Nut midline carcinoma

Summary

Nut midline carcinoma (MONDO:0005563) is a cancer with 1 cohort gene (1 CIViC-evidence somatic driver; 1 ClinVar predisposition record) and 13 clinical trials. Molecularly, NUTM1 Fusion confers sensitivity to Molibresib in NUT Midline Carcinoma (CIViC Level B); 4 further subtype–drug associations are mapped below. Top therapeutic interventions include cisplatin, etoposide phosphate, and birabresib.

At a glance

• Classification: Cancer
• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 9
• Clinical trials: 13
• Precision-medicine evidence (CIViC): 5 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		310	Worldwide	Validated
Point prevalence	<1 / 1 000 000	0.0002	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0002664	Neoplasm	Very frequent (80-99%)
HP:0001909	Leukemia	Frequent (30-79%)
HP:0002860	Squamous cell carcinoma	Frequent (30-79%)
HP:0003006	Neuroblastoma	Frequent (30-79%)
HP:0012182	Oropharyngeal squamous cell carcinoma	Frequent (30-79%)
HP:0012254	Ewing sarcoma	Frequent (30-79%)
HP:0045026	Abnormality of the mediastinum	Frequent (30-79%)
HP:0100757	Pancreatoblastoma	Frequent (30-79%)
HP:0012142	Pancreatic squamous cell carcinoma	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	nut midline carcinoma
Mondo ID	MONDO:0005563
EFO	EFO:0005783
Orphanet	443167
DOID	DOID:0060463
NCIT	C45716
UMLS	C1707291
MedGen	312999
GARD	0021852
Is cancer (heuristic)	yes

Also known as: carcinoma with t(15;19)(q13;p13.1) translocation · Midline carcinoma of children and Young adults with NUT rearrangement · NMC · nuclear protein in testis midline carcinoma · NUT carcinoma · NUT Midline carcinoma · NUT midline carcinoma of the head and neck

Data availability: 1 ClinVar variant · 16 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › cancer › carcinoma › undifferentiated carcinoma › nut midline carcinoma

Related subtypes (13): endometrial undifferentiated carcinoma, salivary gland large cell carcinoma, sinonasal undifferentiated carcinoma, thymic undifferentiated carcinoma, thyroid gland undifferentiated (anaplastic) carcinoma, undifferentiated gallbladder carcinoma, undifferentiated ovarian carcinoma, undifferentiated pancreatic carcinoma, undifferentiated carcinoma of the corpus uteri, undifferentiated carcinoma of esophagus, undifferentiated carcinoma of stomach, undifferentiated carcinoma of liver and intrahepatic biliary tract, undifferentiated carcinoma of nasopharynx

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
3238622	NM_023034.2(NSD3):c.3237C>G (p.Asn1079Lys)	NSD3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
NSD3	LoF	LUSC

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NSD3	HGNC:12767	ENSG00000147548	Q9BZ95	Histone-lysine N-methyltransferase NSD3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NSD3	Histone-lysine N-methyltransferase NSD3	Histone methyltransferase.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NSD3	Transcription factor	no	2.1.1.356	PWWP_dom, SET_dom, Znf_PHD

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic epithelium	1
ganglionic eminence	1
pylorus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NSD3	272	ubiquitous	marker	pylorus, colonic epithelium, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NSD3	2,035

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NSD3	Q9BZ95	25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
PKMTs methylate histone lysines	1	160.8×	0.006	NSD3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
methylation	1	170.2×	0.018	NSD3
regulation of DNA-templated transcription	1	31.6×	0.036	NSD3
positive regulation of DNA-templated transcription	1	27.9×	0.036	NSD3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
NSD3	VENETOCLAX

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NSD3	5	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VENETOCLAX	4	NSD3
SURAMIN	3	NSD3
SINEFUNGIN	2	NSD3
MOLIBRESIB	2	NSD3
PF-03882845	1	NSD3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NSD3	155	Binding:153, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NSD3	2.1.1.356, 2.1.1.370, 2.1.1.371, 2.1.1.372	[histone H3]-lysine27 N-trimethyltransferase, [histone H3]-lysine4 N-dimethyltransferase, [histone H3]-lysine27 N-dimethyltransferase, [histone H4]-lysine20 N-trimethyltransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
NSD3	155

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

4 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.

Compound	Max phase	Cohort target (bioactivity)
VENETOCLAX	4	NSD3
SURAMIN	3	NSD3
SINEFUNGIN	2	NSD3
PF-03882845	1	NSD3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NSD3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 13.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	6
Not specified	4
PHASE1/PHASE2	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05019716	PHASE1/PHASE2	RECRUITING	Testing the Safety and Efficacy of the Addition of a New Anti-cancer Drug, ZEN003694, to Chemotherapy Treatment (Cisplatin and Etoposide or Carboplatin and Paclitaxel) for Adult and Pediatric Patients (12-17 Years) With NUT Carcinoma
NCT07050186	PHASE2	RECRUITING	Cemiplimab for the Treatment of Incurable Metastatic or Unresectable NUT Carcinoma
NCT04116359	PHASE1/PHASE2	WITHDRAWN	Testing of the Addition of a New Anti-cancer Drug, Molibresib, to Chemotherapy Treatment (Etoposide and Cisplatin) for Patients With NUT Carcinoma
NCT05372640	PHASE1	RECRUITING	Testing the Safety and Efficacy of the Combination of Two Anti-cancer Drugs, ZEN003694 and Abemaciclib, for Adult and Pediatric Patients (12-17 Years) With Metastatic or Unresectable NUT Carcinoma, Breast Cancer and Other Solid Tumors
NCT05488548	PHASE1	RECRUITING	Dual BET and CBP/p300 Inhibitor in Patients With Targeted Advanced Solid Tumors and Hematological Malignancies
NCT02259114	PHASE1	COMPLETED	A Dose-Finding Study of Birabresib (MK-8628), a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in Adults With Selected Advanced Solid Tumors (MK-8628-003)
NCT02307240	PHASE1	COMPLETED	Open Label, Multi-center Study to Assess the Safety, Tolerability and Pharmacokinetics of CUDC-907 in Subjects With Advanced/Relapsed Solid Tumors
NCT02516553	PHASE1	COMPLETED	BI 894999 First in Human Dose Finding Study in Advanced Malignancies
NCT02698176	PHASE1	TERMINATED	A Dose Exploration Study With Birabresib (MK-8628) in Participants With Selected Advanced Solid Tumors (MK-8628-006)
NCT05265429	Not specified	RECRUITING	Biology of Young Lung Cancer Study: The YOUNG LUNG Study
NCT05812027	Not specified	ACTIVE_NOT_RECRUITING	A Screening Study to Collect Samples for TAA, HLA & HLA Loss of Heterozygosity in Patients With Metastatic Solid Tumors
NCT07072143	Not specified	RECRUITING	An International Study on Pediatric Patients With Rare Tumors.
NCT07459127	Not specified	ACTIVE_NOT_RECRUITING	Multicenter Retrospective Cohort of Pulmonary NUT Carcinoma

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CISPLATIN	4	2
ETOPOSIDE PHOSPHATE	4	1
BIRABRESIB	2	2
MOLIBRESIB	2	2
ZEN-3694	2	2
FIMEPINOSTAT	2	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 5 predictive associations from 5 curated evidence items; also 5 diagnostic.

Molecular subtype	Therapy	Effect	Level	CIViC
NUTM1 Fusion	Molibresib	Sensitivity/Response	CIViC B	EID12055
BRD4::NUTM1 Fusion	Vorinostat	Sensitivity/Response	CIViC C	EID12100
BRD4::NUTM1 Fusion	Birabresib	Sensitivity/Response	CIViC C	EID7018
BRD4::NUTM1 Fusion	Panobinostat	Sensitivity/Response	CIViC D	EID12099
BRD4::NUTM1 Fusion	JQ1	Sensitivity/Response	CIViC D	EID1781