Medulloblastoma

Summary

Medulloblastoma (MONDO:0007959) is a disease (an umbrella term covering 14 Mondo subtypes) caused by variants in SUFU, ELP1, and GPR161, with 27 cohort genes and 144 clinical trials. The dominant Reactome pathway is Hedgehog ‘off’ state (5 cohort genes). Molecularly, PTCH1 LOH confers sensitivity to Vismodegib in Medulloblastoma (CIViC Level B); 7 further subtype–drug associations are mapped below. Top therapeutic interventions include cisplatin, lomustine, and sonidegib.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal genes: SUFU (GenCC Definitive), ELP1 (GenCC Strong), GPR161 (GenCC Strong)
• Umbrella term: 14 Mondo subtypes
• Cohort genes: 27
• ClinVar variants: 2,224
• Phenotypes (HPO): 34
• Clinical trials: 144
• Precision-medicine evidence (CIViC): 8 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.11	Europe	Validated
Point prevalence	1-9 / 100 000	1	Europe	Validated
Annual incidence	1-9 / 1 000 000	0.74	United States	Validated

Signs & symptoms

Clinical features (HPO)

34 HPO clinical features (Orphanet curated; top 34 by frequency):

HPO ID	Term	Frequency
HP:0002885	Medulloblastoma	Obligate (100%)
HP:0000270	Delayed cranial suture closure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001254	Lethargy	Frequent (30-79%)
HP:0001291	Abnormal cranial nerve morphology	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0002017	Nausea and vomiting	Frequent (30-79%)
HP:0002073	Progressive cerebellar ataxia	Frequent (30-79%)
HP:0002080	Intention tremor	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0002516	Increased intracranial pressure	Frequent (30-79%)
HP:0004481	Progressive macrocephaly	Frequent (30-79%)
HP:0007129	Cerebellar medulloblastoma	Frequent (30-79%)
HP:0009878	Cerebellar ataxia associated with quadrupedal gait	Frequent (30-79%)
HP:0012658	Abnormal brain FDG positron emission tomography	Frequent (30-79%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000529	Progressive visual loss	Occasional (5-29%)
HP:0000651	Diplopia	Occasional (5-29%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0002321	Vertigo	Occasional (5-29%)
HP:0002350	Cerebellar cyst	Occasional (5-29%)
HP:0003418	Back pain	Occasional (5-29%)
HP:0005227	Adenomatous colonic polyposis	Occasional (5-29%)
HP:0005561	Abnormality of bone marrow cell morphology	Occasional (5-29%)
HP:0007352	Cerebellar calcifications	Occasional (5-29%)
HP:0007824	Total ophthalmoplegia	Occasional (5-29%)
HP:0008619	Bilateral sensorineural hearing impairment	Occasional (5-29%)
HP:0010302	Spinal cord tumor	Occasional (5-29%)
HP:0011695	Cerebellar hemorrhage	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Very rare (<1-4%)
HP:0003006	Neuroblastoma	Very rare (<1-4%)
HP:0100526	Neoplasm of the lung	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	medulloblastoma
Mondo ID	MONDO:0007959
EFO	EFO:0002939
MeSH	D008527
OMIM	155255
Orphanet	616
DOID	DOID:0050902, DOID:0060104
ICD-11	290815825
NCIT	C3222
SNOMED CT	443333004
UMLS	C0025149
MedGen	7517
GARD	0007005
MedDRA	10027107
NORD	1422
Anatomy (UBERON)	UBERON:0002037
Is cancer (heuristic)	no

Also known as: cerebellum embryonal neoplasm · CPNET · infratentorial primitive neuroectodermal tumour · localised primitive neuroectodermal tumour · MDB · medulloblastoma · medulloblastoma, autosomal recessive, autosomal dominant, somatic mutation · medulloblastoma, desmoplastic, autosomal recessive, autosomal dominant, somatic mutation · medulloblastoma, malignant · medulloblastoma, somatic · medulloblastomas

Data availability: 2,224 ClinVar variants · 8 GenCC gene-disease records · 65 cell lines · 50 intOGen driver records.

Disease family

An umbrella term covering 14 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › cerebellar disorder › cerebellar neoplasm › medulloblastoma

Related subtypes (7): cerebellar astrocytoma, adult cerebellar neoplasm, papillary meningioma of the cerebellum, childhood cerebellar neoplasm, cerebellar liponeurocytoma, cancer of cerebellum, benign neoplasm of cerebellum

Subtypes (14): brain stem medulloblastoma, large cell medulloblastoma, cerebellar vermis medulloblastoma, adult medulloblastoma, melanotic medulloblastoma, childhood medulloblastoma, medullomyoblastoma with myogenic differentiation, anaplastic/large cell medulloblastoma, medulloblastoma with extensive nodularity, desmoplastic/nodular medulloblastoma, classic medulloblastoma, medulloblastoma WNT activated, medulloblastoma SHH activated, medulloblastoma non-WNT/non-SHH

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

600 retrieved; paginated sample, class counts are floors:

238 uncertain significance, 217 likely benign, 71 conflicting classifications of pathogenicity, 34 pathogenic, 14 pathogenic/likely pathogenic, 11 likely pathogenic, 8 benign/likely benign, 4 benign, 3 pathogenic; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
1460216	NC_000010.10:g.(?104262628)(104595248_?)del	ARL3	Pathogenic	criteria provided, single submitter
126014	NM_000059.4(BRCA2):c.3458del (p.Lys1153fs)	BRCA2	Pathogenic	reviewed by expert panel
126037	NM_000059.4(BRCA2):c.4131_4132insTGAGGA (p.Thr1378Ter)	BRCA2	Pathogenic	reviewed by expert panel
1330148	NM_000059.4(BRCA2):c.6611del (p.Pro2204fs)	BRCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
141199	NM_000059.4(BRCA2):c.2918C>A (p.Ser973Ter)	BRCA2	Pathogenic	reviewed by expert panel
141283	NM_000059.4(BRCA2):c.1909+1G>A	BRCA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
141509	NM_000059.4(BRCA2):c.6816_6820del (p.Gly2274fs)	BRCA2	Pathogenic	reviewed by expert panel
142868	NM_000059.4(BRCA2):c.2059_2063del (p.Leu686_Asp687insTer)	BRCA2	Pathogenic	reviewed by expert panel
1439264	NM_000059.4(BRCA2):c.1766dup (p.Phe590fs)	BRCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1456139	NM_000059.4(BRCA2):c.4793_4794del (p.Leu1598fs)	BRCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1737126	NM_000059.4(BRCA2):c.4022C>G (p.Ser1341Ter)	BRCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
182322	NM_000059.4(BRCA2):c.8174_8185delinsTT (p.Trp2725fs)	BRCA2	Pathogenic	reviewed by expert panel
17584	NM_001904.4(CTNNB1):c.101G>A (p.Gly34Glu)	CTNNB1	Pathogenic; other	no assertion criteria provided
1069416	NM_003640.5(ELP1):c.707_711dup (p.Ala238fs)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072418	NM_003640.5(ELP1):c.1269dup (p.Val424fs)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074533	NM_003640.5(ELP1):c.307G>T (p.Glu103Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074683	NM_003640.5(ELP1):c.737G>A (p.Trp246Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299758	NM_003640.5(ELP1):c.138dup (p.Val47fs)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299759	NM_003640.5(ELP1):c.312T>C (p.Cys104=)	ELP1	Pathogenic	no assertion criteria provided
1353787	NM_003640.5(ELP1):c.3382_3385del (p.Thr1128fs)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1361491	NM_003640.5(ELP1):c.2020C>T (p.Gln674Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1378924	NM_003640.5(ELP1):c.3408del (p.Lys1136fs)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1391877	NM_003640.5(ELP1):c.3378dup (p.Gln1127fs)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451893	NM_003640.5(ELP1):c.2322_2325del (p.Asp775fs)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454132	NM_003640.5(ELP1):c.3595A>T (p.Lys1199Ter)	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460164	NM_003640.5(ELP1):c.1361-1G>T	ELP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1710300	NM_001375883.1(GPR161):c.487_488del (p.Leu163fs)	GPR161	Pathogenic	no assertion criteria provided
17581	NM_001904.4(CTNNB1):c.94G>T (p.Asp32Tyr)	LOC126806658	Pathogenic; other	no assertion criteria provided
17583	NM_001904.4(CTNNB1):c.98C>T (p.Ser33Phe)	LOC126806658	Pathogenic; other	no assertion criteria provided
1072595	NM_016169.4(SUFU):c.37_53del (p.Thr13fs)	LOC130004614	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 57 · Orphanet: 124 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SUFU	Definitive	Autosomal dominant	medulloblastoma	16
ELP1	Strong	Autosomal dominant	medulloblastoma	7
GPR161	Strong	Autosomal dominant	medulloblastoma	3
BRCA2	Limited	Autosomal dominant	medulloblastoma	13
SMO	Limited	Autosomal dominant	medulloblastoma	9
SMOX	Limited	Autosomal dominant	medulloblastoma	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
SMO	Orphanet:1553	Curry-Jones syndrome
SMO	Orphanet:2495	Meningioma
SMO	Orphanet:388	Hirschsprung disease
SUFU	Orphanet:2495	Meningioma
SUFU	Orphanet:251858	Medulloblastoma with extensive nodularity
SUFU	Orphanet:251863	Desmoplastic/nodular medulloblastoma
SUFU	Orphanet:263662	Familial multiple meningioma
SUFU	Orphanet:280200	Microform holoprosencephaly
SUFU	Orphanet:377	Gorlin syndrome
SUFU	Orphanet:475	Isolated Joubert syndrome
GPR161	Orphanet:95496	Pituitary stalk interruption syndrome
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
ELP1	Orphanet:1764	Familial dysautonomia
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
TP53	Orphanet:251899	Choroid plexus carcinoma
TP53	Orphanet:2807	Papilloma of choroid plexus
TP53	Orphanet:293199	Pleomorphic rhabdomyosarcoma
TP53	Orphanet:3318	Essential thrombocythemia
TP53	Orphanet:524	Li-Fraumeni syndrome
TP53	Orphanet:52688	Myelodysplastic syndrome
TP53	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
TP53	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma

Cohort genes → proteins

27 cohort genes, 27 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	3
multi_evidence	24

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	gencc,clinvar
SMO	HGNC:11119	ENSG00000128602	Q99835	Protein smoothened	gencc,civic_evidence
SUFU	HGNC:16466	ENSG00000107882	Q9UMX1	Suppressor of fused homolog	gencc,clinvar
GPR161	HGNC:23694	ENSG00000143147	Q8N6U8	G-protein coupled receptor 161	gencc,clinvar
CTNNB1	HGNC:2514	ENSG00000168036	P35222	Catenin beta-1	clinvar,civic_evidence
ELP1	HGNC:5959	ENSG00000070061	O95163	Elongator complex protein 1	gencc,clinvar
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	civic_evidence
SMOX	HGNC:15862	ENSG00000088826	Q9NWM0	Spermine oxidase	gencc
MYCN	HGNC:7559	ENSG00000134323	P04198	N-myc proto-oncogene protein	civic_evidence
PTCH1	HGNC:9585	ENSG00000185920	Q13635	Protein patched homolog 1	civic_evidence
SMARCA4	HGNC:11100	ENSG00000127616	P51532	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4	clinvar
ARID1A	HGNC:11110	ENSG00000117713	O14497	AT-rich interactive domain-containing protein 1A	clinvar
WRN	HGNC:12791	ENSG00000165392	Q14191	Bifunctional 3’-5’ exonuclease/ATP-dependent helicase WRN	clinvar
DICER1	HGNC:17098	ENSG00000100697	Q9UPY3	Endoribonuclease Dicer	clinvar
ARID1B	HGNC:18040	ENSG00000049618	Q8NFD5	AT-rich interactive domain-containing protein 1B	clinvar
DDX3X	HGNC:2745	ENSG00000215301	O00571	ATP-dependent RNA helicase DDX3X	clinvar
FOXO3	HGNC:3821	ENSG00000118689	O43524	Forkhead box protein O3	clinvar
ARL3	HGNC:694	ENSG00000138175	P36405	ADP-ribosylation factor-like protein 3	clinvar
MUTYH	HGNC:7527	ENSG00000132781	Q9UIF7	Adenine DNA glycosylase	clinvar
NONO	HGNC:7871	ENSG00000147140	Q15233	Non-POU domain-containing octamer-binding protein	clinvar
PRKAR1A	HGNC:9388	ENSG00000108946	P10644	cAMP-dependent protein kinase type I-alpha regulatory subunit	clinvar
MAGI1	HGNC:946	ENSG00000151276	Q96QZ7	Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1	clinvar
BAP1	HGNC:950	ENSG00000163930	Q92560	Ubiquitin carboxyl-terminal hydrolase BAP1	clinvar
PTCH2	HGNC:9586	ENSG00000117425	Q9Y6C5	Protein patched homolog 2	clinvar
RAD50	HGNC:9816	ENSG00000113522	Q92878	DNA repair protein RAD50	clinvar
RB1	HGNC:9884	ENSG00000139687	P06400	Retinoblastoma-associated protein	clinvar
RET	HGNC:9967	ENSG00000165731	P07949	Proto-oncogene tyrosine-protein kinase receptor Ret	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BRCA2	Breast cancer type 2 susceptibility protein	Involved in double-strand break repair and/or homologous recombination.
SMO	Protein smoothened	G protein-coupled receptor which associates with the patched protein (PTCH) to transduce hedgehog protein signaling.
SUFU	Suppressor of fused homolog	Negative regulator in the hedgehog/smoothened signaling pathway.
GPR161	G-protein coupled receptor 161	Key negative regulator of Shh signaling, which promotes the processing of GLI3 into GLI3R during neural tube development.
CTNNB1	Catenin beta-1	Key downstream component of the canonical Wnt signaling pathway.
ELP1	Elongator complex protein 1	Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine).
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
SMOX	Spermine oxidase	Flavoenzyme which catalyzes the oxidation of spermine to spermidine.
MYCN	N-myc proto-oncogene protein	Positively regulates the transcription of MYCNOS in neuroblastoma cells.
PTCH1	Protein patched homolog 1	Acts as a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH).
SMARCA4	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4	ATPase involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
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).
WRN	Bifunctional 3’-5’ exonuclease/ATP-dependent helicase WRN	Multifunctional enzyme that has magnesium and ATP-dependent 3’-5’ DNA-helicase activity on partially duplex substrates.
DICER1	Endoribonuclease Dicer	Double-stranded RNA (dsRNA) endoribonuclease playing a central role in short dsRNA-mediated post-transcriptional gene silencing.
ARID1B	AT-rich interactive domain-containing protein 1B	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
DDX3X	ATP-dependent RNA helicase DDX3X	Multifunctional ATP-dependent RNA helicase.
FOXO3	Forkhead box protein O3	Transcriptional activator that recognizes and binds to the DNA sequence 5’-[AG]TAAA[TC]A-3’ and regulates different processes, such as apoptosis and autophagy.
ARL3	ADP-ribosylation factor-like protein 3	Small GTP-binding protein which cycles between an inactive GDP-bound and an active GTP-bound form, and the rate of cycling is regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP).
MUTYH	Adenine DNA glycosylase	Involved in oxidative DNA damage repair.
NONO	Non-POU domain-containing octamer-binding protein	DNA- and RNA binding protein, involved in several nuclear processes.
PRKAR1A	cAMP-dependent protein kinase type I-alpha regulatory subunit	Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells.
MAGI1	Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1	Plays a role in coupling actin fibers to cell junctions in endothelial cells, via its interaction with AMOTL2 and CDH5.
BAP1	Ubiquitin carboxyl-terminal hydrolase BAP1	Deubiquitinating enzyme that plays a key role in chromatin by mediating deubiquitination of histone H2A and HCFC1.
PTCH2	Protein patched homolog 2	Plays a role in the control of cellular growth.
RAD50	DNA repair protein RAD50	Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis.
RB1	Retinoblastoma-associated protein	Tumor suppressor that is a key regulator of the G1/S transition of the cell cycle.
RET	Proto-oncogene tyrosine-protein kinase receptor Ret	Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN,…

Protein-family classification

Druggable: 9 · Difficult: 4 · Unknown: 14 · 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
Kinase	2	2.0×	0.728
Enzyme (other)	4	1.8×	0.728
GPCR	2	1.8×	0.728
Protease	1	1.4×	0.800
Other/Unknown	14	0.9×	0.800
Transcription factor	3	0.9×	0.800
Scaffold/PPI	1	0.6×	0.800

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
SMO	GPCR	yes		Frizzled/Smoothened_7TM, Frizzled/SFRP, GPCR_2-like_7TM
SUFU	Other/Unknown	no		Suppressor_of_fused, Suppressor_of_fused_euk, SUFU-like_domain
GPR161	GPCR	yes		GPCR_Rhodpsn, GPCR_Rhodpsn_7TM
CTNNB1	Other/Unknown	no		Armadillo, ARM-like, Beta-catenin
ELP1	Scaffold/PPI	no		Elp1, WD40/YVTN_repeat-like_dom_sf, Beta-prop_ELP1_1st
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
SMOX	Enzyme (other)	yes	1.5.3.16	Amino_oxidase, FAD/NAD-bd_sf, Flavin_monoamine_oxidase
MYCN	Transcription factor	no		Tscrpt_reg_Myc, bHLH_dom, Tscrpt_reg_Myc_N
PTCH1	Other/Unknown	no		SSD, TM_rcpt_patched, HMGCR/SNAP/NPC1-like_SSD
SMARCA4	Other/Unknown	no		SNF2_N, Bromodomain, Helicase_C-like
ARID1A	Other/Unknown	no		ARID_dom, ARM-like, ARM-type_fold
WRN	Enzyme (other)	yes	3.6.4.12	Helicase_C-like, HRDC_dom, 3’-5’_exonuclease_dom
DICER1	Enzyme (other)	yes	3.1.26.3	RNase_III_dom, Helicase_C-like, PAZ_dom
ARID1B	Other/Unknown	no		ARID_dom, BAF250/Osa, BAF250_C
DDX3X	Enzyme (other)	yes	3.6.4.13	RNA-helicase_DEAD-box_CS, Helicase_C-like, DEAD/DEAH_box_helicase_dom
FOXO3	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_2, FOXO-TAD
ARL3	Other/Unknown	no		Small_GTP-bd, Small_GTPase_ARF/SAR, P-loop_NTPase
MUTYH	Other/Unknown	no		NUDIX_hydrolase_dom, HhH_motif, HhH-GPD_domain
NONO	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, NOPS
PRKAR1A	Other/Unknown	no		cNMP-bd_dom, cAMP_dep_PK_reg_su_I/II_a/b, cAMP_dep_PK_reg_su
MAGI1	Kinase	yes		WW_dom, PDZ, Guanylate_kin-like_dom
BAP1	Protease	yes	3.4.19.12	Peptidase_C12_UCH, Peptidase_C12_UCH_sf, Papain-like_cys_pep_sf
PTCH2	Other/Unknown	no		SSD, TM_rcpt_patched, HMGCR/SNAP/NPC1-like_SSD
RAD50	Other/Unknown	no		Rad50_eukaryotes, Zn_hook_RAD50, P-loop_NTPase
RB1	Other/Unknown	no		RB_B, RB_A, Cyclin-like_dom
RET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Cadherin-like_dom

Expression context

Cohort genes with no expression data: 0.

25 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)	27
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	7
ganglionic eminence	4
cortical plate	3
embryo	3
male germ line stem cell (sensu Vertebrata) in testis	2
secondary oocyte	2
right ovary	2
adrenal tissue	2
dorsal root ganglion	2
bone marrow cell	2
calcaneal tendon	2
sperm	2
colonic epithelium	2
sural nerve	2
choroid plexus epithelium	2
mucosa of paranasal sinus	2
corpus callosum	2
left testis	2
left ovary	1
kidney epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BRCA2	184	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
SMO	225	ubiquitous	marker	ventricular zone, left ovary, right ovary
SUFU	226	ubiquitous	yes	upper arm skin, kidney epithelium, vena cava
GPR161	266	ubiquitous	marker	cortical plate, ganglionic eminence, myometrium
CTNNB1	295	ubiquitous	marker	adrenal tissue, ventricular zone, periodontal ligament
ELP1	291	ubiquitous	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
SMOX	258	ubiquitous	marker	amygdala, lower esophagus mucosa, C1 segment of cervical spinal cord
MYCN	223	broad	yes	ventricular zone, cortical plate, embryo
PTCH1	275	ubiquitous	marker	tibia, dorsal root ganglion, trigeminal ganglion
SMARCA4	295	ubiquitous	marker	ganglionic eminence, cortical plate, cervix squamous epithelium
ARID1A	286	ubiquitous	marker	bone marrow cell, ventricular zone, embryo
WRN	252	ubiquitous	marker	calcaneal tendon, sperm, male germ cell
DICER1	295	ubiquitous	marker	cauda epididymis, caput epididymis, tongue squamous epithelium
ARID1B	256	ubiquitous	marker	bone marrow cell, colonic epithelium, sural nerve
DDX3X	294	ubiquitous	marker	choroid plexus epithelium, oocyte, sperm
FOXO3	288	ubiquitous	marker	secondary oocyte, trabecular bone tissue, cerebellar vermis
ARL3	299	ubiquitous	marker	bronchial epithelial cell, mucosa of paranasal sinus, epithelium of bronchus
MUTYH	134	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
NONO	168	ubiquitous	marker	endometrium epithelium, embryo, ganglionic eminence
PRKAR1A	295	ubiquitous	marker	mucosa of paranasal sinus, germinal epithelium of ovary, lateral nuclear group of thalamus
MAGI1	133	ubiquitous	marker	ventricular zone, sural nerve, corpus callosum
BAP1	253	ubiquitous	marker	left testis, right testis, right frontal lobe
PTCH2	162	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, left testis, right ovary
RAD50	134	ubiquitous	marker	corpus callosum, calcaneal tendon, colonic epithelium
RB1	287	ubiquitous	marker	epithelium of nasopharynx, choroid plexus epithelium, visceral pleura
RET	193	broad	marker	substantia nigra pars reticulata, dorsal root ganglion, substantia nigra pars compacta

Protein interactions among cohort

Intra-cohort edges: 28.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
CTNNB1	15,668
DICER1	8,268
SMARCA4	8,138
MYCN	7,345
DDX3X	6,454
FOXO3	4,989
BRCA2	4,839
RB1	4,374
RET	4,203

Intra-cohort edges

A	B	Sources
ARID1A	ARID1B	biogrid_interaction, string_interaction
ARID1A	SMARCA4	biogrid_interaction, intact, string_interaction
ARID1B	SMARCA4	biogrid_interaction, string_interaction
ARL3	TP53	biogrid_interaction
ARL3	WRN	biogrid_interaction
BRCA2	TP53	string_interaction
CTNNB1	DDX3X	string_interaction
CTNNB1	FOXO3	string_interaction
CTNNB1	SMARCA4	string_interaction
FOXO3	RB1	biogrid_interaction
FOXO3	TP53	string_interaction
GPR161	PRKAR1A	biogrid_interaction, intact
GPR161	PTCH1	string_interaction
GPR161	SMO	string_interaction
GPR161	SUFU	string_interaction
MUTYH	SMARCA4	intact
MYCN	NONO	biogrid_interaction
MYCN	TP53	string_interaction
PRKAR1A	PTCH2	string_interaction
PRKAR1A	RET	string_interaction
PTCH1	RET	string_interaction
PTCH1	SMO	intact, string_interaction
PTCH1	SUFU	string_interaction
PTCH2	RET	string_interaction
PTCH2	SMO	biogrid_interaction, string_interaction
PTCH2	SUFU	string_interaction
RB1	TP53	string_interaction
SMO	SUFU	string_interaction

Structural data

PDB: 25 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TP53	P04637	313
WRN	Q14191	51
CTNNB1	P35222	50
RET	P07949	34
SMARCA4	P51532	31
DICER1	Q9UPY3	21
RB1	P06400	19
DDX3X	O00571	17
PTCH1	Q13635	16
MAGI1	Q96QZ7	16
SMO	Q99835	15
BRCA2	P51587	14
SUFU	Q9UMX1	10
NONO	Q15233	9
ARID1A	O14497	7
FOXO3	O43524	7
RAD50	Q92878	6
ELP1	O95163	5
BAP1	Q92560	4
MUTYH	Q9UIF7	3
PRKAR1A	P10644	3
GPR161	Q8N6U8	2
SMOX	Q9NWM0	2
MYCN	P04198	2
ARID1B	Q8NFD5	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARL3	P36405	92.73
PTCH2	Q9Y6C5	79.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 275. Enrichment computed across 27 evidence-associated genes (25 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 25 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Hedgehog ‘off’ state	5	35.7×	6e-05	SMO, SUFU, GPR161, PRKAR1A, PTCH1
Regulation of MITF-M-dependent genes involved in pigmentation	4	42.5×	3e-04	CTNNB1, SMARCA4, ARID1A, ARID1B
Formation of the canonical BAF (cBAF) complex	3	76.1×	7e-04	SMARCA4, ARID1A, ARID1B
Impaired BRCA2 binding to PALB2	3	54.8×	8e-04	BRCA2, WRN, RAD50
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	3	54.8×	8e-04	SMARCA4, ARID1A, ARID1B
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	3	50.8×	8e-04	BRCA2, WRN, RAD50
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	3	50.8×	8e-04	BRCA2, WRN, RAD50
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	3	50.8×	8e-04	BRCA2, WRN, RAD50
Hedgehog ‘on’ state	4	25.4×	8e-04	SMO, SUFU, GPR161, PTCH1
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	3	47.3×	9e-04	BRCA2, WRN, RAD50
Homologous DNA Pairing and Strand Exchange	3	45.7×	9e-04	BRCA2, WRN, RAD50
Regulation of endogenous retroelements	3	44.2×	9e-04	SMARCA4, ARID1A, ARID1B
Impaired BRCA2 binding to RAD51	3	37.0×	0.001	BRCA2, WRN, RAD50
Resolution of D-loop Structures through Holliday Junction Intermediates	3	36.1×	0.001	BRCA2, WRN, RAD50
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	3	36.1×	0.001	SMARCA4, ARID1A, ARID1B
GLI proteins bind promoters of Hh responsive genes to promote transcription	2	130.5×	0.002	PTCH1, PTCH2
Presynaptic phase of homologous DNA pairing and strand exchange	3	32.6×	0.002	BRCA2, WRN, RAD50
Positive Regulation of CDH1 Gene Transcription	2	76.1×	0.004	ARID1A, RB1
Class B/2 (Secretin family receptors)	3	22.8×	0.004	SMO, PTCH1, PTCH2
HDR through Homologous Recombination (HRR)	3	22.8×	0.004	BRCA2, WRN, RAD50
Signaling by Hedgehog	3	22.1×	0.004	SMO, SUFU, PRKAR1A
MITF-M-dependent gene expression	3	21.8×	0.004	SMARCA4, ARID1A, ARID1B
HDR through MMEJ (alt-NHEJ)	2	70.3×	0.004	BRCA2, RAD50
Formation of Senescence-Associated Heterochromatin Foci (SAHF)	2	53.7×	0.006	TP53, RB1
RMTs methylate histone arginines	3	17.6×	0.006	SMARCA4, ARID1A, ARID1B
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	3	17.6×	0.006	TP53, BAP1, RAD50
Transcriptional regulation by RUNX1	3	17.6×	0.006	SMARCA4, ARID1A, ARID1B
Activation of SMO	2	50.8×	0.007	SMO, PTCH1
Formation of the nephric duct	2	50.8×	0.007	CTNNB1, RET
Formation of the embryonic stem cell BAF (esBAF) complex	2	48.1×	0.007	SMARCA4, ARID1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 27 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of DNA-templated transcription	10	10.3×	1e-05	BRCA2, CTNNB1, SMARCA4, ARID1A, TP53, ARID1B, FOXO3, MYCN (+2 more)
negative regulation of gene expression	7	17.9×	3e-05	SMO, CTNNB1, DICER1, DDX3X, MYCN, PRKAR1A, RB1
negative regulation of smoothened signaling pathway	4	67.5×	7e-05	SUFU, PTCH1, PTCH2, RB1
transcription initiation-coupled chromatin remodeling	4	56.7×	1e-04	SMARCA4, ARID1A, TP53, ARID1B
positive regulation of double-strand break repair	4	51.0×	1e-04	SMARCA4, ARID1A, ARID1B, RAD50
positive regulation of miRNA transcription	4	43.0×	2e-04	SMARCA4, TP53, FOXO3, MYCN
positive regulation of cell differentiation	4	39.6×	3e-04	CTNNB1, SMARCA4, ARID1A, ARID1B
dorsal/ventral neural tube patterning	3	89.2×	4e-04	SMO, SUFU, PTCH1
regulation of G0 to G1 transition	3	74.9×	6e-04	SMARCA4, ARID1A, ARID1B
double-strand break repair	4	30.1×	6e-04	BRCA2, TP53, WRN, RAD50
positive regulation of mesenchymal cell proliferation	3	66.9×	6e-04	SMO, CTNNB1, MYCN
regulation of nucleotide-excision repair	3	66.9×	6e-04	SMARCA4, ARID1A, ARID1B
negative regulation of transcription by RNA polymerase II	9	5.9×	6e-04	SMO, SUFU, CTNNB1, SMARCA4, TP53, DICER1, FOXO3, PTCH1 (+1 more)
regulation of mitotic metaphase/anaphase transition	3	55.1×	1e-03	SMARCA4, ARID1A, ARID1B
epidermal cell fate specification	2	249.7×	0.001	PTCH1, PTCH2
positive regulation of T cell differentiation	3	50.6×	0.001	SMARCA4, ARID1A, ARID1B
in utero embryonic development	5	13.3×	0.001	SMO, CTNNB1, TP53, BAP1, PTCH1
negative regulation of cell growth	4	21.3×	0.001	SMARCA4, TP53, DDX3X, RB1
neuroblast proliferation	3	40.7×	0.002	SMO, CTNNB1, TP53
positive regulation of myoblast differentiation	3	40.7×	0.002	SMARCA4, ARID1A, ARID1B
positive regulation of gene expression	6	8.6×	0.002	SMO, CTNNB1, TP53, DDX3X, MYCN, RET
DNA damage response, signal transduction by p53 class mediator	3	39.8×	0.002	BRCA2, TP53, FOXO3
positive regulation of epidermal cell differentiation	2	156.0×	0.002	PTCH1, PTCH2
epithelial cell proliferation	3	34.7×	0.002	SMO, MYCN, RB1
stem cell proliferation	3	34.7×	0.002	CTNNB1, TP53, PTCH1
regulation of G1/S transition of mitotic cell cycle	3	34.0×	0.002	SMARCA4, ARID1A, ARID1B
cellular senescence	3	32.9×	0.002	BRCA2, TP53, WRN
response to UV-C	2	124.8×	0.002	BRCA2, WRN
negative regulation of glial cell proliferation	2	124.8×	0.002	TP53, RB1
positive regulation of neuron apoptotic process	3	30.2×	0.003	CTNNB1, TP53, FOXO3

Therapeutics

Drugs indicated for this disease

1 approved, 9 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Carmustine	Approved (phase 4)
Carboplatin	Phase 3 (in late-stage trials)
Cisplatin	Phase 3 (in late-stage trials)
Etoposide	Phase 3 (in late-stage trials)
Filgrastim	Phase 3 (in late-stage trials)
Isotretinoin	Phase 3 (in late-stage trials)
Lomustine	Phase 3 (in late-stage trials)
Methotrexate	Phase 3 (in late-stage trials)
Thiotepa	Phase 3 (in late-stage trials)
Vincristine	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Bevacizumab, Celecoxib, Cytarabine, Etoposide Phosphate, Fenofibric Acid, Gemcitabine, Irinotecan, Melphalan, Ornithine, Pegfilgrastim, Pemetrexed, Pomalidomide, Rivoceranib, Sonidegib, Temozolomide, Thalidomide, Tipifarnib, Topotecan, Trofosfamide, Vismodegib.

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 6 · Phased (≥1): 9 · Undrugged: 18

Druggability breadth: 23 of 27 evidence-associated genes (85%) 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
SMO	INFIGRATINIB
CTNNB1	DITHIAZANINE IODIDE
TP53	NITROFURANTOIN
WRN	INDIGOTINDISULFONATE
DDX3X	IMATINIB
RET	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
RET	135	4
SMO	11	4
CTNNB1	4	4
SMARCA4	2	2
WRN	2	4
DDX3X	1	4
RAD50	1	2
RB1	1	2
BRCA2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
INFIGRATINIB	4	RET, SMO
SONIDEGIB	4	SMO
SONIDEGIB PHOSPHATE	4	SMO
VISMODEGIB	4	SMO
DITHIAZANINE IODIDE	4	CTNNB1
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 6.

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

Symbol	Assays	Type breakdown
RET	1,586	Binding:1573, Functional:10, ADMET:3
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
CTNNB1	361	Binding:358, Functional:3
SMARCA4	230	Binding:207, ADMET:12, Functional:11
SMO	131	Binding:111, Functional:20
RB1	59	Binding:59
WRN	32	Binding:30, Functional:2
DDX3X	32	Binding:31, ADMET:1
FOXO3	19	Binding:19
SMOX	18	Binding:15, ADMET:3
MYCN	11	Binding:11
DICER1	8	Binding:8
NONO	7	Binding:7
RAD50	7	Binding:7
ARID1A	6	Binding:6
BAP1	5	Binding:4, Functional:1
PTCH1	4	Binding:4
MAGI1	4	Binding:4
GPR161	2	Binding:2
PRKAR1A	2	Binding:2
SUFU	1	Binding:1
ELP1	1	Binding:1
MUTYH	1	Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SMOX	1.5.3.16	spermine oxidase
WRN	3.6.4.12	DNA helicase
DICER1	3.1.26.3	ribonuclease III
DDX3X	3.6.4.13	RNA helicase
BAP1	3.4.19.12	ubiquitinyl hydrolase 1
RET	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SMO	131
CTNNB1	361
TP53	869
SMARCA4	230
RET	1,586

Pharmacogenomics

Cohort genes with a PharmGKB record: 27; 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)
INFIGRATINIB	4	RET, SMO
SONIDEGIB PHOSPHATE	4	SMO
DITHIAZANINE IODIDE	4	CTNNB1
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	6	SMO, CTNNB1, TP53, WRN, DDX3X, RET
B	Phased (≥1) drug, not yet approved	3	SMARCA4, RAD50, RB1
C	Druggable family + PDB, no drug	5	GPR161, SMOX, DICER1, MAGI1, BAP1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	13	BRCA2, SUFU, ELP1, MYCN, PTCH1, ARID1A, ARID1B, FOXO3, ARL3, MUTYH (+3 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SUFU	1	SMO
GPR161	2	SMO
PTCH1	4	SMO
ARID1A	6	SMARCA4
ARID1B	0	SMARCA4
FOXO3	19	CTNNB1
BRCA2	0	—
ELP1	1	—
SMOX	18	—
MYCN	11	—
DICER1	8	—
ARL3	0	—
MUTYH	1	—
NONO	7	—
PRKAR1A	2	—
MAGI1	4	—
BAP1	5	—
PTCH2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 144.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	49
PHASE1	44
Not specified	23
PHASE1/PHASE2	15
PHASE3	5
EARLY_PHASE1	5
PHASE4	2
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02875314	PHASE4	ACTIVE_NOT_RECRUITING	HeadStart4: Newly Diagnosed Children (<10 y/o) With Medulloblastoma and Other CNS Embryonal Tumors
NCT04081701	PHASE4	RECRUITING	68-Ga DOTATATE PET/MRI in the Diagnosis and Management of Somatostatin Receptor Positive CNS Tumors.
NCT00392327	PHASE3	ACTIVE_NOT_RECRUITING	Chemotherapy and Radiation Therapy in Treating Young Patients With Newly Diagnosed, Previously Untreated, High-Risk Medulloblastoma/PNET
NCT07291102	PHASE3	NOT_YET_RECRUITING	Comparison of Neurocognitive Outcome in Two Standard Regimen for Treatment of Low-risk Medulloblastoma
NCT00085735	PHASE3	COMPLETED	Comparison of Radiation Therapy Regimens in Combination With Chemotherapy in Treating Young Patients With Newly Diagnosed Standard-Risk Medulloblastoma
NCT00336024	PHASE3	COMPLETED	Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumors or High-Risk Medulloblastoma
NCT00749723	PHASE2/PHASE3	COMPLETED	Therapy Optimization Trial for the Treatment of Relapsed or Refractory Brain Tumors in Children
NCT01351870	PHASE3	COMPLETED	Hyperfractionated Versus Conventionally Fractionated Radiotherapy in Standard Risk Medulloblastoma (PNET4)
NCT00840047	PHASE2	ACTIVE_NOT_RECRUITING	Methionine PET/CT Studies In Patients With Cancer
NCT01356290	PHASE2	RECRUITING	Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma, ATRT and Rare CNS Tumors
NCT01878617	PHASE2	ACTIVE_NOT_RECRUITING	A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma
NCT02724579	PHASE2	ACTIVE_NOT_RECRUITING	Reduced Craniospinal Radiation Therapy and Chemotherapy in Treating Younger Patients With Newly Diagnosed WNT-Driven Medulloblastoma
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)
NCT03709680	PHASE2	ACTIVE_NOT_RECRUITING	Study Of Palbociclib Combined With Chemotherapy In Pediatric Patients With Recurrent/Refractory Solid Tumors
NCT04049669	PHASE2	ACTIVE_NOT_RECRUITING	Pediatric Trial of Indoximod With Chemotherapy and Radiation for Relapsed Brain Tumors or Newly Diagnosed DIPG
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
NCT04501718	PHASE2	RECRUITING	Apatinib Combined with Temozolomide and Etoposide Capsules in the Treatment of Recurrent Medulloblastoma in Children
NCT04696029	PHASE2	RECRUITING	DFMO as Maintenance Therapy for Molecular High/Very High Risk and Relapsed Medulloblastoma
NCT04743661	PHASE2	ACTIVE_NOT_RECRUITING	131I-Omburtamab, in Recurrent Medulloblastoma and Ependymoma
NCT05096481	PHASE2	RECRUITING	PEP-CMV Vaccine Targeting CMV Antigen to Treat Newly Diagnosed Pediatric HGG and DIPG and Recurrent Medulloblastoma
NCT05128903	PHASE2	ACTIVE_NOT_RECRUITING	Quantitative Assessment of Radiation-induced Neuroinflammation - A Proof of Principle Study
NCT05278208	PHASE1/PHASE2	RECRUITING	Lutathera for Treatment of Recurrent or Progressive High-Grade CNS Tumors
NCT05535166	PHASE2	RECRUITING	Molecular and Clinical Risk-Directed Therapy for Infants and Young Children With Newly Diagnosed Medulloblastoma
NCT06161519	PHASE1/PHASE2	RECRUITING	PLX038 in Primary Central Nervous System Tumors Containing MYC or MYCN Amplifications
NCT06485908	PHASE1/PHASE2	NOT_YET_RECRUITING	Axitinib and Oral Metronomic Etoposide for Pediatric Children and AYA Refractory/Relapsing Medulloblastoma and Ependymoma
NCT06607692	PHASE1/PHASE2	RECRUITING	Study in Children and Adolescents of 177Lu-DOTATATE (Lutathera®) Combined With the PARP Inhibitor Olaparib for the Treatment of Recurrent or Relapsed Solid Tumours Expressing Somatostatin Receptor (SSTR) (LuPARPed).
NCT06639607	PHASE1/PHASE2	NOT_YET_RECRUITING	PEP-CMV + Nivolumab for Newly Diagnosed Diffuse Midline Glioma/High-grade Glioma and Recurrent Diffuse Midline Glioma/High-grade Glioma, Medulloblastoma, and Ependymoma
NCT06701812	PHASE2	RECRUITING	Digoxin Medulloblastoma Study
NCT06804655	PHASE2	NOT_YET_RECRUITING	Pharmacoscopy for Patients With Refractory Primary Brain Tumors
NCT07346157	PHASE1/PHASE2	NOT_YET_RECRUITING	Liothyronine in Combination With BIT Regimen for Medulloblastoma With or Without Minimal Residual Disease
NCT00031590	PHASE2	TERMINATED	Low-Dose Radiation and Combination Chemotherapy Following Surgery in Children With Newly Diagnosed Medulloblastoma
NCT00180791	PHASE2	UNKNOWN	High Risk Primitive Neuroectodermal (PNET) Brain Tumors in Childhood
NCT00180947	PHASE2	UNKNOWN	Study of Vinorelbine and Cyclofosfamide Among Patients With Refractory Tumours or in Relapse
NCT00404495	PHASE2	COMPLETED	Combination of Irinotecan and Temozolomide in Children With Brain Tumors.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CISPLATIN	4	11
LOMUSTINE	4	6
SONIDEGIB	4	6
EDOTREOTIDE GALLIUM GA-68	4	3
THIOTEPA	4	3
ETOPOSIDE PHOSPHATE	4	2
ISOTRETINOIN	4	2
TIPIRACIL HYDROCHLORIDE	4	2
FENOFIBRIC ACID	4	1
LEUCOVORIN	4	1
MANNITOL	4	1
NIFURTIMOX	4	1
SODIUM THIOSULFATE	4	1
SORBITOL	4	1
TEMOZOLOMIDE	4	1
VINCRISTINE	4	1
VINORELBINE	4	1
VISMODEGIB	4	1
METHIONINE	3	1
TROFOSFAMIDE	3	1
CHEMBL4228794	0	1
CHEMBL4248195	0	1
CHEMBL1486475	0	1
CHEMBL1234268	0	1
CHEMBL3753202	0	1
CARBOPLATINE	0	1
RACEMETHIONINE	-1	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 8 predictive associations from 9 curated evidence items; also 5 prognostic.

Molecular subtype	Therapy	Effect	Level	CIViC
PTCH1 LOH	Vismodegib	Sensitivity/Response	CIViC B	EID749
PTCH1 Mutation	Sonidegib	Sensitivity/Response	CIViC B	EID748
SMO D473H	Vismodegib	Resistance	CIViC C	EID745 +1
MYCN Amplification	Arsenic Trioxide	Sensitivity/Response	CIViC D	EID5327
PTCH1 Deletion	Sonidegib	Sensitivity/Response	CIViC D	EID5326
SMO D473H	Patidegib	Sensitivity/Response	CIViC D	EID1099
MYCN Amplification	Sonidegib	Resistance	CIViC D	EID5325
SUFU Deletion	Sonidegib	Resistance	CIViC D	EID5324