Retinoblastoma

Summary

Retinoblastoma (MONDO:0008380) is a disease (an umbrella term covering 7 Mondo subtypes) caused by RB1 (GenCC Definitive), with 11 cohort genes and 106 clinical trials. The dominant Reactome pathway is Cyclin E associated events during G1/S transition (3 cohort genes). Top therapeutic interventions include topotecan, 2-mercaptoethanesulfonic acid, and thiotepa.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: RB1 (GenCC Definitive)
• Umbrella term: 7 Mondo subtypes
• Cohort genes: 11
• ClinVar variants: 3,627
• Phenotypes (HPO): 27
• Clinical trials: 106

Clinical features

Epidemiology

Prevalence records

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

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	6	Worldwide	Validated
Annual incidence	<1 / 1 000 000	0.05	Europe	Validated
Lifetime Prevalence	1-9 / 100 000	1.05	Europe	Validated
Annual incidence	<1 / 1 000 000	0.018	Austria	Validated
Annual incidence	<1 / 1 000 000	0.073	Belgium	Validated
Annual incidence	<1 / 1 000 000	0.035	Bulgaria	Validated
Annual incidence	<1 / 1 000 000	0.04	Croatia	Validated
Annual incidence	<1 / 1 000 000	0.018	Estonia	Validated
Annual incidence	<1 / 1 000 000	0.053	Finland	Validated
Annual incidence	<1 / 1 000 000	0.033	Germany	Validated
Annual incidence	<1 / 1 000 000	0.043	Iceland	Validated
Annual incidence	<1 / 1 000 000	0.071	Ireland	Validated
Annual incidence	<1 / 1 000 000	0.045	Italy	Validated
Annual incidence	<1 / 1 000 000	0.016	Latvia	Validated
Annual incidence	<1 / 1 000 000	0.017	Lithuania	Validated
Annual incidence	<1 / 1 000 000	0.094	Malta	Validated
Annual incidence	<1 / 1 000 000	0.071	Norway	Validated
Annual incidence	<1 / 1 000 000	0.038	Poland	Validated
Annual incidence	<1 / 1 000 000	0.047	Portugal	Validated
Annual incidence	<1 / 1 000 000	0.042	Slovakia	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0009919	Retinoblastoma	Obligate (100%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000501	Glaucoma	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0000555	Leukocoria	Frequent (30-79%)
HP:0031615	Hypopyon	Frequent (30-79%)
HP:0000554	Uveitis	Occasional (5-29%)
HP:0001100	Heterochromia iridis	Occasional (5-29%)
HP:0001909	Leukemia	Occasional (5-29%)
HP:0002665	Lymphoma	Occasional (5-29%)
HP:0002669	Osteosarcoma	Occasional (5-29%)
HP:0002859	Rhabdomyosarcoma	Occasional (5-29%)
HP:0002861	Melanoma	Occasional (5-29%)
HP:0007663	Reduced visual acuity	Occasional (5-29%)
HP:0007703	Abnormality of retinal pigmentation	Occasional (5-29%)
HP:0007862	Retinal calcification	Occasional (5-29%)
HP:0007902	Vitreous hemorrhage	Occasional (5-29%)
HP:0011886	Hyphema	Occasional (5-29%)
HP:0012372	Abnormal eye morphology	Occasional (5-29%)
HP:0025244	Subretinal pigment epithelium hemorrhage	Occasional (5-29%)
HP:0025337	Red eye	Occasional (5-29%)
HP:0100243	Leiomyosarcoma	Occasional (5-29%)
HP:0100658	Cellulitis	Occasional (5-29%)
HP:0000175	Cleft palate	Very rare (<1-4%)
HP:0009733	Glioma	Very rare (<1-4%)
HP:0012254	Ewing sarcoma	Very rare (<1-4%)
HP:0030408	Pineoblastoma	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	retinoblastoma
Mondo ID	MONDO:0008380
MeSH	D012175
Orphanet	790
DOID	DOID:768
ICD-11	1855353671
NCIT	C7541
SNOMED CT	370967009
UMLS	C0035335
MedGen	20552
GARD	0007563
MedDRA	10038916
Anatomy (UBERON)	UBERON:0003902
Is cancer (heuristic)	no

Also known as: eye cancer, retinoblastoma · RB · RB1 · retinoblastoma · retinoblastoma, malignant

Data availability: 3,627 ClinVar variants · 1 GenCC gene-disease record · 193 cell lines · 1 intOGen driver record.

Disease family

An umbrella term covering 7 Mondo subtypes.

Classification path: disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › cancer › nervous system cancer › sensory system cancer › ocular cancer › retinal cancer › retinal cell cancer › retinoblastoma

Subtypes (7): trilateral retinoblastoma, bilateral retinoblastoma, unilateral retinoblastoma, intraocular retinoblastoma, extraocular retinoblastoma, hereditary retinoblastoma, non-hereditary retinoblastoma

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:

250 uncertain significance, 165 pathogenic, 123 likely benign, 26 conflicting classifications of pathogenicity, 15 pathogenic/likely pathogenic, 11 likely pathogenic, 7 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1074926	NC_000013.10:g.(?48611883)(48939117_?)del	ITM2B	Pathogenic	criteria provided, single submitter
1459011	NC_000013.10:g.(?48611883)(48878195_?)del	ITM2B	Pathogenic	criteria provided, single submitter
1070856	NC_000013.10:g.(?48877851)(49054207_?)del	LPAR6	Pathogenic	criteria provided, single submitter
1071014	NC_000013.10:g.(?48985727)(49039514_?)dup	LPAR6	Pathogenic	criteria provided, single submitter
100808	NM_000321.3(RB1):c.1960G>A (p.Val654Met)	RB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1037460	NM_000321.3(RB1):c.1589A>G (p.Lys530Arg)	RB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1064435	NM_000321.3(RB1):c.1050-8_1050-2del	RB1	Pathogenic	criteria provided, single submitter
1066671	NM_000321.3(RB1):c.939G>A (p.Glu313=)	RB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068590	NM_000321.3(RB1):c.1049+2T>A	RB1	Pathogenic	criteria provided, single submitter
1068629	NM_000321.3(RB1):c.566T>A (p.Leu189Ter)	RB1	Pathogenic	criteria provided, single submitter
1069184	NM_000321.3(RB1):c.1937_1940del (p.Ser646fs)	RB1	Pathogenic	criteria provided, single submitter
1069198	NM_000321.3(RB1):c.1166dup (p.Leu389fs)	RB1	Pathogenic	criteria provided, single submitter
1069207	NM_000321.3(RB1):c.1237G>T (p.Glu413Ter)	RB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1069507	NM_000321.3(RB1):c.2236G>T (p.Glu746Ter)	RB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070129	NM_000321.3(RB1):c.1519_1523dup (p.Gly509fs)	RB1	Pathogenic	criteria provided, single submitter
1070330	NM_000321.3(RB1):c.43_80del (p.Ala15fs)	RB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070857	NC_000013.10:g.(?48947531)(48947691_?)del	RB1	Pathogenic	criteria provided, single submitter
1071013	NC_000013.10:g.(?48937921)(48942750_?)del	RB1	Pathogenic	criteria provided, single submitter
1071015	NC_000013.10:g.(?48881406)(48955589_?)dup	RB1	Pathogenic	criteria provided, single submitter
1071048	NM_000321.3(RB1):c.399del (p.Leu134fs)	RB1	Pathogenic	criteria provided, single submitter
1071423	NM_000321.3(RB1):c.1281del (p.Glu428fs)	RB1	Pathogenic	criteria provided, single submitter
1071424	NM_000321.3(RB1):c.1597G>T (p.Glu533Ter)	RB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1071425	NM_000321.3(RB1):c.1332G>A (p.Gln444=)	RB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1071426	NM_000321.3(RB1):c.1422-2A>G	RB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1071565	NM_000321.3(RB1):c.2520+5G>C	RB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071566	NM_000321.3(RB1):c.2536C>T (p.Gln846Ter)	RB1	Pathogenic	criteria provided, single submitter
1072961	NM_000321.3(RB1):c.100G>T (p.Glu34Ter)	RB1	Pathogenic	criteria provided, single submitter
1073217	NM_000321.3(RB1):c.19del (p.Arg7fs)	RB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073218	NM_000321.3(RB1):c.62dup (p.Ala22fs)	RB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073219	NM_000321.3(RB1):c.264+1G>T	RB1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 46 · 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
RB1	Definitive	Autosomal dominant	hereditary retinoblastoma	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RB1	Orphanet:1587	Monosomy 13q14 syndrome
RB1	Orphanet:357027	Hereditary retinoblastoma
RB1	Orphanet:357034	Non-hereditary retinoblastoma
RB1	Orphanet:668	Osteosarcoma
RB1	Orphanet:70573	Small cell lung cancer
LPAR6	Orphanet:170	Woolly hair
LPAR6	Orphanet:55654	Hypotrichosis simplex
CDKN2A	Orphanet:1333	Familial pancreatic carcinoma
CDKN2A	Orphanet:1501	Adrenocortical carcinoma
CDKN2A	Orphanet:252206	Melanoma and neural system tumor syndrome
CDKN2A	Orphanet:404560	Familial atypical multiple mole melanoma syndrome
CDKN2A	Orphanet:524	Li-Fraumeni syndrome
CDKN2A	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
CDKN2A	Orphanet:618	Familial melanoma
CDKN2A	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia
FANCM	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
FANCM	Orphanet:84	Fanconi anemia
PALB2	Orphanet:1333	Familial pancreatic carcinoma
PALB2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
PALB2	Orphanet:178	Chordoma
PALB2	Orphanet:227535	Hereditary breast cancer
PALB2	Orphanet:84	Fanconi anemia
ITM2B	Orphanet:397758	Retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies
ITM2B	Orphanet:97345	ABri amyloidosis
ITM2B	Orphanet:97346	ADan amyloidosis
MAX	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
MUTYH	Orphanet:247798	MUTYH-related polyposis
MUTYH	Orphanet:440437	Familial colorectal cancer Type X
NF1	Orphanet:139474	17q11.2 microduplication syndrome
NF1	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
NF1	Orphanet:293199	Pleomorphic rhabdomyosarcoma
NF1	Orphanet:363700	Neurofibromatosis type 1 due to NF1 mutation or intragenic deletion
NF1	Orphanet:638	Neurofibromatosis-Noonan syndrome
NF1	Orphanet:86834	Juvenile myelomonocytic leukemia
NF1	Orphanet:97685	17q11 microdeletion syndrome
NF1	Orphanet:99756	Alveolar rhabdomyosarcoma
NF1	Orphanet:99757	Embryonal rhabdomyosarcoma
PTCH1	Orphanet:220386	Semilobar holoprosencephaly
PTCH1	Orphanet:2353	Schilbach-Rott syndrome
PTCH1	Orphanet:280195	Septopreoptic holoprosencephaly
PTCH1	Orphanet:280200	Microform holoprosencephaly
PTCH1	Orphanet:377	Gorlin syndrome
PTCH1	Orphanet:77301	Monosomy 9q22.3 syndrome
PTCH1	Orphanet:93924	Lobar holoprosencephaly
PTCH1	Orphanet:93925	Alobar holoprosencephaly
PTCH1	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly

Cohort genes → proteins

11 cohort genes, 11 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	1
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RB1	HGNC:9884	ENSG00000139687	P06400	Retinoblastoma-associated protein	gencc,clinvar
CDKN1A	HGNC:1784	ENSG00000124762	P38936	Cyclin-dependent kinase inhibitor 1	civic_evidence
LPAR6	HGNC:15520	ENSG00000139679	P43657	Lysophosphatidic acid receptor 6	clinvar
CDKN2A	HGNC:1787	ENSG00000147889	P42771	Cyclin-dependent kinase inhibitor 2A	clinvar
FANCM	HGNC:23168	ENSG00000187790	Q8IYD8	Fanconi anemia group M protein	clinvar
PALB2	HGNC:26144	ENSG00000083093	Q86YC2	Partner and localizer of BRCA2	clinvar
ITM2B	HGNC:6174	ENSG00000136156	Q9Y287	Integral membrane protein 2B	clinvar
MAX	HGNC:6913	ENSG00000125952	P61244	Protein max	clinvar
MUTYH	HGNC:7527	ENSG00000132781	Q9UIF7	Adenine DNA glycosylase	clinvar
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	clinvar
PTCH1	HGNC:9585	ENSG00000185920	Q13635	Protein patched homolog 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RB1	Retinoblastoma-associated protein	Tumor suppressor that is a key regulator of the G1/S transition of the cell cycle.
CDKN1A	Cyclin-dependent kinase inhibitor 1	Plays an important role in controlling cell cycle progression and DNA damage-induced G2 arrest.
LPAR6	Lysophosphatidic acid receptor 6	Binds to oleoyl-L-alpha-lysophosphatidic acid (LPA).
CDKN2A	Cyclin-dependent kinase inhibitor 2A	Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6.
FANCM	Fanconi anemia group M protein	DNA-dependent ATPase component of the Fanconi anemia (FA) core complex.
PALB2	Partner and localizer of BRCA2	Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks.
ITM2B	Integral membrane protein 2B	Plays a regulatory role in the processing of the amyloid-beta A4 precursor protein (APP) and acts as an inhibitor of the amyloid-beta peptide aggregation and fibrils deposition.
MAX	Protein max	Transcription regulator.
MUTYH	Adenine DNA glycosylase	Involved in oxidative DNA damage repair.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.
PTCH1	Protein patched homolog 1	Acts as a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH).

Protein-family classification

Druggable: 1 · Difficult: 3 · Unknown: 7 · Druggable fraction: 0.09

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	2	3.1×	0.520
GPCR	1	2.2×	0.558
Other/Unknown	7	1.1×	0.558
Transcription factor	1	0.8×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RB1	Other/Unknown	no		RB_B, RB_A, Cyclin-like_dom
CDKN1A	Other/Unknown	no		CDI_dom, CDKN1A, CDI_dom_sf
LPAR6	GPCR	yes		GPCR_Rhodpsn, GPCR_Rhodpsn_7TM
CDKN2A	Scaffold/PPI	no		Ankyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor, Tumor_suppres_ARF
FANCM	Other/Unknown	no		Helicase_C-like, ERCC4_domain, RuvA_2-like
PALB2	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, PALB2_WD40, WD40_repeat_dom_sf
ITM2B	Other/Unknown	no		BRICHOS_dom, ITM2
MAX	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf
MUTYH	Other/Unknown	no		NUDIX_hydrolase_dom, HhH_motif, HhH-GPD_domain
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot
PTCH1	Other/Unknown	no		SSD, TM_rcpt_patched, HMGCR/SNAP/NPC1-like_SSD

Expression context

Cohort genes with no expression data: 0.

10 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)	11
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	2
choroid plexus epithelium	1
epithelium of nasopharynx	1
visceral pleura	1
mucosa of stomach	1
stromal cell of endometrium	1
vena cava	1
gingiva	1
gingival epithelium	1
lower esophagus mucosa	1
cervix squamous epithelium	1
parotid gland	1
pituitary gland	1
male germ line stem cell (sensu Vertebrata) in testis	1
sperm	1
buccal mucosa cell	1
secondary oocyte	1
germinal epithelium of ovary	1
metanephric glomerulus	1
renal glomerulus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RB1	287	ubiquitous	marker	epithelium of nasopharynx, choroid plexus epithelium, visceral pleura
CDKN1A	297	ubiquitous	marker	stromal cell of endometrium, mucosa of stomach, vena cava
LPAR6	269	ubiquitous	marker	gingival epithelium, gingiva, lower esophagus mucosa
CDKN2A	220	ubiquitous	marker	parotid gland, cervix squamous epithelium, pituitary gland
FANCM	203	ubiquitous	marker	sperm, oocyte, male germ line stem cell (sensu Vertebrata) in testis
PALB2	232	ubiquitous	yes	secondary oocyte, buccal mucosa cell, oocyte
ITM2B	295	ubiquitous	marker	renal glomerulus, metanephric glomerulus, germinal epithelium of ovary
MAX	299	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
MUTYH	134	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue
PTCH1	275	ubiquitous	marker	tibia, dorsal root ganglion, trigeminal ganglion

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDKN2A	9,311
CDKN1A	6,974
PALB2	5,641
NF1	5,540
RB1	4,374
PTCH1	3,368
FANCM	2,764
ITM2B	1,917
MUTYH	1,815
LPAR6	822

Intra-cohort edges

A	B	Sources
CDKN1A	CDKN2A	string_interaction
CDKN2A	RB1	string_interaction
FANCM	PALB2	string_interaction
ITM2B	LPAR6	string_interaction

Structural data

PDB: 11 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NF1	P21359	26
RB1	P06400	19
PTCH1	Q13635	16
CDKN1A	P38936	13
MAX	P61244	12
FANCM	Q8IYD8	7
CDKN2A	P42771	5
PALB2	Q86YC2	4
MUTYH	Q9UIF7	3
LPAR6	P43657	2
ITM2B	Q9Y287	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 151. Enrichment computed across 11 evidence-associated genes (11 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 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cyclin E associated events during G1/S transition	3	77.9×	6e-04	RB1, CDKN1A, MAX
Cyclin A:Cdk2-associated events at S phase entry	3	72.4×	6e-04	RB1, CDKN1A, MAX
Cyclin D associated events in G1	3	63.6×	6e-04	RB1, CDKN1A, CDKN2A
Mitotic G1 phase and G1/S transition	3	50.2×	9e-04	CDKN1A, CDKN2A, MAX
p53-Dependent G1 DNA Damage Response	2	129.8×	0.002	CDKN1A, CDKN2A
p53-Dependent G1/S DNA damage checkpoint	2	129.8×	0.002	CDKN1A, CDKN2A
Formation of Senescence-Associated Heterochromatin Foci (SAHF)	2	122.1×	0.002	RB1, CDKN1A
G1/S DNA Damage Checkpoints	2	122.1×	0.002	CDKN1A, CDKN2A
KEAP1-NFE2L2 pathway	3	32.8×	0.002	CDKN1A, CDKN2A, PALB2
Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)	2	115.3×	0.002	RB1, CDKN1A
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	2	103.8×	0.002	CDKN1A, CDKN2A
G1 Phase	2	71.6×	0.004	CDKN1A, CDKN2A
Oncogene Induced Senescence	2	61.1×	0.005	RB1, CDKN2A
Transcriptional activation of p53 responsive genes	1	1038.2×	0.007	CDKN1A
Defective MUTYH substrate binding	1	1038.2×	0.007	MUTYH
Defective MUTYH substrate processing	1	1038.2×	0.007	MUTYH
Evasion of Oncogene Induced Senescence Due to p14ARF Defects	1	1038.2×	0.007	CDKN2A
Evasion of Oxidative Stress Induced Senescence Due to p14ARF Defects	1	1038.2×	0.007	CDKN2A
Defective translocation of RB1 mutants to the nucleus	1	1038.2×	0.007	RB1
Transcriptional regulation by RUNX3	2	49.4×	0.007	CDKN1A, CDKN2A
G1/S Transition	2	42.4×	0.007	CDKN1A, MAX
Cell Cycle, Mitotic	3	13.1×	0.009	CDKN1A, CDKN2A, MAX
S Phase	2	33.0×	0.010	CDKN1A, MAX
MITF-M-dependent gene expression	2	33.0×	0.010	CDKN1A, CDKN2A
Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4	1	519.1×	0.011	CDKN2A
Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4	1	519.1×	0.011	CDKN2A
Defective Intrinsic Pathway for Apoptosis Due to p14ARF Loss of Function	1	519.1×	0.011	CDKN2A
Diseases of Cellular Senescence	1	346.1×	0.012	CDKN2A
Evasion of Oncogene Induced Senescence Due to p16INK4A Defects	1	346.1×	0.012	CDKN2A
Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6	1	346.1×	0.012	CDKN2A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Ras protein signal transduction	4	74.7×	5e-05	RB1, CDKN1A, CDKN2A, NF1
keratinocyte proliferation	3	158.5×	1e-04	CDKN1A, CDKN2A, PTCH1
oncogene-induced cell senescence	2	437.7×	8e-04	CDKN1A, CDKN2A
smooth muscle tissue development	2	191.5×	0.003	NF1, PTCH1
replicative senescence	2	180.2×	0.003	CDKN1A, CDKN2A
negative regulation of cell growth	3	39.3×	0.003	RB1, CDKN1A, CDKN2A
negative regulation of cell-matrix adhesion	2	161.3×	0.003	CDKN2A, NF1
negative regulation of stem cell proliferation	2	153.2×	0.003	NF1, PTCH1
embryonic organ development	2	87.5×	0.007	PALB2, PTCH1
negative regulation of smoothened signaling pathway	2	82.8×	0.007	RB1, PTCH1
fibroblast proliferation	2	71.3×	0.009	CDKN1A, NF1
regulation of cell cycle	3	20.3×	0.009	RB1, CDKN1A, CDKN2A
negative regulation of G1/S transition of mitotic cell cycle	2	65.2×	0.009	RB1, CDKN1A
positive regulation of mast cell apoptotic process	1	1532.0×	0.010	NF1
regulation of glial cell differentiation	1	1532.0×	0.010	NF1
observational learning	1	1532.0×	0.010	NF1
stem cell proliferation	2	56.7×	0.010	NF1, PTCH1
regulation of G1/S transition of mitotic cell cycle	2	55.7×	0.010	CDKN1A, CDKN2A
cellular senescence	2	53.8×	0.010	CDKN1A, CDKN2A
keratinocyte differentiation	2	45.1×	0.012	CDKN1A, CDKN2A
regulation of mitotic cell cycle	2	43.8×	0.013	RB1, PTCH1
response to chlorate	1	766.0×	0.013	PTCH1
neural plate axis specification	1	766.0×	0.013	PTCH1
nuclear body organization	1	766.0×	0.013	CDKN2A
gamma-aminobutyric acid secretion, neurotransmission	1	766.0×	0.013	NF1
cell proliferation involved in metanephros development	1	766.0×	0.013	PTCH1
negative regulation of cardiac muscle tissue regeneration	1	766.0×	0.013	CDKN1A
Schwann cell proliferation	1	510.7×	0.013	NF1
forebrain astrocyte development	1	510.7×	0.013	NF1
sister chromatid biorientation	1	510.7×	0.013	RB1

Therapeutics

Drugs indicated for this disease

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

Drug	Development status
Carboplatin	Phase 3 (in late-stage trials)
Cisplatin	Phase 3 (in late-stage trials)
Doxorubicin	Phase 3 (in late-stage trials)
Etoposide	Phase 3 (in late-stage trials)
Filgrastim	Phase 3 (in late-stage trials)
Melphalan	Phase 3 (in late-stage trials)
Thiotepa	Phase 3 (in late-stage trials)
Topotecan	Phase 3 (in late-stage trials)
Vincristine	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Conbercept, Cyclosporine, Pegfilgrastim, Ranibizumab, Temozolomide.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 10

Druggability breadth: 7 of 11 evidence-associated genes (64%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RB1	1	2
CDKN1A	0	0
LPAR6	0	0
CDKN2A	0	0
FANCM	0	0
PALB2	0	0
ITM2B	0	0
MAX	0	0
MUTYH	0	0
NF1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EBVACICLIB	2	RB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MAX	97	Binding:97
RB1	59	Binding:59
CDKN1A	16	Binding:8, Functional:8
LPAR6	5	Binding:4, Functional:1
PTCH1	4	Binding:4
CDKN2A	2	Binding:2
MUTYH	1	Functional:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 11; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
EBVACICLIB	2	RB1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	RB1
C	Druggable family + PDB, no drug	1	LPAR6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	9	CDKN1A, CDKN2A, FANCM, PALB2, ITM2B, MAX, MUTYH, NF1, PTCH1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CDKN1A	16	—
LPAR6	5	—
CDKN2A	2	—
FANCM	0	—
PALB2	0	—
ITM2B	0	—
MAX	97	—
MUTYH	1	—
NF1	0	—
PTCH1	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 106.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	46
PHASE2	25
PHASE1	20
PHASE3	6
PHASE4	3
EARLY_PHASE1	3
PHASE1/PHASE2	2
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00336531	PHASE4	COMPLETED	Efficacy of Prophylactic Itraconazole in High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation
NCT02319486	PHASE4	COMPLETED	CEV With/Without Periocular Carboplatin Chemotherapy for Extraocular Retinoblastoma
NCT02933333	PHASE4	UNKNOWN	G-CSF Alone or Combination With GM-CSF on Prevention and Treatment of Infection in Children With Malignant Tumor
NCT04681417	PHASE2/PHASE3	RECRUITING	Ocular Conservative Treatment for Retinoblastoma : Efficacy of the New Management Strategies and Visual Outcome
NCT04799002	PHASE3	RECRUITING	Topotecan and Melphalan for Retinoblastoma
NCT05080010	PHASE3	RECRUITING	Adjuvant Chemotherapy for High-risk Postenucleation Retinoblastoma
NCT00186888	PHASE3	COMPLETED	Study of Treatment for Patients With Cancer of the Eye -Retinoblastoma
NCT01906814	PHASE3	UNKNOWN	Adjuvant Chemotherapy for High-risk Retinoblastoma After Enucleation
NCT01987596	PHASE3	TERMINATED	Study of Fixed vs. Flexible Filgrastim to Accelerate Bone Marrow Recovery After Chemotherapy in Children With Cancer
NCT02137928	PHASE3	UNKNOWN	Carboplatin Periocular Injection for Retinoblastoma
NCT01783535	PHASE2	ACTIVE_NOT_RECRUITING	Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma
NCT02866136	PHASE2	ACTIVE_NOT_RECRUITING	Conservative Treatments of Retinoblastoma
NCT02870907	PHASE2	ACTIVE_NOT_RECRUITING	Adjuvant Treatment in Extensive Unilateral Retinoblastoma Primary Enucleated (RB SFCE 2009)
NCT05504291	PHASE2	RECRUITING	A Study to Give Treatment Inside the Eye to Treat Retinoblastoma
NCT06679634	PHASE2	RECRUITING	Retinoblastoma Phase II Expanded Access Clinical Trial
NCT00002515	PHASE2	COMPLETED	Combination Chemotherapy Followed by Bone Marrow Transplantation in Treating Patients With Rare Cancer
NCT00002675	PHASE2	COMPLETED	Chemotherapy in Treating Patients With Retinoblastoma
NCT00002794	PHASE2	COMPLETED	Carboplatin Plus Vincristine in Treating Children With Retinoblastoma
NCT00003173	PHASE2	COMPLETED	High-Dose Thiotepa Plus Peripheral Stem Cell Transplantation in Treating Patients With Refractory Solid Tumors
NCT00003273	PHASE2	WITHDRAWN	Chemotherapy Followed by Peripheral Stem Cell Transplantation in Treating Children With Newly Diagnosed Brain Tumor
NCT00004006	PHASE2	COMPLETED	Combination Chemotherapy, Radiation Therapy, and Bone Marrow Transplantation in Treating Patients With Retinoblastoma
NCT00006102	PHASE2	COMPLETED	Rebeccamycin Analogue in Treating Children With Solid Tumors or Non-Hodgkin’s Lymphoma
NCT00024258	PHASE2	COMPLETED	Arsenic Trioxide in Treating Patients With Advanced Neuroblastoma or Other Childhood Solid Tumors
NCT00110110	PHASE2	UNKNOWN	Combination Chemotherapy and Cyclosporine Followed by Focal Therapy for Bilateral Retinoblastoma
NCT00179920	PHASE2	COMPLETED	Chemotherapy Treatment for Children With Intraocular Germ-Line Retinoblastoma
NCT00432445	PHASE2	TERMINATED	Proton Beam Radiation Therapy for Intraocular and Periocular Retinoblastoma
NCT00445965	PHASE2	COMPLETED	Iodine I 131 Monoclonal Antibody 3F8 in Treating Patients With Central Nervous System Cancer or Leptomeningeal Cancer
NCT00831844	PHASE2	COMPLETED	Cixutumumab in Treating Patients With Relapsed or Refractory Solid Tumors
NCT00901238	PHASE1/PHASE2	COMPLETED	Intra-arterial Chemotherapy(Chemosurgery) for Retinoblastoma
NCT00906113	PHASE1/PHASE2	UNKNOWN	Intra-arterial Chemotherapy for Children With Retinoblastoma
NCT01151748	PHASE2	WITHDRAWN	Intra-arterial Chemotherapy for Advanced Intraocular Retinoblastoma
NCT01293539	PHASE2	TERMINATED	Intra-arterial Chemotherapy for the Treatment of Intraocular Retinoblastoma
NCT01393769	PHASE2	TERMINATED	Intra-arterial Chemotherapy With Melphalan for the Treatment of Retinoblastoma (RTB) in Advanced Intraocular Stage
NCT01857752	PHASE2	TERMINATED	Phase II Study Temozolomide for Retinoblastoma Metastatic to the Central Nervous System for Patients From Guatemala
NCT01899066	PHASE2	UNKNOWN	Efficacy Study of Lucentis in the Treatment of Retinoblastoma
NCT04455139	PHASE2	TERMINATED	A Prospective International Multicenter Clinical Trial for Eyes With Relapsed Retinoblastoma
NCT04990271	PHASE2	UNKNOWN	A Clinical Study on the Efficacy and Safety of VEC Intravenous Chemotherapy Combined With Conbercept Intravitreal Injection in the Treatment of Retinoblastoma
NCT03618381	PHASE1	ACTIVE_NOT_RECRUITING	EGFR806 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults
NCT04483778	PHASE1	ACTIVE_NOT_RECRUITING	B7H3 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults
NCT05650749	PHASE1	RECRUITING	GPC2 CAR T Cells for Relapsed or Refractory Neuroblastoma and Metastatic Retinoblastoma

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TOPOTECAN	4	5
2-MERCAPTOETHANESULFONIC ACID	4	4
THIOTEPA	4	3
DOXORUBICIN	4	2
ETOPOSIDE PHOSPHATE	4	2
MELPHALAN	4	2
AMIFOSTINE	4	1
ARSENIC TRIOXIDE	4	1
ITRACONAZOLE	4	1
NITROGLYCERIN	4	1
TEMOZOLOMIDE	4	1
URSODIOL	4	1
VINCRISTINE	4	1
ALVOCIDIB	3	3
BECATECARIN	3	1
RACOTUMOMAB	3	1
REGRAMOSTIM	3	1
CIXUTUMUMAB	2	1
CHEMBL4228794	0	1
CHEMBL4248195	0	1
HYOSCYAMINE	-1	1