Cholesteatoma of middle ear

Summary

Cholesteatoma of middle ear (MONDO:0006533) is a disease with 2 cohort genes and 2 clinical trials.

At a glance

• Cohort genes: 2
• ClinVar variants: 8
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cholesteatoma of middle ear
Mondo ID	MONDO:0006533
EFO	EFO:1000678
MeSH	D018424
DOID	DOID:10964
ICD-10-CM	H71
ICD-11	2134365487
NCIT	C3654
SNOMED CT	194339007
UMLS	C0155490
MedGen	57836
Anatomy (UBERON)	UBERON:0001756
Is cancer (heuristic)	no

Also known as: cholesteatoma (disease) of middle ear · cholesteatoma of middle ear · cholesteatoma of middle ear and mastoid · cholesteatoma of the middle ear · Epidermosis of ear · Epidermosis of middle ear · middle ear cholesteatoma · middle ear cholesteatoma (disease) · unspecified cholesteatoma (morphologic abnormality)

Data availability: 8 ClinVar variants.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › auditory system disorder › middle ear disorder › cholesteatoma of middle ear

Related subtypes (5): necrosis of ear ossicle, tympanic membrane disorder, eustachian tube disorder, otitis media, neoplasm of middle ear

Subtypes (1): cholesteatoma of attic

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

8 retrieved; paginated sample, class counts are floors:

5 other, 2 conflicting classifications of pathogenicity; other, 1 uncertain significance; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
1039617	NM_017617.5(NOTCH1):c.433G>A (p.Ala145Thr)	NOTCH1	Conflicting classifications of pathogenicity; other	criteria provided, conflicting classifications
637001	NM_017617.5(NOTCH1):c.1220C>T (p.Pro407Leu)	NOTCH1	Conflicting classifications of pathogenicity; other	criteria provided, conflicting classifications
12577	NM_002467.6(MYC):c.220C>G (p.Pro74Ala)	MYC	other	criteria provided, single submitter
2413166	NM_002467.6(MYC):c.223C>A (p.Pro75Thr)	MYC	other	criteria provided, single submitter
2413167	NM_017617.5(NOTCH1):c.2969+1G>T	NOTCH1	other	criteria provided, single submitter
2413168	NM_017617.5(NOTCH1):c.3304G>T (p.Glu1102Ter)	NOTCH1	other	criteria provided, single submitter
2413169	NM_017617.5(NOTCH1):c.1412T>C (p.Ile471Thr)	NOTCH1	other	criteria provided, single submitter
850097	NM_017617.5(NOTCH1):c.4513T>C (p.Cys1505Arg)	NOTCH1	Uncertain significance; other	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYC	Orphanet:480541	High grade B-cell lymphoma with MYC and/ or BCL2 and/or BCL6 rearrangement
MYC	Orphanet:543	Burkitt lymphoma
MYC	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia
NOTCH1	Orphanet:402075	Familial bicuspid aortic valve
NOTCH1	Orphanet:974	Adams-Oliver syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MYC	HGNC:7553	ENSG00000136997	P01106	Myc proto-oncogene protein	clinvar
NOTCH1	HGNC:7881	ENSG00000148400	P46531	Neurogenic locus notch homolog protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYC	Myc proto-oncogene protein	Transcription factor that binds DNA in a non-specific manner, yet also specifically recognizes the core sequence 5’-CAC[GA]TG-3'.
NOTCH1	Neurogenic locus notch homolog protein 1	Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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
Scaffold/PPI	1	8.6×	0.225
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYC	Transcription factor	no		Tscrpt_reg_Myc, Myc-LZ, bHLH_dom
NOTCH1	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left uterine tube	1
upper leg skin	1
vena cava	1
colonic epithelium	1
ventricular zone	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYC	256	ubiquitous	marker	upper leg skin, vena cava, left uterine tube
NOTCH1	272	ubiquitous	marker	ventricular zone, colonic epithelium, visceral pleura

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYC	20,608
NOTCH1	7,411

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOTCH1	P46531	29
MYC	P01106	25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 81. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of NFE2L2 gene expression	2	1427.5×	3e-05	MYC, NOTCH1
NOTCH1 Intracellular Domain Regulates Transcription	2	237.9×	5e-04	MYC, NOTCH1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	2	196.9×	5e-04	MYC, NOTCH1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	2	196.9×	5e-04	MYC, NOTCH1
Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling	1	1142.0×	0.010	NOTCH1
Defective LFNG causes SCDO3	1	1142.0×	0.010	NOTCH1
TFAP2 (AP-2) family regulates transcription of cell cycle factors	1	1142.0×	0.010	MYC
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	951.7×	0.011	NOTCH1
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	815.7×	0.011	NOTCH1
Binding of TCF/LEF:CTNNB1 to target gene promoters	1	571.0×	0.013	MYC
RUNX3 regulates WNT signaling	1	571.0×	0.013	MYC
Regulation of CDH1 mRNA translation by microRNAs	1	519.1×	0.013	MYC
NFE2L2 regulating tumorigenic genes	1	475.8×	0.013	NOTCH1
RUNX3 regulates NOTCH signaling	1	407.9×	0.013	NOTCH1
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	380.7×	0.013	NOTCH1
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	356.9×	0.013	NOTCH1
Repression of WNT target genes	1	356.9×	0.013	MYC
Pre-NOTCH Processing in Golgi	1	317.2×	0.013	NOTCH1
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1	317.2×	0.013	MYC
MECP2 regulates neuronal receptors and channels	1	300.5×	0.013	NOTCH1
Signaling by ALK	1	285.5×	0.013	MYC
NOTCH4 Intracellular Domain Regulates Transcription	1	285.5×	0.013	NOTCH1
Transcription of E2F targets under negative control by DREAM complex	1	271.9×	0.013	MYC
G0 and Early G1	1	219.6×	0.013	MYC
NOTCH3 Intracellular Domain Regulates Transcription	1	219.6×	0.013	NOTCH1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	203.9×	0.013	MYC
Signaling by NOTCH1 in Cancer	1	203.9×	0.013	MYC
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	203.9×	0.013	MYC
Notch-HLH transcription pathway	1	203.9×	0.013	NOTCH1
Formation of paraxial mesoderm	1	203.9×	0.013	NOTCH1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
skeletal muscle cell differentiation	2	343.9×	0.002	MYC, NOTCH1
positive regulation of epithelial cell proliferation	2	244.2×	0.002	MYC, NOTCH1
coronary sinus valve morphogenesis	1	8426.0×	0.002	NOTCH1
Notch signaling pathway involved in regulation of secondary heart field cardioblast proliferation	1	8426.0×	0.002	NOTCH1
foregut morphogenesis	1	8426.0×	0.002	NOTCH1
regulation of epithelial cell proliferation involved in prostate gland development	1	8426.0×	0.002	NOTCH1
venous endothelial cell differentiation	1	8426.0×	0.002	NOTCH1
positive regulation of metanephric cap mesenchymal cell proliferation	1	8426.0×	0.002	MYC
positive regulation of acinar cell proliferation	1	8426.0×	0.002	MYC
acinar cell proliferation	1	8426.0×	0.002	MYC
endocardium morphogenesis	1	4213.0×	0.002	NOTCH1
coronary vein morphogenesis	1	4213.0×	0.002	NOTCH1
cardiac right atrium morphogenesis	1	4213.0×	0.002	NOTCH1
growth involved in heart morphogenesis	1	4213.0×	0.002	NOTCH1
obsolete negative regulation of cell proliferation involved in heart valve morphogenesis	1	4213.0×	0.002	NOTCH1
cell differentiation in spinal cord	1	4213.0×	0.002	NOTCH1
positive regulation of aorta morphogenesis	1	4213.0×	0.002	NOTCH1
NK T cell proliferation	1	2808.7×	0.002	MYC
mitral valve formation	1	2808.7×	0.002	NOTCH1
cardiac chamber formation	1	2808.7×	0.002	NOTCH1
auditory receptor cell fate commitment	1	2808.7×	0.002	NOTCH1
protein-DNA complex disassembly	1	2808.7×	0.002	MYC
retinal cone cell differentiation	1	2808.7×	0.002	NOTCH1
secretory columnal luminar epithelial cell differentiation involved in prostate glandular acinus development	1	2808.7×	0.002	NOTCH1
cardiac vascular smooth muscle cell development	1	2808.7×	0.002	NOTCH1
vasculogenesis involved in coronary vascular morphogenesis	1	2808.7×	0.002	NOTCH1
regulation of cell adhesion involved in heart morphogenesis	1	2808.7×	0.002	NOTCH1
distal tubule development	1	2808.7×	0.002	NOTCH1
chemical synaptic transmission, postsynaptic	1	2808.7×	0.002	NOTCH1
apoptotic process involved in embryonic digit morphogenesis	1	2808.7×	0.002	NOTCH1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MYC	3	3
NOTCH1	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
RESVERATROL	3	MYC
EZOBRESIB	2	MYC
AVASIMIBE	2	MYC
VAREGACESTAT	2	NOTCH1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MYC	202	Binding:202
NOTCH1	23	Binding:19, ADMET:4

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MYC	202

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

4 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
RESVERATROL	3	MYC
EZOBRESIB	2	MYC
AVASIMIBE	2	MYC
VAREGACESTAT	2	NOTCH1

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	2	MYC, NOTCH1
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: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04489550	Not specified	COMPLETED	How Long Must the MRI Follow-up Last to Safely Identify Middle Ear Residual Cholesteatoma
NCT04672187	Not specified	COMPLETED	Associations of Pre- and Intraoperative Endoscopic Findings of Middle Ear Status in Cholesteatoma