Hepatoblastoma

Summary

Hepatoblastoma (MONDO:0018666) is a disease with 51 cohort genes and 56 clinical trials. The dominant Reactome pathway is Diseases of DNA repair (5 cohort genes). Top therapeutic interventions include irinotecan, larotrectinib, and cabozantinib.

At a glance

• Prevalence: <1 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 51
• ClinVar variants: 64
• Clinical trials: 56
• Precision-medicine evidence (CIViC): 2 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

23 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.02	Europe	Validated
Annual incidence	<1 / 1 000 000	0.009	Austria	Validated
Annual incidence	<1 / 1 000 000	0.019	Belgium	Validated
Annual incidence	<1 / 1 000 000	0.008	Bulgaria	Validated
Annual incidence	<1 / 1 000 000	0.042	Croatia	Validated
Annual incidence	<1 / 1 000 000	0.005	Czech Republic	Validated
Annual incidence	<1 / 1 000 000	0.046	Estonia	Validated
Annual incidence	<1 / 1 000 000	0.031	Finland	Validated
Annual incidence	<1 / 1 000 000	0.021	Germany	Validated
Annual incidence	<1 / 1 000 000	0.043	Ireland	Validated
Annual incidence	<1 / 1 000 000	0.017	Italy	Validated
Annual incidence	<1 / 1 000 000	0.022	Latvia	Validated
Annual incidence	<1 / 1 000 000	0.004	Lithuania	Validated
Annual incidence	<1 / 1 000 000	0.031	Malta	Validated
Annual incidence	<1 / 1 000 000	0.033	Norway	Validated
Annual incidence	<1 / 1 000 000	0.023	Poland	Validated
Annual incidence	<1 / 1 000 000	0.008	Portugal	Validated
Annual incidence	<1 / 1 000 000	0.032	Slovakia	Validated
Annual incidence	<1 / 1 000 000	0.025	Slovenia	Validated
Annual incidence	<1 / 1 000 000	0.009	Spain	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hepatoblastoma
Mondo ID	MONDO:0018666
EFO	EFO:1000292
MeSH	D018197
Orphanet	449
DOID	DOID:687
ICD-10-CM	C22.2
ICD-11	1241693063, 1556608523
NCIT	C3728
UMLS	C0206624
MedGen	61644
GARD	0002657
MedDRA	10062001
Is cancer (heuristic)	no

Also known as: HBL · hepatoblastoma · hepatoblastoma, malignant · paediatric embryonal hepatoma · paediatric hepatoblastoma · pediatric embryonal hepatoma · pediatric hepatoblastoma

Data availability: 64 ClinVar variants · 259 cell lines · 1 intOGen driver record.

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 › embryonal neoplasm › hepatoblastoma

Related subtypes (11): notochordal tumor, rhabdoid tumor, primitive neuroectodermal tumor, blastoma, Wilms tumor, testicular embryonal carcinoma, medulloblastoma, pineoblastoma, congenital mesoblastic nephroma, intraocular medulloepithelioma, Ewing sarcoma/peripheral primitive neuroectodermal tumor

Subtypes (2): mixed hepatoblastoma, macrotrabecular hepatoblastoma

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

64 retrieved; paginated sample, class counts are floors:

24 uncertain significance, 22 conflicting classifications of pathogenicity, 5 likely pathogenic, 3 likely benign, 3 pathogenic, 2 benign, 2 other, 1 pathogenic/likely pathogenic, 1 pathogenic; other, 1 benign; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
1343300	NM_000038.6(APC):c.3747C>A (p.Cys1249Ter)	APC	Pathogenic	criteria provided, multiple submitters, no conflicts
817	NM_000038.6(APC):c.4183A>T (p.Ser1395Cys)	APC	Pathogenic	no assertion criteria provided
4073702	NM_001382508.1(DROSHA):c.927dup (p.Glu310fs)	DROSHA	Pathogenic	criteria provided, single submitter
17581	NM_001904.4(CTNNB1):c.94G>T (p.Asp32Tyr)	LOC126806658	Pathogenic; other	no assertion criteria provided
12359	NM_000546.6(TP53):c.722C>T (p.Ser241Phe)	TP53	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343291	NM_000123.4(ERCC5):c.1081del (p.Leu361fs)	BIVM-ERCC5	Likely pathogenic	no assertion criteria provided
17580	NM_001904.4(CTNNB1):c.121A>G (p.Thr41Ala)	CTNNB1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
17582	NM_001904.4(CTNNB1):c.101G>T (p.Gly34Val)	CTNNB1	Likely pathogenic	criteria provided, single submitter
1343310	NM_207122.2(EXT2):c.1242C>T (p.Ile414=)	EXT2	Likely pathogenic	no assertion criteria provided
3068313	NM_000214.3(JAG1):c.3445_3448del (p.Ile1149fs)	JAG1	Likely pathogenic	criteria provided, single submitter
127434	NM_000051.4(ATM):c.6998C>A (p.Thr2333Lys)	ATM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
133603	NM_000051.4(ATM):c.1595G>A (p.Cys532Tyr)	ATM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
237815	NM_000465.4(BARD1):c.1247T>G (p.Leu416Arg)	BARD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
37861	NM_000059.4(BRCA2):c.3858_3860del (p.Lys1286del)	BRCA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
89040	NM_000059.4(BRCA2):c.1096T>G (p.Leu366Val)	BRCA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
345877	NM_000094.4(COL7A1):c.1370C>T (p.Pro457Leu)	COL7A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
420113	NM_001360.3(DHCR7):c.988G>A (p.Val330Met)	DHCR7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1343301	NM_001429.4(EP300):c.4235C>T (p.Ala1412Val)	EP300	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134114	NM_000400.4(ERCC2):c.545C>T (p.Ala182Val)	ERCC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134268	NM_000135.4(FANCA):c.3524C>T (p.Pro1175Leu)	FANCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
456351	NM_001018115.3(FANCD2):c.2273G>C (p.Cys758Ser)	FANCD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313209	NM_020937.4(FANCM):c.2859A>C (p.Lys953Asn)	FANCM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
570775	NM_000043.6(FAS):c.667A>C (p.Asn223His)	FAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
405459	NM_001110556.2(FLNA):c.1997C>T (p.Ala666Val)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1343294	NM_000168.6(GLI3):c.233C>T (p.Ser78Leu)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1343295	NM_000168.6(GLI3):c.245G>A (p.Arg82Lys)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
188358	NM_000245.4(MET):c.1715G>A (p.Ser572Asn)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
220150	NM_000179.3(MSH6):c.334A>G (p.Asn112Asp)	MSH6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242753	NM_001022.4(RPS19):c.164C>T (p.Thr55Met)	RPS19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30445	NM_005475.3(SH2B3):c.622G>C (p.Glu208Gln)	SH2B3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 180 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CTNNB1	Orphanet:1501	Adrenocortical carcinoma
CTNNB1	Orphanet:210159	Adult hepatocellular carcinoma
CTNNB1	Orphanet:2780	Osteopathia striata-cranial sclerosis syndrome
CTNNB1	Orphanet:33402	Pediatric hepatocellular carcinoma
CTNNB1	Orphanet:404473	Intellectual disability-eye abnormalities-microcephaly-peripheral spasticity syndrome
CTNNB1	Orphanet:54595	Craniopharyngioma
CTNNB1	Orphanet:569248	Microcystic stromal tumor
CTNNB1	Orphanet:689430	Adenoid ameloblastoma
CTNNB1	Orphanet:873	Desmoid tumor
CTNNB1	Orphanet:891	Familial exudative vitreoretinopathy
CTNNB1	Orphanet:91414	Pilomatrixoma
CTNNB1	Orphanet:952	Acrofacial dysostosis, Weyers type
RPS19	Orphanet:124	Diamond-Blackfan anemia
BRCA2	Orphanet:1331	Familial prostate cancer
BRCA2	Orphanet:1333	Familial pancreatic carcinoma
BRCA2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRCA2	Orphanet:178	Chordoma
BRCA2	Orphanet:227535	Hereditary breast cancer
BRCA2	Orphanet:319462	Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations
BRCA2	Orphanet:440437	Familial colorectal cancer Type X
BRCA2	Orphanet:654	Nephroblastoma
BRCA2	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
BRCA2	Orphanet:694963	Inflammatory breast cancer
BRCA2	Orphanet:70567	Cholangiocarcinoma
BRCA2	Orphanet:84	Fanconi anemia
ARID1A	Orphanet:1465	Coffin-Siris syndrome
STK11	Orphanet:2869	Peutz-Jeghers syndrome
TERT	Orphanet:146	Differentiated thyroid carcinoma
TERT	Orphanet:1501	Adrenocortical carcinoma
TERT	Orphanet:1775	Dyskeratosis congenita
TERT	Orphanet:2032	Idiopathic pulmonary fibrosis
TERT	Orphanet:2495	Meningioma
TERT	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
TERT	Orphanet:457246	Clear cell sarcoma of kidney
TERT	Orphanet:618	Familial melanoma
TERT	Orphanet:88	Idiopathic aplastic anemia
TGFBR2	Orphanet:144	Lynch syndrome
TGFBR2	Orphanet:284973	Marfan syndrome type 2
TGFBR2	Orphanet:60030	Loeys-Dietz syndrome
TGFBR2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
TGFBR2	Orphanet:99977	Squamous cell carcinoma of the esophagus
FAS	Orphanet:117	Behçet disease
FAS	Orphanet:3261	Autoimmune lymphoproliferative syndrome
FAS	Orphanet:3437	Vogt-Koyanagi-Harada disease
TP53	Orphanet:1333	Familial pancreatic carcinoma
TP53	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
TP53	Orphanet:1501	Adrenocortical carcinoma
TP53	Orphanet:210159	Adult hepatocellular carcinoma
TP53	Orphanet:251576	Gliosarcoma
TP53	Orphanet:251579	Giant cell glioblastoma

Cohort genes → proteins

51 cohort genes, 50 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	51

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CTNNB1	HGNC:2514	ENSG00000168036	P35222	Catenin beta-1	clinvar,civic_evidence
RPS19	HGNC:10402	ENSG00000105372	P39019	Small ribosomal subunit protein eS19	clinvar
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	clinvar
ARID1A	HGNC:11110	ENSG00000117713	O14497	AT-rich interactive domain-containing protein 1A	clinvar
STK11	HGNC:11389	ENSG00000118046	Q15831	Serine/threonine-protein kinase STK11	clinvar
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	clinvar
TGFBR2	HGNC:11773	ENSG00000163513	P37173	TGF-beta receptor type-2	clinvar
FAS	HGNC:11920	ENSG00000026103	P25445	Tumor necrosis factor receptor superfamily member 6	clinvar
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	clinvar
JMJD1C	HGNC:12313	ENSG00000171988	Q15652	Jumonji domain-containing protein 1C	clinvar
VHL	HGNC:12687	ENSG00000134086	P40337	von Hippel-Lindau disease tumor suppressor	clinvar
NDRG4	HGNC:14466	ENSG00000103034	Q9ULP0	Protein NDRG4	clinvar
DROSHA	HGNC:17904	ENSG00000113360	Q9NRR4	Ribonuclease 3	clinvar
DOCK8	HGNC:19191	ENSG00000107099	Q8NF50	Dedicator of cytokinesis protein 8	clinvar
NYNRIN	HGNC:20165	ENSG00000205978	Q9P2P1	Protein NYNRIN	clinvar
RHBDF2	HGNC:20788	ENSG00000129667	Q6PJF5	Inactive rhomboid protein 2	clinvar
KCTD11	HGNC:21302	ENSG00000213859	Q693B1	BTB/POZ domain-containing protein KCTD11	clinvar
COL7A1	HGNC:2214	ENSG00000114270	Q02388	Collagen alpha-1(VII) chain	clinvar
FANCM	HGNC:23168	ENSG00000187790	Q8IYD8	Fanconi anemia group M protein	clinvar
SLX4	HGNC:23845	ENSG00000188827	Q8IY92	Structure-specific endonuclease subunit SLX4	clinvar
FLCN	HGNC:27310	ENSG00000154803	Q8NFG4	Folliculin	clinvar
DHCR7	HGNC:2860	ENSG00000172893	Q9UBM7	7-dehydrocholesterol reductase	clinvar
DIS3L2	HGNC:28648	ENSG00000144535	Q8IYB7	DIS3-like exonuclease 2	clinvar
FRMPD1	HGNC:29159	ENSG00000070601	Q5SYB0	FERM and PDZ domain-containing protein 1	clinvar
SH2B3	HGNC:29605	ENSG00000111252	Q9UQQ2	SH2B adapter protein 3	clinvar
EP300	HGNC:3373	ENSG00000100393	Q09472	Histone acetyltransferase p300	clinvar
ERCC2	HGNC:3434	ENSG00000104884	P18074	General transcription and DNA repair factor IIH helicase subunit XPD	clinvar
EXT2	HGNC:3513	ENSG00000151348	Q93063	Exostosin-2	clinvar
FAH	HGNC:3579	ENSG00000103876	P16930	Fumarylacetoacetase	clinvar
FANCA	HGNC:3582	ENSG00000187741	O15360	Fanconi anemia group A protein	clinvar
FANCD2	HGNC:3585	ENSG00000144554	Q9BXW9	Fanconi anemia group D2 protein	clinvar
FASN	HGNC:3594	ENSG00000169710	P49327	Fatty acid synthase	clinvar
FGFR3	HGNC:3690	ENSG00000068078	P22607	Fibroblast growth factor receptor 3	clinvar
FH	HGNC:3700	ENSG00000091483	P07954	Fumarate hydratase, mitochondrial	clinvar
FLNA	HGNC:3754	ENSG00000196924	P21333	Filamin-A	clinvar
GBA1	HGNC:4177	ENSG00000177628	P04062	Lysosomal acid glucosylceramidase	clinvar
GLI3	HGNC:4319	ENSG00000106571	P10071	Transcriptional activator GLI3	clinvar
BIVM-ERCC5	HGNC:43690	ENSG00000270181		BIVM-ERCC5 readthrough	clinvar
APC	HGNC:583	ENSG00000134982	P25054	Adenomatous polyposis coli protein	clinvar
JAG1	HGNC:6188	ENSG00000101384	P78504	Protein jagged-1	clinvar
KDR	HGNC:6307	ENSG00000128052	P35968	Vascular endothelial growth factor receptor 2	clinvar
MET	HGNC:7029	ENSG00000105976	P08581	Hepatocyte growth factor receptor	clinvar
MN1	HGNC:7180	ENSG00000169184	Q10571	Transcriptional activator MN1	clinvar
MSH2	HGNC:7325	ENSG00000095002	P43246	DNA mismatch repair protein Msh2	clinvar
MSH6	HGNC:7329	ENSG00000116062	P52701	DNA mismatch repair protein Msh6	clinvar
MUTYH	HGNC:7527	ENSG00000132781	Q9UIF7	Adenine DNA glycosylase	clinvar
ATM	HGNC:795	ENSG00000149311	Q13315	Serine-protein kinase ATM	clinvar
BARD1	HGNC:952	ENSG00000138376	Q99728	BRCA1-associated RING domain protein 1	clinvar
RECQL	HGNC:9948	ENSG00000004700	P46063	ATP-dependent DNA helicase Q1	clinvar
RECQL4	HGNC:9949	ENSG00000160957	O94761	ATP-dependent DNA helicase Q4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CTNNB1	Catenin beta-1	Key downstream component of the canonical Wnt signaling pathway.
RPS19	Small ribosomal subunit protein eS19	Component of the small ribosomal subunit.
BRCA2	Breast cancer type 2 susceptibility protein	Involved in double-strand break repair and/or homologous recombination.
ARID1A	AT-rich interactive domain-containing protein 1A	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
STK11	Serine/threonine-protein kinase STK11	Tumor suppressor serine/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage…
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
TGFBR2	TGF-beta receptor type-2	Transmembrane serine/threonine kinase forming with the TGF-beta type I serine/threonine kinase receptor, TGFBR1, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3.
FAS	Tumor necrosis factor receptor superfamily member 6	Receptor for TNFSF6/FASLG.
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
JMJD1C	Jumonji domain-containing protein 1C	Demethylates lysine in proteins, such as STAT3 or MDC1.
VHL	von Hippel-Lindau disease tumor suppressor	Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex.
NDRG4	Protein NDRG4	Contributes to the maintenance of intracerebral BDNF levels within the normal range, which is necessary for the preservation of spatial learning and the resistance to neuronal cell death caused by ischemic stress.
DROSHA	Ribonuclease 3	Ribonuclease III double-stranded (ds) RNA-specific endoribonuclease that is involved in the initial step of microRNA (miRNA) biogenesis.
DOCK8	Dedicator of cytokinesis protein 8	Guanine nucleotide exchange factor (GEF) which specifically activates small GTPase CDC42 by exchanging bound GDP for free GTP.
RHBDF2	Inactive rhomboid protein 2	Regulates ADAM17 protease, a sheddase of the epidermal growth factor (EGF) receptor ligands and TNF, thereby plays a role in sleep, cell survival, proliferation, migration and inflammation.
KCTD11	BTB/POZ domain-containing protein KCTD11	Plays a role as a marker and a regulator of neuronal differentiation; Up-regulated by a variety of neurogenic signals, such as retinoic acid, epidermal growth factor/EGF and NGFB/nerve growth factor.
COL7A1	Collagen alpha-1(VII) chain	Stratified squamous epithelial basement membrane protein that forms anchoring fibrils which may contribute to epithelial basement membrane organization and adherence by interacting with extracellular matrix (ECM) proteins such as type IV c…
FANCM	Fanconi anemia group M protein	DNA-dependent ATPase component of the Fanconi anemia (FA) core complex.
SLX4	Structure-specific endonuclease subunit SLX4	Regulatory subunit that interacts with and increases the activity of different structure-specific endonucleases.
FLCN	Folliculin	Multi-functional protein, involved in both the cellular response to amino acid availability and in the regulation of glycolysis.
DHCR7	7-dehydrocholesterol reductase	Oxidoreductase that catalyzes the last step of the cholesterol synthesis pathway, which transforms cholesta-5,7-dien-3beta-ol (7-dehydrocholesterol,7-DHC) into cholesterol by reducing the C7-C8 double bond of its sterol core.
DIS3L2	DIS3-like exonuclease 2	3’-5’-exoribonuclease that specifically recognizes RNAs polyuridylated at their 3’ end and mediates their degradation.
FRMPD1	FERM and PDZ domain-containing protein 1	Stabilizes membrane-bound GPSM1, and thereby promotes its interaction with GNAI1.
SH2B3	SH2B adapter protein 3	Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.
EP300	Histone acetyltransferase p300	Functions as a histone acetyltransferase and regulates transcription via chromatin remodeling.
ERCC2	General transcription and DNA repair factor IIH helicase subunit XPD	ATP-dependent 5’-3’ DNA helicase.
EXT2	Exostosin-2	Glycosyltransferase forming with EXT1 the heterodimeric heparan sulfate polymerase which catalyzes the elongation of the heparan sulfate glycan backbone.
FANCA	Fanconi anemia group A protein	DNA repair protein that may operate in a postreplication repair or a cell cycle checkpoint function.
FANCD2	Fanconi anemia group D2 protein	Required for maintenance of chromosomal stability.
FASN	Fatty acid synthase	Fatty acid synthetase is a multifunctional enzyme that catalyzes the de novo biosynthesis of long-chain saturated fatty acids starting from acetyl-CoA and malonyl-CoA in the presence of NADPH.
FGFR3	Fibroblast growth factor receptor 3	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis.
FH	Fumarate hydratase, mitochondrial	Catalyzes the reversible stereospecific interconversion of fumarate to L-malate.
FLNA	Filamin-A	Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins.
GBA1	Lysosomal acid glucosylceramidase	Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1’)-N-acylsphing-4-enine) into free ceramides (such as N-acylsphing-4-enine) and glucose.
GLI3	Transcriptional activator GLI3	Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development.
APC	Adenomatous polyposis coli protein	Tumor suppressor.
JAG1	Protein jagged-1	Ligand for multiple Notch receptors and involved in the mediation of Notch signaling.
KDR	Vascular endothelial growth factor receptor 2	Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD.
MET	Hepatocyte growth factor receptor	Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand.
MN1	Transcriptional activator MN1	Transcriptional activator which specifically regulates expression of TBX22 in the posterior region of the developing palate.
MSH2	DNA mismatch repair protein Msh2	Component of the post-replicative DNA mismatch repair system (MMR).
MSH6	DNA mismatch repair protein Msh6	Component of the post-replicative DNA mismatch repair system (MMR).
MUTYH	Adenine DNA glycosylase	Involved in oxidative DNA damage repair.
ATM	Serine-protein kinase ATM	Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor.
BARD1	BRCA1-associated RING domain protein 1	E3 ubiquitin-protein ligase.
RECQL	ATP-dependent DNA helicase Q1	DNA helicase that plays a role in DNA damage repair and genome stability.
RECQL4	ATP-dependent DNA helicase Q4	An ATP-dependent DNA helicase which unwinds dsDNA with a 3’-overhang in a 3’-5’ direction.
REN	Renin	Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retenti…

Protein-family classification

Druggable: 22 · Difficult: 6 · Unknown: 23 · Druggable fraction: 0.43

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
Enzyme (other)	12	2.8×	0.006
Kinase	6	3.3×	0.034
Protease	2	1.4×	0.920
Antibody/Immunoglobulin	2	1.1×	0.920
Other/Unknown	23	0.8×	0.954
Scaffold/PPI	2	0.7×	0.954
Transcription factor	4	0.7×	0.954

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CTNNB1	Other/Unknown	no		Armadillo, ARM-like, Beta-catenin
RPS19	Other/Unknown	no		Ribosomal_eS19, Ribosomal_eS19_CS, WH-like_DNA-bd_sf
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
ARID1A	Other/Unknown	no		ARID_dom, ARM-like, ARM-type_fold
STK11	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
TGFBR2	Kinase	yes	2.7.10.2	TGFB_receptor, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
FAS	Other/Unknown	no		Death_dom, TNFR/NGFR_Cys_rich_reg, Fas_rcpt
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
JMJD1C	Enzyme (other)	yes	1.14.11.65	JmjC_dom, LSDs-like, KDM3A/B_DUF7030
VHL	Enzyme (other)	yes	2.3.2.B13	VHL_tumour_suppress_b/a_dom, VHL_alpha_dom, VHL_beta_dom
NDRG4	Other/Unknown	no		NDRG, AB_hydrolase_fold
DROSHA	Enzyme (other)	yes	3.1.26.3	RNase_III_dom, RNase_III, dsRBD_dom
DOCK8	Other/Unknown	no		ARM-type_fold, DOCK_C/D_N, DOCK
NYNRIN	Other/Unknown	no		Integrase_cat-core, RNaseH_domain, RNaseH-like_sf
RHBDF2	Protease	yes		iRhom1_2_N, Peptidase_S54_rhomboid_dom, Rhomboid-like_sf
KCTD11	Other/Unknown	no		T1-type_BTB, SKP1/BTB/POZ_sf, KCTD11/21_C
COL7A1	Antibody/Immunoglobulin	yes		VWF_A, Kunitz_BPTI, FN3_dom
FANCM	Other/Unknown	no		Helicase_C-like, ERCC4_domain, RuvA_2-like
SLX4	Other/Unknown	no		BTB/POZ_dom, Rad18_UBZ4, SKP1/BTB/POZ_sf
FLCN	Other/Unknown	no		Folliculin, Folliculin_DENN, Folliculin/SMCR8_longin
DHCR7	Enzyme (other)	yes	1.3.1.21	ERG24_DHCR-like, Sterol_reductase_CS
DIS3L2	Other/Unknown	no		RNase_II/R, NA-bd_OB-fold, RNase_II/R_CS
FRMPD1	Scaffold/PPI	no		FERM_domain, PDZ, PH-like_dom_sf
SH2B3	Scaffold/PPI	no		SH2, PH_domain, PH-like_dom_sf
EP300	Transcription factor	no	2.3.1.48	Znf_TAZ, Znf_ZZ, Bromodomain
ERCC2	Enzyme (other)	yes	3.6.4.12	RAD3/XPD, DNA/RNA_helicase_DEAH_CS, Helicase-like_DEXD_c2
EXT2	Enzyme (other)	yes	2.4.1.224	Exostosin, GT64_dom, Nucleotide-diphossugar_trans
FAH	Enzyme (other)	yes	3.7.1.2	Fumarylacetoacetase, Fumarylacetoacetase-like_C, Fumarylacetoacetase_N
FANCA	Other/Unknown	no		FANCA, Fanconi_A_N, Fanconi_A_C
FANCD2	Other/Unknown	no		FANCD2
FASN	Enzyme (other)	yes	2.3.1.39	Thioesterase, Ac_transferase_dom_sf, Ppantetheine_attach_site
FGFR3	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
FH	Enzyme (other)	yes	4.2.1.2	Fumarate_lyase_fam, Fum_hydII, L-Aspartase-like
FLNA	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
GBA1	Enzyme (other)	yes	3.2.1.45	Glyco_hydro_30, GH_hydrolase_sf, GH30_C
GLI3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
BIVM-ERCC5	Other/Unknown	no
APC	Other/Unknown	no		Armadillo, APC_rpt, SAMP
JAG1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, VWF_dom
KDR	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS
MET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Semap_dom
MN1	Other/Unknown	no		MN1
MSH2	Other/Unknown	no		DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS-lik_N, DNA_mismatch_repair_MutS_core
MSH6	Other/Unknown	no		PWWP_dom, DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS-lik_N
MUTYH	Other/Unknown	no		NUDIX_hydrolase_dom, HhH_motif, HhH-GPD_domain
ATM	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
BARD1	Transcription factor	no	2.3.2.27	BRCT_dom, Znf_RING, Ankyrin_rpt
RECQL	Enzyme (other)	yes	3.6.4.12	Helicase_C-like, DNA_helicase_ATP-dep_RecQ, DEAD/DEAH_box_helicase_dom
RECQL4	Enzyme (other)	yes	3.6.4.12	Helicase_C-like, DNA_helicase_ATP-dep_RecQ, DEAD/DEAH_box_helicase_dom

Expression context

Cohort genes with no expression data: 0.

48 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)	51
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	12
right hemisphere of cerebellum	7
stromal cell of endometrium	6
cerebellar hemisphere	6
male germ line stem cell (sensu Vertebrata) in testis	5
secondary oocyte	4
monocyte	4
cerebellar cortex	4
adrenal tissue	3
skin of hip	3
upper leg skin	3
bone marrow cell	3
ganglionic eminence	3
calcaneal tendon	3
mononuclear cell	3
germinal epithelium of ovary	3
oocyte	3
buccal mucosa cell	3
embryo	2
left testis	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CTNNB1	295	ubiquitous	marker	adrenal tissue, ventricular zone, periodontal ligament
RPS19	301	ubiquitous	marker	upper leg skin, right uterine tube, skin of hip
BRCA2	184	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
ARID1A	286	ubiquitous	marker	bone marrow cell, ventricular zone, embryo
STK11	238	ubiquitous	marker	left testis, right testis, hindlimb stylopod muscle
TERT	105	broad	yes	stromal cell of endometrium, type B pancreatic cell, olfactory bulb
TGFBR2	289	ubiquitous	marker	pericardium, tibia, parietal pleura
FAS	280	ubiquitous	marker	rectum, left ovary, right ovary
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
JMJD1C	291	ubiquitous	marker	calcaneal tendon, right hemisphere of cerebellum, cerebellar hemisphere
VHL	186	ubiquitous	marker	cortical plate, monocyte, mononuclear cell
NDRG4	234	ubiquitous	marker	right hemisphere of cerebellum, cerebellar cortex, cerebellar hemisphere
DROSHA	283	ubiquitous	marker	endothelial cell, ventricular zone, germinal epithelium of ovary
DOCK8	236	ubiquitous	marker	bone marrow cell, leukocyte, monocyte
NYNRIN	201	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
RHBDF2	241	ubiquitous	marker	granulocyte, monocyte, mononuclear cell
KCTD11	132	ubiquitous	marker	lower esophagus mucosa, tibial nerve, esophagus mucosa
COL7A1	267	ubiquitous	marker	stromal cell of endometrium, skin of abdomen, skin of leg
FANCM	203	ubiquitous	marker	sperm, oocyte, male germ line stem cell (sensu Vertebrata) in testis
SLX4	175	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
FLCN	261	ubiquitous	marker	buccal mucosa cell, right hemisphere of cerebellum, cerebellar hemisphere
DHCR7	257	ubiquitous	marker	adrenal tissue, right lobe of liver, right adrenal gland cortex
DIS3L2	241	ubiquitous	marker	sural nerve, sperm, buccal mucosa cell
FRMPD1	167	broad	marker	dorsal root ganglion, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
SH2B3	260	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
EP300	292	ubiquitous	marker	colonic epithelium, adrenal tissue, bone marrow cell
ERCC2	184	ubiquitous	marker	stromal cell of endometrium, right adrenal gland, left adrenal gland
EXT2	269	ubiquitous	marker	stromal cell of endometrium, cartilage tissue, smooth muscle tissue
FAH	255	ubiquitous	marker	right lobe of liver, liver, right adrenal gland
FANCA	185	ubiquitous	marker	right testis, ventricular zone, left testis

Protein interactions among cohort

Intra-cohort edges: 45.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
CTNNB1	15,668
EP300	10,122
ATM	7,383
DROSHA	6,846
FASN	6,551
RECQL4	6,330
MET	5,823
TGFBR2	5,777
TERT	5,717

Intra-cohort edges

A	B	Sources
APC	CTNNB1	intact, string_interaction
ARID1A	MSH2	string_interaction
ATM	BARD1	string_interaction
ATM	BRCA2	string_interaction
ATM	FANCD2	string_interaction
ATM	MSH2	string_interaction
ATM	MSH6	string_interaction
ATM	RECQL4	string_interaction
ATM	STK11	string_interaction
ATM	TP53	biogrid_interaction, string_interaction
BARD1	BRCA2	string_interaction
BRCA2	FANCD2	intact, string_interaction
BRCA2	FLNA	string_interaction
BRCA2	MSH2	string_interaction
BRCA2	MSH6	string_interaction
BRCA2	STK11	string_interaction
BRCA2	TP53	string_interaction
CTNNB1	EP300	string_interaction
CTNNB1	FANCA	biogrid_interaction
CTNNB1	JAG1	string_interaction
CTNNB1	KCTD11	biogrid_interaction
CTNNB1	KDR	string_interaction
CTNNB1	MET	biogrid_interaction
CTNNB1	TERT	string_interaction
DROSHA	TP53	intact, string_interaction
EP300	MN1	biogrid_interaction
EP300	TP53	biogrid_interaction, intact, string_interaction
FANCA	FANCD2	string_interaction
FANCA	FANCM	biogrid_interaction, intact, string_interaction
FANCA	SLX4	string_interaction
FANCD2	FANCM	string_interaction
FANCD2	SLX4	string_interaction
FANCM	RECQL	string_interaction
FANCM	SLX4	string_interaction
FGFR3	VHL	biogrid_interaction
FLNA	SH2B3	biogrid_interaction
MET	SH2B3	intact
MSH2	MSH6	biogrid_interaction, intact, string_interaction
MSH2	MUTYH	intact, string_interaction
MSH2	RECQL	biogrid_interaction
MSH2	SLX4	intact, string_interaction
MSH6	MUTYH	string_interaction
NDRG4	TP53	biogrid_interaction
RHBDF2	TGFBR2	intact
STK11	TP53	string_interaction

Structural data

PDB: 42 · AlphaFold-only: 8 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TP53	P04637	313
RPS19	P39019	210
VHL	P40337	142
MET	P08581	130
REN	P00797	91
EP300	Q09472	60
GBA1	P04062	58
KDR	P35968	54
ERCC2	P18074	51
CTNNB1	P35222	50
FASN	P49327	34
APC	P25054	31
MSH2	P43246	30
FLNA	P21333	26
TERT	O14746	23
TGFBR2	P37173	22
FGFR3	P22607	15
BRCA2	P51587	14
ATM	Q13315	14
FANCD2	Q9BXW9	13
DROSHA	Q9NRR4	12
BARD1	Q99728	11
FAH	P16930	8
MSH6	P52701	8
ARID1A	O14497	7
FAS	P25445	7
FANCM	Q8IYD8	7
SLX4	Q8IY92	7
FH	P07954	7
JAG1	P78504	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DHCR7	Q9UBM7	91.64
NDRG4	Q9ULP0	85.27
KCTD11	Q693B1	85.00
DOCK8	Q8NF50	75.17
SH2B3	Q9UQQ2	63.45
NYNRIN	Q9P2P1	60.04
MN1	Q10571	42.47
COL7A1	Q02388

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 477. Enrichment computed across 51 evidence-associated genes (43 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 43 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Diseases of DNA repair	5	66.4×	4e-06	BRCA2, MSH2, MSH6, ATM, BARD1
Resolution of D-Loop Structures	4	59.0×	1e-04	BRCA2, SLX4, ATM, BARD1
TP53 Regulates Transcription of DNA Repair Genes	5	21.1×	5e-04	TP53, ERCC2, FANCD2, MSH2, ATM
DNA Repair	6	13.7×	5e-04	BRCA2, SLX4, MSH2, MSH6, ATM, BARD1
Defective homologous recombination repair (HRR) due to PALB2 loss of function	3	66.4×	7e-04	BRCA2, ATM, BARD1
Homology Directed Repair	4	28.7×	7e-04	BRCA2, SLX4, ATM, BARD1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	4	28.7×	7e-04	BRCA2, SLX4, ATM, BARD1
Resolution of D-loop Structures through Holliday Junction Intermediates	4	28.0×	7e-04	BRCA2, SLX4, ATM, BARD1
Defective Mismatch Repair Associated With MSH6	2	265.6×	7e-04	MSH2, MSH6
Diseases of DNA Double-Strand Break Repair	3	56.9×	7e-04	BRCA2, ATM, BARD1
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	3	56.9×	7e-04	BRCA2, ATM, BARD1
Fanconi Anemia Pathway	4	25.9×	7e-04	FANCM, SLX4, FANCA, FANCD2
DNA Double-Strand Break Repair	4	23.1×	9e-04	BRCA2, SLX4, ATM, BARD1
Defective Mismatch Repair Associated With MSH2	2	177.1×	0.001	MSH2, MSH6
Regulation of TP53 Activity through Methylation	3	37.9×	0.002	TP53, EP300, ATM
HDR through Homologous Recombination (HRR)	4	17.7×	0.002	BRCA2, SLX4, ATM, BARD1
Mismatch Repair	2	132.8×	0.002	MSH2, MSH6
Diseases of Mismatch Repair (MMR)	2	132.8×	0.002	MSH2, MSH6
Impaired BRCA2 binding to PALB2	3	31.9×	0.003	BRCA2, ATM, BARD1
LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production	2	106.2×	0.003	CTNNB1, EP300
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	3	29.5×	0.003	BRCA2, ATM, BARD1
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	3	29.5×	0.003	BRCA2, ATM, BARD1
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	3	29.5×	0.003	BRCA2, ATM, BARD1
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	3	27.5×	0.003	BRCA2, ATM, BARD1
Homologous DNA Pairing and Strand Exchange	3	26.6×	0.004	BRCA2, ATM, BARD1
Impaired BRCA2 binding to RAD51	3	21.5×	0.006	BRCA2, ATM, BARD1
Regulation of TP53 Activity through Phosphorylation	4	10.9×	0.008	STK11, TP53, ATM, BARD1
PI5P Regulates TP53 Acetylation	2	59.0×	0.008	TP53, EP300
Presynaptic phase of homologous DNA pairing and strand exchange	3	19.0×	0.008	BRCA2, ATM, BARD1
TP53 Regulates Transcription of Caspase Activators and Caspases	2	44.3×	0.014	TP53, ATM

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 50 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
determination of adult lifespan	6	51.9×	1e-06	TP53, ERCC2, GBA1, MSH2, MSH6, ATM
DNA repair	9	11.5×	3e-05	SLX4, FANCA, FH, MSH2, MSH6, MUTYH, BARD1, RECQL (+1 more)
regulation of regulatory T cell differentiation	3	112.3×	6e-04	DROSHA, FANCA, FANCD2
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	4	39.6×	7e-04	BRCA2, TP53, EP300, MSH2
T cell differentiation in thymus	4	32.9×	0.001	CTNNB1, TP53, GBA1, GLI3
in utero embryonic development	7	10.1×	0.001	CTNNB1, TGFBR2, TP53, FLCN, ERCC2, GLI3, MSH2
nucleotide-excision repair	4	30.6×	0.001	BRCA2, TP53, SLX4, ERCC2
neuroblast proliferation	4	29.3×	0.001	CTNNB1, TP53, KCTD11, GLI3
embryonic hemopoiesis	3	59.5×	0.001	TGFBR2, SH2B3, KDR
replicative senescence	3	59.5×	0.001	TERT, TP53, ATM
double-strand break repair via homologous recombination	5	15.6×	0.001	BRCA2, SLX4, ATM, RECQL, RECQL4
stem cell proliferation	4	25.0×	0.002	CTNNB1, TP53, GLI3, KDR
response to X-ray	3	53.2×	0.002	BRCA2, TP53, MSH2
chondrocyte differentiation	4	24.1×	0.002	CTNNB1, EXT2, FGFR3, GLI3
positive regulation of apoptotic process	7	7.9×	0.002	CTNNB1, FAS, TP53, FLCN, APC, ATM, BARD1
hematopoietic stem cell differentiation	3	46.0×	0.002	TP53, SH2B3, ERCC2
somatic recombination of immunoglobulin gene segments	2	168.5×	0.003	MSH2, MSH6
regulation of CD40 signaling pathway	2	168.5×	0.003	FANCA, FANCD2
megakaryocyte development	3	42.1×	0.003	SH2B3, EP300, FLNA
mismatch repair	3	38.9×	0.003	MSH2, MSH6, MUTYH
hematopoietic stem cell proliferation	3	38.9×	0.003	BRCA2, ERCC2, GBA1
regulation of bone development	2	134.8×	0.003	GLI3, KDR
positive regulation of mesenchymal cell proliferation	3	36.1×	0.003	CTNNB1, TGFBR2, KDR
response to gamma radiation	3	34.9×	0.003	BRCA2, TP53, FANCD2
intrinsic apoptotic signaling pathway by p53 class mediator	3	34.9×	0.003	STK11, TP53, ERCC2
branching involved in blood vessel morphogenesis	3	31.6×	0.004	CTNNB1, TGFBR2, KDR
positive regulation of transforming growth factor beta receptor signaling pathway	3	31.6×	0.004	STK11, FLCN, EP300
positive regulation of stem cell proliferation	3	31.6×	0.004	CTNNB1, TERT, KDR
double-strand break repair	4	16.2×	0.004	BRCA2, TP53, MSH2, ATM
negative regulation of brown fat cell differentiation	2	112.3×	0.004	FLCN, EP300

Therapeutics

Drugs indicated for this disease

0 approved, 13 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Amifostine	Phase 3 (in late-stage trials)
Carboplatin	Phase 3 (in late-stage trials)
Cisplatin	Phase 3 (in late-stage trials)
Dexrazoxane	Phase 3 (in late-stage trials)
Doxorubicin	Phase 3 (in late-stage trials)
Etoposide	Phase 3 (in late-stage trials)
Fluorouracil	Phase 3 (in late-stage trials)
Gemcitabine	Phase 3 (in late-stage trials)
Irinotecan	Phase 3 (in late-stage trials)
Oxaliplatin	Phase 3 (in late-stage trials)
Sorafenib	Phase 3 (in late-stage trials)
Temsirolimus	Phase 3 (in late-stage trials)
Vincristine	Phase 3 (in late-stage trials)

Drug target analysis

Approved (phase 4): 17 · Phase ≥3: 18 · Phased (≥1): 20 · Undrugged: 31

Druggability breadth: 33 of 51 evidence-associated genes (65%) 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
CTNNB1	DITHIAZANINE IODIDE
RPS19	GENTAMICIN SULFATE
STK11	FEDRATINIB
TERT	BERBERINE
TGFBR2	PONATINIB
TP53	NITROFURANTOIN
VHL	OSIMERTINIB
DHCR7	DOXORUBICIN
ERCC2	SUNITINIB
FASN	RABEPRAZOLE
FGFR3	PONATINIB
GBA1	MIGALASTAT
KDR	VANDETANIB
MET	AFATINIB
ATM	AMIODARONE HYDROCHLORIDE
RECQL	LEVODOPA
REN	CAPTOPRIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
KDR	172	4
RECQL	115	4
MET	95	4
FGFR3	64	4
ATM	35	4
TGFBR2	22	4
STK11	17	4
ERCC2	16	4
REN	13	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DITHIAZANINE IODIDE	4	ATM, CTNNB1, RECQL
GENTAMICIN SULFATE	4	RPS19
FEDRATINIB	4	FGFR3, KDR, MET, STK11, TGFBR2
PACRITINIB	4	STK11
NINTEDANIB	4	FGFR3, KDR, MET, STK11
SUNITINIB	4	ERCC2, FGFR3, KDR, MET, STK11
MIDOSTAURIN	4	FGFR3, KDR, MET, STK11
BERBERINE	4	TERT
DOXORUBICIN	4	DHCR7, TERT
PONATINIB	4	FGFR3, KDR, TGFBR2
VEMURAFENIB	4	KDR, TGFBR2
SORAFENIB	4	FGFR3, KDR, MET, TGFBR2
DABRAFENIB	4	MET, TGFBR2
TOVORAFENIB	4	TGFBR2
PAZOPANIB	4	FGFR3, KDR, MET, TGFBR2
DASATINIB	4	FGFR3, KDR, TGFBR2
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	RECQL, TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	ATM, TP53
FURAZOLIDONE	4	ATM, TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 21.

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

Symbol	Assays	Type breakdown
VHL	3,575	Binding:3482, Functional:54, ADMET:39
KDR	2,687	Binding:2594, Functional:64, ADMET:27, Toxicity:2
MET	2,015	Binding:2005, Functional:6, ADMET:4
FGFR3	975	Binding:948, Functional:18, ADMET:9
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
EP300	767	Binding:763, Functional:3, ADMET:1
REN	541	Binding:472, Functional:68, ADMET:1
GBA1	436	Binding:403, Functional:33
TERT	391	Binding:389, Functional:2
CTNNB1	361	Binding:358, Functional:3
STK11	244	Binding:244
ATM	240	Binding:233, Functional:5, ADMET:2
TGFBR2	188	Binding:188
FASN	142	Binding:136, Functional:6
RPS19	97	Binding:97
DHCR7	43	Functional:23, Binding:20
APC	24	Binding:24
MSH6	10	Binding:10
MSH2	9	Binding:9
FAS	8	Binding:8
FLNA	7	Binding:7
ARID1A	6	Binding:6
RECQL	6	Functional:4, Binding:2
ERCC2	3	Binding:3
JMJD1C	2	Binding:2
DIS3L2	2	Binding:2
FANCD2	2	Binding:2
KCTD11	1	Binding:1
FAH	1	Binding:1
FH	1	Binding:1
JAG1	1	Binding:1
MUTYH	1	Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
STK11	2.7.11.1	non-specific serine/threonine protein kinase
TGFBR2	2.7.10.2	non-specific protein-tyrosine kinase
JMJD1C	1.14.11.65	[histone H3]-dimethyl-L-lysine9 demethylase
VHL	2.3.2.B13
DROSHA	3.1.26.3	ribonuclease III
DHCR7	1.3.1.21	7-dehydrocholesterol reductase
EP300	2.3.1.48	histone acetyltransferase
ERCC2	3.6.4.12	DNA helicase
EXT2	2.4.1.224, 2.4.1.225	glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase, N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase
FAH	3.7.1.2	fumarylacetoacetase
FASN	2.3.1.39, 2.3.1.85	[acyl-carrier-protein] S-malonyltransferase, fatty-acid synthase system
FGFR3	2.7.10.1	receptor protein-tyrosine kinase
FH	4.2.1.2	fumarate hydratase
GBA1	3.2.1.45	glucosylceramidase
KDR	2.7.10.1	receptor protein-tyrosine kinase
MET	2.7.10.1	receptor protein-tyrosine kinase
ATM	2.7.11.1	non-specific serine/threonine protein kinase
BARD1	2.3.2.27	RING-type E3 ubiquitin transferase
RECQL	3.6.4.12	DNA helicase
RECQL4	3.6.4.12	DNA helicase
REN	3.4.23.15	renin

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CTNNB1	361
STK11	244
TERT	391
TGFBR2	188
TP53	869
VHL	3,575
EP300	767
FASN	142
FGFR3	975
GBA1	436
KDR	2,687
MET	2,015
ATM	240
REN	541

Pharmacogenomics

Cohort genes with a PharmGKB record: 50; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

28 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)
DITHIAZANINE IODIDE	4	ATM, CTNNB1, RECQL
GENTAMICIN SULFATE	4	RPS19
FEDRATINIB	4	FGFR3, KDR, MET, STK11, TGFBR2
PACRITINIB	4	STK11
NINTEDANIB	4	FGFR3, KDR, MET, STK11
SUNITINIB	4	ERCC2, FGFR3, KDR, MET, STK11
MIDOSTAURIN	4	FGFR3, KDR, MET, STK11
BERBERINE	4	TERT
DOXORUBICIN	4	DHCR7, TERT
PONATINIB	4	FGFR3, KDR, TGFBR2
DABRAFENIB	4	MET, TGFBR2
TOVORAFENIB	4	TGFBR2
PAZOPANIB	4	FGFR3, KDR, MET, TGFBR2
DASATINIB	4	FGFR3, KDR, TGFBR2
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	RECQL, TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	ATM, TP53
FURAZOLIDONE	4	ATM, TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	17	CTNNB1, RPS19, STK11, TERT, TGFBR2, TP53, VHL, DHCR7, ERCC2, FASN (+7 more)
B	Phased (≥1) drug, not yet approved	3	EP300, FLNA, MSH6
C	Druggable family + PDB, no drug	7	JMJD1C, DROSHA, RHBDF2, EXT2, FAH, FH, RECQL4
D	Druggable family + AlphaFold only, no drug	1	COL7A1
E	Difficult family or no structure, no drug	23	BRCA2, ARID1A, FAS, NDRG4, DOCK8, NYNRIN, KCTD11, FANCM, SLX4, FLCN (+13 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DROSHA	0	TP53
APC	24	CTNNB1
MUTYH	1	MSH6
BRCA2	0	—
ARID1A	6	—
FAS	8	—
JMJD1C	2	—
NDRG4	0	—
DOCK8	0	—
NYNRIN	0	—
RHBDF2	0	—
KCTD11	1	—
COL7A1	0	—
FANCM	0	—
SLX4	0	—
FLCN	0	—
DIS3L2	2	—
FRMPD1	0	—
SH2B3	0	—
EXT2	0	—
FAH	1	—
FANCA	0	—
FANCD2	2	—
FH	1	—
GLI3	0	—
BIVM-ERCC5	0	—
JAG1	1	—
MN1	0	—
MSH2	9	—
BARD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 56.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	19
Not specified	15
PHASE1	10
PHASE1/PHASE2	6
PHASE3	3
PHASE2/PHASE3	2
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02933333	PHASE4	UNKNOWN	G-CSF Alone or Combination With GM-CSF on Prevention and Treatment of Infection in Children With Malignant Tumor
NCT03017326	PHASE3	ACTIVE_NOT_RECRUITING	Paediatric Hepatic International Tumour Trial
NCT03533582	PHASE3	ACTIVE_NOT_RECRUITING	Cisplatin and Combination Chemotherapy in Treating Children and Young Adults With Hepatoblastoma or Liver Cancer After Surgery
NCT04478292	PHASE3	RECRUITING	A Multi-institutional Study for Treatment of Children With Newly Diagnosed Hepatoblastoma Using a Modified PHITT Strategy
NCT03728543	PHASE2/PHASE3	UNKNOWN	the Efficacy and Safety of Sugammadex in Children 0-2 Years Old
NCT05322187	PHASE2/PHASE3	UNKNOWN	Sequential PD-1/PD-L1 Inhibitor and LENvatinib in TLCT and Refractory Hepatoblastoma After Chemotherapy
NCT02867592	PHASE2	ACTIVE_NOT_RECRUITING	Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03210714	PHASE2	ACTIVE_NOT_RECRUITING	Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213652	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03213704	PHASE2	ACTIVE_NOT_RECRUITING	Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)
NCT03698994	PHASE2	ACTIVE_NOT_RECRUITING	Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)
NCT04195555	PHASE2	ACTIVE_NOT_RECRUITING	Ivosidenib in Treating Patients With Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With IDH1 Mutations (A Pediatric MATCH Treatment Trial)
NCT04284774	PHASE2	ACTIVE_NOT_RECRUITING	Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial
NCT04320888	PHASE2	ACTIVE_NOT_RECRUITING	Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediatric MATCH Treatment Trial
NCT04634357	PHASE1/PHASE2	RECRUITING	ET140203 T Cells in Pediatric Subjects With Hepatoblastoma, HCN-NOS, or Hepatocellular Carcinoma
NCT04851119	PHASE1/PHASE2	RECRUITING	Tegavivint for the Treatment of Recurrent or Refractory Solid Tumors, Including Lymphomas and Desmoid Tumors
NCT04901702	PHASE1/PHASE2	RECRUITING	Study of Onivyde With Talazoparib or Temozolomide in Children With Recurrent Solid Tumors and Ewing Sarcoma
NCT06521567	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study of Cobolimab Plus Dostarlimab in Pediatric and Young Adult Participants With Cancer
NCT06638931	PHASE2	RECRUITING	Agnostic Therapy in Rare Solid Tumors
NCT07300449	PHASE2	RECRUITING	A Prospective Multicenter Clinical Study of SCCG Protocol and ctDNA 5hmc in Predicting the Chemotherapy Sensitivity and Monitoring the Recurrence and Metastasis of Hepatoblastoma in Children and Adolescents
NCT00179816	PHASE1/PHASE2	UNKNOWN	Tandem Peripheral Blood Stem Cell (PBSC) Rescue for High Risk Solid Tumors
NCT01125800	PHASE1/PHASE2	COMPLETED	A Phase I Dose Finding and Safety Study of Oral LDE225 in Children and a Phase II Portion to Assess Preliminary Efficacy in Recurrent or Refractory MB
NCT01154816	PHASE2	COMPLETED	Alisertib in Treating Young Patients With Recurrent or Refractory Solid Tumors or Leukemia
NCT02011126	PHASE2	WITHDRAWN	Imetelstat Sodium in Treating Younger Patients With Relapsed or Refractory Solid Tumors
NCT03213665	PHASE2	COMPLETED	Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)
NCT03213678	PHASE2	COMPLETED	Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)
NCT03220035	PHASE2	COMPLETED	Vemurafenib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With BRAF V600 Mutations (A Pediatric MATCH Treatment Trial)
NCT03233204	PHASE2	COMPLETED	Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)
NCT03526250	PHASE2	COMPLETED	Palbociclib in Treating Patients With Relapsed or Refractory Rb Positive Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Activating Alterations in Cell Cycle Genes (A Pediatric MATCH Treatment Trial)
NCT05302921	PHASE2	COMPLETED	Neoadjuvant Dual Checkpoint Inhibition and Cryoablation in Relapsed/Refractory Pediatric Solid Tumors
NCT03618381	PHASE1	ACTIVE_NOT_RECRUITING	EGFR806 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults
NCT04308330	PHASE1	RECRUITING	Vorinostat in Combination With Chemotherapy in Relapsed/Refractory Solid Tumors and CNS Malignancies
NCT04337177	PHASE1	ACTIVE_NOT_RECRUITING	Flavored, Oral Irinotecan VAL-413 (Orotecan®) Given With Temozolomide for Treatment of Recurrent Pediatric Solid Tumors
NCT04483778	PHASE1	ACTIVE_NOT_RECRUITING	B7H3 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults
NCT04897321	PHASE1	RECRUITING	B7-H3-Specific Chimeric Antigen Receptor Autologous T-Cell Therapy for Pediatric Patients With Solid Tumors (3CAR)
NCT06198296	PHASE1	RECRUITING	Immunotherapy For Adults With GPC3-Positive Solid Tumors Using IL-15 and IL-21 Armored GPC3-CAR T Cells
NCT07148050	PHASE1	RECRUITING	Immunotherapy for Solid Tumor Malignancies in Pediatrics Using Interleukin-15 and -21 Armored Glypican-3-specific Chimeric Antigen Receptor T Cells
NCT01331135	PHASE1	COMPLETED	Aflac ST0901 CHOANOME - Sirolimus in Solid Tumors
NCT02390843	PHASE1	COMPLETED	Simvastatin With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
IRINOTECAN	4	5
LAROTRECTINIB	4	4
CABOZANTINIB	4	3
ENSARTINIB	4	2
ERDAFITINIB	4	2
IVOSIDENIB	4	2
SELPERCATINIB	4	2
SELUMETINIB	4	2
SORAFENIB	4	2
TAZEMETOSTAT	4	2
VEMURAFENIB	4	2
DOSTARLIMAB	4	1
IMETELSTAT SODIUM	4	1
SONIDEGIB	4	1
TALAZOPARIB	4	1
URSODIOL	4	1
TIPIFARNIB	3	2
ALISERTIB	3	1
PUCOTENLIMAB	3	1
REGRAMOSTIM	3	1
SAMOTOLISIB	2	2
ULIXERTINIB	2	2
COBOLIMAB	2	1
TEGAVIVINT	2	1
CHEMBL3415553	0	2
CHEMBL4209555	0	2
CHEMBL5398431	0	2
CHEMBL5430810	0	2
PLX-4720	0	2
CHEMBL4215501	0	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 2 predictive associations from 2 curated evidence items; also 6 diagnostic.

Molecular subtype	Therapy	Effect	Level	CIViC
CTNNB1 T41A		Sensitivity/Response	CIViC B	EID6078
CTNNB1 S37C		Sensitivity/Response	CIViC E	EID6089