Keratoacanthoma

Summary

Keratoacanthoma (MONDO:0002527) is a disease with 3 cohort genes and 2 clinical trials.

At a glance

• Cohort genes: 3
• ClinVar variants: 5
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	keratoacanthoma
Mondo ID	MONDO:0002527
MeSH	D007636
DOID	DOID:3149
ICD-11	516478127
NCIT	C3146
SNOMED CT	254662007
UMLS	C0022572
MedGen	5954
Is cancer (heuristic)	no

Data availability: 5 ClinVar variants.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › skin neoplasm › epithelial skin neoplasm › keratoacanthoma

Related subtypes (4): sebaceous adenoma, skin carcinoma, sweat gland adenoma, benign epithelial skin neoplasm

Subtypes (2): generalized eruptive keratoacanthoma, familial keratoacanthoma

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

5 retrieved; paginated sample, class counts are floors:

4 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1344732	NM_017617.5(NOTCH1):c.2272G>T (p.Glu758Ter)	NOTCH1	Pathogenic	no assertion criteria provided
1344783	NM_017617.5(NOTCH1):c.3463C>T (p.Gln1155Ter)	NOTCH1	Pathogenic	no assertion criteria provided
1344880	NM_024408.4(NOTCH2):c.1211C>T (p.Pro404Leu)	NOTCH2	Pathogenic	no assertion criteria provided
156446	NM_006218.4(PIK3CA):c.353G>A (p.Gly118Asp)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts
1344877	NM_024408.4(NOTCH2):c.1243G>A (p.Asp415Asn)	NOTCH2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 19 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NOTCH1	Orphanet:402075	Familial bicuspid aortic valve
NOTCH1	Orphanet:974	Adams-Oliver syndrome
NOTCH2	Orphanet:261629	Alagille syndrome due to a NOTCH2 point mutation
NOTCH2	Orphanet:955	Hajdu-Cheney syndrome
PIK3CA	Orphanet:140944	CLOVES syndrome
PIK3CA	Orphanet:144	Lynch syndrome
PIK3CA	Orphanet:168984	CLAPO syndrome
PIK3CA	Orphanet:201	Cowden syndrome
PIK3CA	Orphanet:210159	Adult hepatocellular carcinoma
PIK3CA	Orphanet:221061	Familial cerebral cavernous malformation
PIK3CA	Orphanet:2495	Meningioma
PIK3CA	Orphanet:276280	Hemihyperplasia-multiple lipomatosis syndrome
PIK3CA	Orphanet:295239	Macrodactyly of fingers, unilateral
PIK3CA	Orphanet:295243	Macrodactyly of toes, unilateral
PIK3CA	Orphanet:314662	Segmental progressive overgrowth syndrome with fibroadipose hyperplasia
PIK3CA	Orphanet:60040	Megalencephaly-capillary malformation-polymicrogyria syndrome
PIK3CA	Orphanet:714737	Diffuse capillary malformation with overgrowth
PIK3CA	Orphanet:90308	Capillary-lymphatic-venous malformation with segmental distribution
PIK3CA	Orphanet:99802	Hemimegalencephaly

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NOTCH1	HGNC:7881	ENSG00000148400	P46531	Neurogenic locus notch homolog protein 1	clinvar
NOTCH2	HGNC:7882	ENSG00000134250	Q04721	Neurogenic locus notch homolog protein 2	clinvar
PIK3CA	HGNC:8975	ENSG00000121879	P42336	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
NOTCH2	Neurogenic locus notch homolog protein 2	Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination.
PIK3CA	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.33

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	2	11.5×	0.019
Kinase	1	9.2×	0.104

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NOTCH1	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom
NOTCH2	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom
PIK3CA	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_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
colonic epithelium	1
ventricular zone	1
visceral pleura	1
pigmented layer of retina	1
retina	1
skin of hip	1
adrenal tissue	1
calcaneal tendon	1
tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NOTCH1	272	ubiquitous	marker	ventricular zone, colonic epithelium, visceral pleura
NOTCH2	294	ubiquitous	marker	pigmented layer of retina, retina, skin of hip
PIK3CA	284	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH1	7,411
NOTCH2	5,266
PIK3CA	5,157

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIK3CA	P42336	135
NOTCH1	P46531	29
NOTCH2	Q04721	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 85. 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
Defective LFNG causes SCDO3	2	1522.7×	3e-05	NOTCH1, NOTCH2
Pre-NOTCH Processing in the Endoplasmic Reticulum	2	1268.9×	3e-05	NOTCH1, NOTCH2
Pre-NOTCH Processing in Golgi	2	423.0×	2e-04	NOTCH1, NOTCH2
NOTCH4 Intracellular Domain Regulates Transcription	2	380.7×	2e-04	NOTCH1, NOTCH2
Notch-HLH transcription pathway	2	271.9×	3e-04	NOTCH1, NOTCH2
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	2	97.6×	0.002	NOTCH1, NOTCH2
Pre-NOTCH Transcription and Translation	2	81.9×	0.002	NOTCH1, NOTCH2
Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling	1	761.3×	0.011	NOTCH1
MET activates PI3K/AKT signaling	1	634.4×	0.011	PIK3CA
Activated NTRK3 signals through PI3K	1	634.4×	0.011	PIK3CA
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	543.8×	0.011	NOTCH1
Activated NTRK2 signals through PI3K	1	543.8×	0.011	PIK3CA
Signaling by LTK in cancer	1	543.8×	0.011	PIK3CA
Regulation of NFE2L2 gene expression	1	475.8×	0.011	NOTCH1
PI3K/AKT activation	1	423.0×	0.011	PIK3CA
IRS-mediated signalling	1	346.1×	0.011	PIK3CA
PI3K events in ERBB4 signaling	1	346.1×	0.011	PIK3CA
Co-stimulation by ICOS	1	346.1×	0.011	PIK3CA
NOTCH2 intracellular domain regulates transcription	1	317.2×	0.011	NOTCH2
Signaling by FGFR4 in disease	1	317.2×	0.011	PIK3CA
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	1	317.2×	0.011	PIK3CA
NFE2L2 regulating tumorigenic genes	1	317.2×	0.011	NOTCH1
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	292.8×	0.011	PIK3CA
Signaling by PDGFRA extracellular domain mutants	1	292.8×	0.011	PIK3CA
Signaling by LTK	1	292.8×	0.011	PIK3CA
RUNX3 regulates NOTCH signaling	1	271.9×	0.011	NOTCH1
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	253.8×	0.011	NOTCH1
Signaling by FLT3 ITD and TKD mutants	1	253.8×	0.011	PIK3CA
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	237.9×	0.011	NOTCH1
Constitutive Signaling by EGFRvIII	1	237.9×	0.011	PIK3CA

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
cellular response to tumor cell	2	2808.7×	3e-05	NOTCH1, NOTCH2
atrioventricular node development	2	1872.4×	4e-05	NOTCH1, NOTCH2
positive regulation of smooth muscle cell differentiation	2	1248.3×	6e-05	NOTCH1, NOTCH2
left/right axis specification	2	802.5×	1e-04	NOTCH1, NOTCH2
inflammatory response to antigenic stimulus	2	624.1×	1e-04	NOTCH1, NOTCH2
pulmonary valve morphogenesis	2	624.1×	1e-04	NOTCH1, NOTCH2
positive regulation of Ras protein signal transduction	2	591.3×	1e-04	NOTCH1, NOTCH2
negative regulation of anoikis	2	591.3×	1e-04	NOTCH1, PIK3CA
negative regulation of gene expression	3	69.1×	1e-04	NOTCH1, NOTCH2, PIK3CA
positive regulation of BMP signaling pathway	2	303.6×	3e-04	NOTCH1, NOTCH2
humoral immune response	2	187.2×	8e-04	NOTCH1, NOTCH2
heart looping	2	178.3×	8e-04	NOTCH1, NOTCH2
liver development	2	147.8×	0.001	NOTCH1, PIK3CA
coronary sinus valve morphogenesis	1	5617.3×	0.002	NOTCH1
Notch signaling pathway involved in regulation of secondary heart field cardioblast proliferation	1	5617.3×	0.002	NOTCH1
foregut morphogenesis	1	5617.3×	0.002	NOTCH1
response to muscle inactivity	1	5617.3×	0.002	PIK3CA
regulation of epithelial cell proliferation involved in prostate gland development	1	5617.3×	0.002	NOTCH1
venous endothelial cell differentiation	1	5617.3×	0.002	NOTCH1
response to butyrate	1	5617.3×	0.002	PIK3CA
Notch signaling pathway	2	94.4×	0.002	NOTCH1, NOTCH2
endocardium morphogenesis	1	2808.7×	0.003	NOTCH1
coronary vein morphogenesis	1	2808.7×	0.003	NOTCH1
cardiac right atrium morphogenesis	1	2808.7×	0.003	NOTCH1
growth involved in heart morphogenesis	1	2808.7×	0.003	NOTCH1
obsolete negative regulation of cell proliferation involved in heart valve morphogenesis	1	2808.7×	0.003	NOTCH1
cell differentiation in spinal cord	1	2808.7×	0.003	NOTCH1
positive regulation of aorta morphogenesis	1	2808.7×	0.003	NOTCH1
cholangiocyte proliferation	1	2808.7×	0.003	NOTCH2
regulation of osteoclast development	1	2808.7×	0.003	NOTCH2

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
PIK3CA	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3CA	67	4
NOTCH1	1	2
NOTCH2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDELALISIB	4	PIK3CA
ALPELISIB	4	PIK3CA
DUVELISIB	4	PIK3CA
COPANLISIB	4	PIK3CA
FEDRATINIB	4	PIK3CA
ROMIDEPSIN	4	PIK3CA
COPANLISIB HYDROCHLORIDE	4	PIK3CA
LENIOLISIB	4	PIK3CA
BELINOSTAT	4	PIK3CA
INAVOLISIB	4	PIK3CA
SUNITINIB	4	PIK3CA
DASATINIB	4	PIK3CA
CRIZOTINIB	4	PIK3CA
MIDOSTAURIN	4	PIK3CA
DACTOLISIB	3	PIK3CA
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	PIK3CA
TASELISIB	3	PIK3CA
EPIGALOCATECHIN GALLATE	3	PIK3CA
GEDATOLISIB	3	PIK3CA
LESTAURTINIB	3	PIK3CA
VAREGACESTAT	2	NOTCH1
OMIPALISIB	2	PIK3CA
VISTUSERTIB	2	PIK3CA
FIMEPINOSTAT	2	PIK3CA
EGANELISIB	2	PIK3CA
BERZOSERTIB	2	PIK3CA
BIMIRALISIB	2	PIK3CA
PICTILISIB	2	PIK3CA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PIK3CA	2,034	Binding:2009, ADMET:19, Toxicity:4, Functional:2
NOTCH1	23	Binding:19, ADMET:4
NOTCH2	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PIK3CA	2.7.1.137, 2.7.1.153, 2.7.11.1	phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PIK3CA	2,034

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).

Chemical tractability of cohort targets

30 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)
IDELALISIB	4	PIK3CA
ALPELISIB	4	PIK3CA
DUVELISIB	4	PIK3CA
COPANLISIB	4	PIK3CA
FEDRATINIB	4	PIK3CA
ROMIDEPSIN	4	PIK3CA
COPANLISIB HYDROCHLORIDE	4	PIK3CA
LENIOLISIB	4	PIK3CA
BELINOSTAT	4	PIK3CA
INAVOLISIB	4	PIK3CA
SUNITINIB	4	PIK3CA
DASATINIB	4	PIK3CA
CRIZOTINIB	4	PIK3CA
MIDOSTAURIN	4	PIK3CA
DACTOLISIB	3	PIK3CA
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	PIK3CA
TASELISIB	3	PIK3CA
EPIGALOCATECHIN GALLATE	3	PIK3CA
GEDATOLISIB	3	PIK3CA
LESTAURTINIB	3	PIK3CA
VAREGACESTAT	2	NOTCH1
OMIPALISIB	2	PIK3CA
VISTUSERTIB	2	PIK3CA
FIMEPINOSTAT	2	PIK3CA
EGANELISIB	2	PIK3CA
BERZOSERTIB	2	PIK3CA
BIMIRALISIB	2	PIK3CA
PICTILISIB	2	PIK3CA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PIK3CA
B	Phased (≥1) drug, not yet approved	1	NOTCH1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NOTCH2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NOTCH2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03630198	PHASE4	COMPLETED	Pain Outcomes Following Intralesional Corticosteroid Injections
NCT03714828	PHASE2	COMPLETED	Study of TVEC in Patients With Cutaneous Squamous Cell Cancer