UNKNOWN	Maintenance Therapy With Anti-PD-1 Antibody for Patients With NK/T-cell Lymphoma
NCT04405375	PHASE2	UNKNOWN	GPED Regimen for Relapsed/Refractory or Advanced ENKTCL
NCT04425070	PHASE1/PHASE2	TERMINATED	A Study of Evaluating the Safety and Efficacy of ATG-010 Combined With Chemotherapy Sequential With ATG-010 Monotherapy Maintenance in Peripheral T- and NK/T-cell Lymphoma
NCT04509466	PHASE1/PHASE2	TERMINATED	Clinical Study of Liposomal Mitoxantrone Hydrochloride Injection Combined With Pegaspargase in the Treatment of NKTCL
NCT04602065	PHASE1/PHASE2	TERMINATED	Evaluation of Safety and Efficacy of IBI318 Monotherapy for Relapsed/Refractory Extranodal NK/T Cell Lymphoma (Nasal Type) Trial
NCT04676789	PHASE2	UNKNOWN	Anti-PD-1 Antibody and Pegaspargase Combined With Radiotherapy in Early-Stage ENKTL
NCT04899414	PHASE2	UNKNOWN	Dexamethasone, Azacytidine,Pegaspargase and Tislelizumab for NK/T Cell Lymphoma
NCT04004637	PHASE1	UNKNOWN	CD7 CAR-T Cells for Patients With R/R CD7+ NK/T Cell Lymphoma,T-lymphoblastic Lymphoma and Acute Lymphocytic Leukemia
NCT04008394	PHASE1	UNKNOWN	Anti-CD30 CAR-T Therapy in Patients With Refractory/Relapsed Lymphocyte Malignancies
NCT04230330	PHASE1	WITHDRAWN	Nivolumab in Combination With GDP/ L-asparaginase in NK/ T-cell Lymphoma
NCT07162012	EARLY_PHASE1	RECRUITING	Safety and Efficacy of Anti-EBV Autologous TCR-T Cell Injection in Relapsed/Refractory EBV-Positive Lymphoma
NCT05208853	EARLY_PHASE1	UNKNOWN	An Exploratory Clinical Study Evaluating the Safety and Efficacy of Anti CD30 CAR T Cells in Patients With CD30+ Relapsed/Refractory Lymphoma
NCT01787409	Not specified	ACTIVE_NOT_RECRUITING	Cholecalciferol in Improving Survival in Patients With Newly Diagnosed Cancer With Vitamin D Insufficiency
NCT05662540	Not specified	RECRUITING	PET/MR in the Staging and Efficacy Evaluation of Newly Diagnosed NK/T-cell Lymphoma
NCT05978141	Not specified	RECRUITING	A Registry for People With T-cell Lymphoma
NCT06362148	Not specified	ACTIVE_NOT_RECRUITING	Circulating Tumor DNA in Peripheral T-cell Lymphomas

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PEGASPARGASE	4	9
ETOPOSIDE	4	5
TISLELIZUMAB	4	2
TORIPALIMAB	4	1
CAMRELIZUMAB	3	1
TUCIDINOSTAT	3	1
DANBURSTOTUG	2	1
DIBOTATUG	2	1
ZEPRUMETOSTAT	2	1
CHEMBL4087968	0	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 1 predictive associations from 1 curated evidence items.

Molecular subtype	Therapy	Effect	Level	CIViC
ALK R214H	Crizotinib	Sensitivity/Response	CIViC C	EID4827