Cholangiocarcinoma

Summary

Cholangiocarcinoma (MONDO:0019087) is a disease with 41 cohort genes (5 GWAS associations across 4 studies) and 520 clinical trials. The dominant Reactome pathway is Interleukin-4 and Interleukin-13 signaling (7 cohort genes). Molecularly, FGFR2::v Fusion OR FGFR2::? Fusion confers sensitivity to Infigratinib in Cholangiocarcinoma (CIViC Level A); 34 further subtype–drug associations are mapped below. Top therapeutic interventions include pemigatinib, ivosidenib, and floxuridine.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 41
• GWAS associations: 5
• ClinVar variants: 12
• Phenotypes (HPO): 8
• Clinical trials: 520
• Precision-medicine evidence (CIViC): 35 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

8 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	4.2	Worldwide	Validated
Point prevalence	1-9 / 100 000	2.1	Worldwide	Validated
Point prevalence	1-9 / 100 000		Europe	Validated
Annual incidence	1-9 / 100 000	1	United States	Validated
Annual incidence	>1 / 1000	113	Thailand	Validated
Annual incidence	1-9 / 1 000 000	0.1	Australia	Validated
Annual incidence	1-9 / 100 000	4	Europe	Not yet validated
Annual incidence	1-9 / 100 000	5.5	Japan	Not yet validated

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0000952	Jaundice	Very frequent (80-99%)
HP:0011985	Acholic stools	Very frequent (80-99%)
HP:0100574	Biliary tract neoplasm	Very frequent (80-99%)
HP:0000989	Pruritus	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0001945	Fever	Occasional (5-29%)
HP:0002027	Abdominal pain	Occasional (5-29%)
HP:0002039	Anorexia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cholangiocarcinoma
Mondo ID	MONDO:0019087
EFO	EFO:0005221
MeSH	D018281
Orphanet	70567
DOID	DOID:4947
ICD-11	2110597275
NCIT	C4436
SNOMED CT	312104005
UMLS	C0206698
MedGen	60210
GARD	0009304
MedDRA	10004593, 10008593
NORD	926
Is cancer (heuristic)	no

Also known as: bile duct cancer · CC · CCA · Cholangiocar.- intra/extrahepatic · cholangiocarcinoma · cholangiocarcinoma, intrahepatic and extrahepatic bile ducts (adenocarcinoma) · cholangiocarcinoma, malignant · Cholangiocellular carcinoma · intrahepatic bile duct cancer (cholangiocarcinoma)

Data availability: 12 ClinVar variants · 5 GWAS associations (4 studies) · 132 cell lines · 63 intOGen driver records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease by body system or component › digestive system disorder › digestive system cancer › liver cancer › biliary tract cancer › bile duct cancer › bile duct carcinoma › extrahepatic bile duct carcinoma › extrahepatic bile duct adenocarcinoma › adenocarcinoma of gallbladder and extrahepatic biliary tract › cholangiocarcinoma

Related subtypes (1): combined hepatocellular carcinoma and cholangiocarcinoma

Subtypes (1): intrahepatic cholangiocarcinoma

Genetics & variants

GWAS landscape

5 GWAS associations across 4 studies. Top hits map to 5 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs190121281	4e-09	TMEM161A - MEF2B	A	2.09
rs7731017	1e-06	DCTN4	G	4.81
rs3769839	1e-06	SP140, SP110	G
rs2675647	3e-06	CABCOCO1, LINC02625	C
rs34985176	4e-06	LINC02019 - DOCK3	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90018803	Sakaue S	2021	832	475,259	A cross-population atlas of genetic associations for 220 human phenotypes.
GCST90018583	Sakaue S	2021	418	159,201	A cross-population atlas of genetic associations for 220 human phenotypes.
GCST005855	Alberts R	2017	188	3,147	Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis.
GCST005860	Alberts R	2017	188	0	Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	5

MAF distribution

Bucket	Variants
common (>=0.05)	3
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intron_variant	3
intergenic_variant	2

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs190121281	19	19141970	G>A		intergenic_variant	TMEM161A - MEF2B	4e-09	Tier 4: intronic/intergenic
rs7731017	5	150732056	T>C	0.011	intron_variant	DCTN4	1e-06	Tier 4: intronic/intergenic
rs3769839	2	230211910	T>C	0.05	intron_variant	SP140, SP110	1e-06	Tier 4: intronic/intergenic
rs2675647	10	61758862	T>G	0.05	intron_variant	CABCOCO1, LINC02625	3e-06	Tier 4: intronic/intergenic
rs34985176	3	50673570	T>A,C	0.05	intergenic_variant	LINC02019 - DOCK3	4e-06	Tier 4: intronic/intergenic

ClinVar germline variants

12 retrieved; paginated sample, class counts are floors:

4 other, 3 benign, 1 other; risk factor, 1 benign; other, 1 conflicting classifications of pathogenicity, 1 pathogenic, 1 benign; affects; association; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
637959	FGFR2-CLIP1 fusion		Pathogenic	no assertion criteria provided
14718	NC_000007.14:g.22727026C>G	IL6	other; risk factor	no assertion criteria provided
2571397	NM_001530.4(HIF1A):c.1744C>T (p.Pro582Ser)	HIF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2571395	NC_000004.12:g.73740307A>T	CXCL8	other	no assertion criteria provided
2571393	NM_000963.4(PTGS2):c.*427T>C	PTGS2	other	no assertion criteria provided
2571394	NC_000001.11:g.186681189C>G	PTGS2	other	no assertion criteria provided
2571392	NM_003376.6(VEGFA):c.*237C>T	VEGFA	other	no assertion criteria provided
2571396	NM_000634.3(CXCR1):c.827G>C (p.Ser276Thr)	CXCR1	Benign; other	no assertion criteria provided
225998	NM_001963.6(EGF):c.-382A>G	EGF	Benign	criteria provided, multiple submitters, no conflicts
134021	NM_005228.5(EGFR):c.1562G>A (p.Arg521Lys)	EGFR	Benign	criteria provided, multiple submitters, no conflicts
16873	NC_000001.11:g.206773062T>G	IL10	Benign	criteria provided, multiple submitters, no conflicts
869137	NM_000576.3(IL1B):c.315C>T (p.Phe105=)	IL1B	Benign; Affects; association; other	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 59 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EGFR	Orphanet:251576	Gliosarcoma
EGFR	Orphanet:251579	Giant cell glioblastoma
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease
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
ERBB2	Orphanet:213726	Serous carcinoma of the corpus uteri
ERBB2	Orphanet:2800	Extramammary Paget disease
ERBB2	Orphanet:388	Hirschsprung disease
ERBB2	Orphanet:99976	Adenocarcinoma of the oesophagus and oesophagogastric junction
FGFR2	Orphanet:1540	Jackson-Weiss syndrome
FGFR2	Orphanet:1555	Cutis gyrata-acanthosis nigricans-craniosynostosis syndrome
FGFR2	Orphanet:168624	Familial scaphocephaly syndrome, McGillivray type
FGFR2	Orphanet:207	Crouzon syndrome
FGFR2	Orphanet:2363	Lacrimoauriculodentodigital syndrome
FGFR2	Orphanet:313855	FGFR2-related bent bone dysplasia
FGFR2	Orphanet:596008	Antley-Bixler syndrome without genital anomaly or disorder of steroidogenesis
FGFR2	Orphanet:794	Saethre-Chotzen syndrome
FGFR2	Orphanet:87	Apert syndrome
FGFR2	Orphanet:93258	Pfeiffer syndrome type 1
FGFR2	Orphanet:93259	Pfeiffer syndrome type 2
FGFR2	Orphanet:93260	Pfeiffer syndrome type 3
IDH1	Orphanet:163634	Maffucci syndrome
IDH1	Orphanet:251576	Gliosarcoma
IDH1	Orphanet:251579	Giant cell glioblastoma
IDH1	Orphanet:296	Ollier disease
IDH1	Orphanet:86845	Acute myeloid leukaemia with myelodysplasia-related features
IDH1	Orphanet:99646	Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria
DCTN4	Orphanet:586	Cystic fibrosis
DOCK3	Orphanet:528084	Non-specific syndromic intellectual disability
EGF	Orphanet:210159	Adult hepatocellular carcinoma
EGF	Orphanet:620368	EGF-related primary hypomagnesemia with intellectual disability
IL10	Orphanet:117	Behçet disease
IL10	Orphanet:238569	Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections syndrome
IL10	Orphanet:536	Systemic lupus erythematosus

Cohort genes → proteins

41 cohort genes, 38 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	25
civic_only	6
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EGFR	HGNC:3236	ENSG00000146648	P00533	Epidermal growth factor receptor	clinvar,civic_evidence
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	civic_evidence
CDKN2A	HGNC:1787	ENSG00000147889	P42771	Cyclin-dependent kinase inhibitor 2A	civic_evidence
ERRFI1	HGNC:18185	ENSG00000116285	Q9UJM3	ERBB receptor feedback inhibitor 1	civic_evidence
ERBB2	HGNC:3430	ENSG00000141736	P04626	Receptor tyrosine-protein kinase erbB-2	civic_evidence
FGFR2	HGNC:3689	ENSG00000066468	P21802	Fibroblast growth factor receptor 2	civic_evidence
IDH1	HGNC:5382	ENSG00000138413	O75874	Isocitrate dehydrogenase [NADP] cytoplasmic	civic_evidence
SP100	HGNC:11206	ENSG00000067066	P23497	Nuclear autoantigen Sp-100	gwas
VEGFA	HGNC:12680	ENSG00000112715	P15692	Vascular endothelial growth factor A, long form	clinvar
ZNF300	HGNC:13091	ENSG00000145908	Q96RE9	Zinc finger protein 300	gwas
CACNA2D2	HGNC:1400	ENSG00000007402	Q9NY47	Voltage-dependent calcium channel subunit alpha-2/delta-2	gwas
DCTN4	HGNC:15518	ENSG00000132912	Q9UJW0	Dynactin subunit 4	gwas
SP140	HGNC:17133	ENSG00000079263	Q13342	Nuclear body protein SP140	gwas
ARID5B	HGNC:17362	ENSG00000150347	Q14865	AT-rich interactive domain-containing protein 5B	gwas
MYOZ3	HGNC:18565	ENSG00000164591	Q8TDC0	Myozenin-3	gwas
CISH	HGNC:1984	ENSG00000114737	Q9NSE2	Cytokine-inducible SH2-containing protein	gwas
C3orf18	HGNC:24837	ENSG00000088543	Q9UK00	Uncharacterized protein C3orf18	gwas
HEMK1	HGNC:24923	ENSG00000114735	Q9Y5R4	MTRF1L release factor glutamine methyltransferase	gwas
SP140L	HGNC:25105	ENSG00000185404	Q9H930	Nuclear body protein SP140-like protein	gwas
RBM22	HGNC:25503	ENSG00000086589	Q9NW64	Pre-mRNA-splicing factor RBM22	gwas
SLC16A14	HGNC:26417	ENSG00000163053	Q7RTX9	Monocarboxylate transporter 14	gwas
FBXO36	HGNC:27020	ENSG00000153832	Q8NEA4	F-box only protein 36	gwas
ZNF300P1	HGNC:27032	ENSG00000197083		zinc finger protein 300 pseudogene 1	gwas
CABCOCO1	HGNC:28678	ENSG00000183346	Q8IVU9	Ciliary-associated calcium-binding coiled-coil protein 1	gwas
IRGM	HGNC:29597	ENSG00000237693	A1A4Y4	Immunity-related GTPase family M protein	gwas
DOCK3	HGNC:2989	ENSG00000088538	Q8IZD9	Dedicator of cytokinesis protein 3	gwas
SMIM3	HGNC:30248	ENSG00000256235	Q9BZL3	Small integral membrane protein 3	gwas
SYNPO	HGNC:30672	ENSG00000171992	Q8N3V7	Synaptopodin	gwas
EGF	HGNC:3229	ENSG00000138798	P01133	Pro-epidermal growth factor	clinvar
MIR4787	HGNC:41653	ENSG00000272543		microRNA 4787	gwas
MIR548AV	HGNC:43537	ENSG00000263750		microRNA 548av	gwas
HIF1A	HGNC:4910	ENSG00000100644	Q16665	Hypoxia-inducible factor 1-alpha	clinvar
IL10	HGNC:5962	ENSG00000136634	P22301	Interleukin-10	clinvar
IL1B	HGNC:5992	ENSG00000125538	P01584	Interleukin-1 beta	clinvar
IL6	HGNC:6018	ENSG00000136244	P05231	Interleukin-6	clinvar
CXCL8	HGNC:6025	ENSG00000169429	P10145	Interleukin-8	clinvar
CXCR1	HGNC:6026	ENSG00000163464	P25024	C-X-C chemokine receptor type 1	clinvar
MAPKAPK3	HGNC:6888	ENSG00000114738	Q16644	MAP kinase-activated protein kinase 3	gwas
NDST1	HGNC:7680	ENSG00000070614	P52848	Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1	gwas
PMP22	HGNC:9118	ENSG00000109099	Q01453	Peripheral myelin protein 22	gwas
PTGS2	HGNC:9605	ENSG00000073756	P35354	Prostaglandin G/H synthase 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EGFR	Epidermal growth factor receptor	Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses.
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
CDKN2A	Cyclin-dependent kinase inhibitor 2A	Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6.
ERRFI1	ERBB receptor feedback inhibitor 1	Negative regulator of EGFR signaling in skin morphogenesis.
ERBB2	Receptor tyrosine-protein kinase erbB-2	Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding.
FGFR2	Fibroblast growth factor receptor 2	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, migration and apoptosis, and in the regulation of embryonic de…
IDH1	Isocitrate dehydrogenase [NADP] cytoplasmic	Catalyzes the NADP(+)-dependent oxidative decarboxylation of isocitrate (D-threo-isocitrate) to 2-ketoglutarate (2-oxoglutarate), which is required by other enzymes such as the phytanoyl-CoA dioxygenase.
SP100	Nuclear autoantigen Sp-100	Together with PML, this tumor suppressor is a major constituent of the PML bodies, a subnuclear organelle involved in a large number of physiological processes including cell growth, differentiation and apoptosis.
VEGFA	Vascular endothelial growth factor A, long form	Participates in the induction of key genes involved in the response to hypoxia and in the induction of angiogenesis such as HIF1A.
ZNF300	Zinc finger protein 300	Has a transcriptional repressor activity.
CACNA2D2	Voltage-dependent calcium channel subunit alpha-2/delta-2	The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel.
DCTN4	Dynactin subunit 4	Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules.
SP140	Nuclear body protein SP140	Component of the nuclear body, also known as nuclear domain 10, PML oncogenic domain, and KR body.
ARID5B	AT-rich interactive domain-containing protein 5B	Transcription coactivator that binds to the 5’-AATA[CT]-3’ core sequence and plays a key role in adipogenesis and liver development.
MYOZ3	Myozenin-3	Myozenins may serve as intracellular binding proteins involved in linking Z line proteins such as alpha-actinin, gamma-filamin, TCAP/telethonin, LDB3/ZASP and localizing calcineurin signaling to the sarcomere.
CISH	Cytokine-inducible SH2-containing protein	SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction.
HEMK1	MTRF1L release factor glutamine methyltransferase	N5-glutamine methyltransferase responsible for the methylation of the glutamine residue in the universally conserved GGQ motif of the mitochondrial translation release factors MTRF1, MTRF1L, MRPL58/ICT1 and MTRFR.
RBM22	Pre-mRNA-splicing factor RBM22	Required for pre-mRNA splicing as component of the activated spliceosome.
SLC16A14	Monocarboxylate transporter 14	Proton-linked monocarboxylate transporter.
FBXO36	F-box only protein 36	Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
CABCOCO1	Ciliary-associated calcium-binding coiled-coil protein 1	Calcium-binding protein.
IRGM	Immunity-related GTPase family M protein	Immunity-related GTPase that plays important roles in innate immunity and inflammatory response.
DOCK3	Dedicator of cytokinesis protein 3	Potential guanine nucleotide exchange factor (GEF).
SYNPO	Synaptopodin	Actin-associated protein that may play a role in modulating actin-based shape and motility of dendritic spines and renal podocyte foot processes.
EGF	Pro-epidermal growth factor	EGF stimulates the growth of various epidermal and epithelial tissues in vivo and in vitro and of some fibroblasts in cell culture.
HIF1A	Hypoxia-inducible factor 1-alpha	Functions as a master transcriptional regulator of the adaptive response to hypoxia.
IL10	Interleukin-10	Major immune regulatory cytokine that acts on many cells of the immune system where it has profound anti-inflammatory functions, limiting excessive tissue disruption caused by inflammation.
IL1B	Interleukin-1 beta	Potent pro-inflammatory cytokine.
IL6	Interleukin-6	Cytokine with a wide variety of biological functions in immunity, tissue regeneration, and metabolism.
CXCL8	Interleukin-8	Chemotactic factor that mediates inflammatory response by attracting neutrophils, basophils, and T-cells to clear pathogens and protect the host from infection.
CXCR1	C-X-C chemokine receptor type 1	Receptor to interleukin-8, which is a powerful neutrophils chemotactic factor.
MAPKAPK3	MAP kinase-activated protein kinase 3	Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, cell migration, chromatin remodeling and transcriptional regulation.
NDST1	Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1	Essential bifunctional enzyme that catalyzes both the N-deacetylation and the N-sulfation of glucosamine (GlcNAc) of the glycosaminoglycan in heparan sulfate.
PMP22	Peripheral myelin protein 22	Might be involved in growth regulation, and in myelinization in the peripheral nervous system.
PTGS2	Prostaglandin G/H synthase 2	Dual cyclooxygenase and peroxidase in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate, AA, C20:4(n-6)), with a particular role in the inflammatory respon…

Protein-family classification

Druggable: 12 · Difficult: 8 · Unknown: 21 · Druggable fraction: 0.29

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	6	4.1×	0.023
Transporter	1	1.9×	0.787
Scaffold/PPI	3	1.3×	0.787
Enzyme (other)	4	1.2×	0.787
Transcription factor	5	1.0×	0.791
Other/Unknown	21	0.9×	0.826
GPCR	1	0.6×	0.826

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EGFR	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
CDKN2A	Scaffold/PPI	no		Ankyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor, Tumor_suppres_ARF
ERRFI1	Kinase	yes		Cdc42-bd-like, EGFR_SigReg_Kinase
ERBB2	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
FGFR2	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
IDH1	Enzyme (other)	yes	1.1.1.42	Isocitrate_DH_NADP, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom
SP100	Other/Unknown	no		SAND_dom, HSR_dom, HMG_box_dom
VEGFA	Other/Unknown	no		PDGF/VEGF_dom, PD_growth_factor_CS, VEGF_C
ZNF300	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
CACNA2D2	Other/Unknown	no		VWF_A, VWA_N, VDCC_a2/dsu
DCTN4	Other/Unknown	no		DCTN4
SP140	Transcription factor	no		SAND_dom, Bromodomain, Znf_PHD
ARID5B	Other/Unknown	no		ARID_dom, ARID5B_ARID/BRIGHT_DNA-bd, ARID_dom_sf
MYOZ3	Other/Unknown	no		MYOZ
CISH	Scaffold/PPI	no		SH2, SOCS_box, CIS_SH2
C3orf18	Other/Unknown	no		C3orf18-like
HEMK1	Enzyme (other)	yes	2.1.1.297	DNA_methylase_N6_adenine_CS, N4/N6-MTase_EcoPI_Mod-like, HemK-like
SP140L	Transcription factor	no		SAND_dom, Bromodomain, Znf_PHD
RBM22	Transcription factor	no		RRM_dom, Znf_CCCH, Nucleotide-bd_a/b_plait_sf
SLC16A14	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
FBXO36	Other/Unknown	no		F-box_dom, F-box-like_dom_sf, SCF_F-box/WD-repeat
ZNF300P1	Other/Unknown	no
CABCOCO1	Other/Unknown	no		CLAMP
IRGM	Other/Unknown	no		Immunity-related_GTPase-like, P-loop_NTPase, G_IRG_dom
DOCK3	Scaffold/PPI	no		SH3_domain, ARM-type_fold, DOCK
SMIM3	Other/Unknown	no		Smim3
SYNPO	Other/Unknown	no		Synaptopodin_domain
EGF	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF
MIR4787	Other/Unknown	no
MIR548AV	Other/Unknown	no
HIF1A	Transcription factor	no		PAS, HIF-1_alpha, PAC
IL10	Other/Unknown	no		IL-10, 4_helix_cytokine-like_core, IL-10_CS
IL1B	Other/Unknown	no		IL-1_fam, IL-1_propep, IL1/FGF
IL6	Other/Unknown	no		IL-6-like, 4_helix_cytokine-like_core, IL6/GCSF/MGF_CS
CXCL8	Other/Unknown	no		Chemokine_CXC, Chemokine_IL8-like_dom, Chemokine_CXC_CS
CXCR1	GPCR	yes		Chemokine_CXCR_1/2, GPCR_Rhodpsn, Chemokine_CXCR1
MAPKAPK3	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
NDST1	Enzyme (other)	yes	2.8.2.8	Sulfotransferase_dom, Heparan_SO4_deacetylase_dom, P-loop_NTPase
PMP22	Other/Unknown	no		PMP22, PMP22/EMP/MP20/Claudin, PMP22_EMP_MP20
PTGS2	Enzyme (other)	yes	1.14.99.1	EGF, Haem_peroxidase_sf, Haem_peroxidase_animal

Expression context

Cohort genes with no expression data: 0.

35 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)	2
broad (>20)	39
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	7
right uterine tube	3
right lobe of thyroid gland	3
type B pancreatic cell	3
cartilage tissue	3
calcaneal tendon	2
body of pancreas	2
right lobe of liver	2
vena cava	2
C1 segment of cervical spinal cord	2
spinal cord	2
corpus epididymis	2
lymph node	2
left lobe of thyroid gland	2
ganglionic eminence	2
skeletal muscle tissue of rectus abdominis	2
spleen	2
olfactory segment of nasal mucosa	2
primordial germ cell in gonad	2
male germ line stem cell (sensu Vertebrata) in testis	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EGFR	285	ubiquitous	marker	nipple, gingiva, gingival epithelium
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
CDKN2A	220	ubiquitous	marker	parotid gland, cervix squamous epithelium, pituitary gland
ERRFI1	256	ubiquitous	marker	body of pancreas, vena cava, right lobe of liver
ERBB2	276	ubiquitous	marker	lower esophagus mucosa, right uterine tube, sural nerve
FGFR2	272	broad	marker	C1 segment of cervical spinal cord, spinal cord, corpus callosum
IDH1	294	ubiquitous	marker	corpus epididymis, jejunal mucosa, adrenal tissue
SP100	286	ubiquitous	marker	calcaneal tendon, lymph node, right lung
VEGFA	297	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
ZNF300	187	ubiquitous	yes	cortical plate, ganglionic eminence, embryo
CACNA2D2	218	broad	marker	lower lobe of lung, cerebellar vermis, superior vestibular nucleus
DCTN4	278	ubiquitous	marker	biceps brachii, skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii
SP140	178	broad	marker	lymph node, granulocyte, spleen
ARID5B	299	ubiquitous	marker	type B pancreatic cell, saphenous vein, pericardium
MYOZ3	200	broad	yes	skeletal muscle tissue of rectus abdominis, vastus lateralis, quadriceps femoris
CISH	227	ubiquitous	marker	granulocyte, left lobe of thyroid gland, right lobe of thyroid gland
C3orf18	258	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
HEMK1	264	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, right lobe of liver
SP140L	242	ubiquitous	marker	granulocyte, spleen, small intestine Peyer’s patch
RBM22	290	ubiquitous	marker	tibia, parietal pleura, pleura
SLC16A14	244	broad	marker	pigmented layer of retina, retina, endothelial cell
FBXO36	167	ubiquitous	marker	sperm, olfactory segment of nasal mucosa, bronchial epithelial cell
ZNF300P1	208	broad	yes	primordial germ cell in gonad, ganglionic eminence, ventricular zone
CABCOCO1	151	broad	marker	olfactory segment of nasal mucosa, male germ line stem cell (sensu Vertebrata) in testis, right uterine tube
IRGM	143	tissue_specific	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, granulocyte
DOCK3	203	broad	marker	frontal pole, Brodmann (1909) area 10, paraflocculus
SMIM3	217	ubiquitous	marker	adipose tissue of abdominal region, omental fat pad, peritoneum
SYNPO	291	ubiquitous	marker	hindlimb stylopod muscle, apex of heart, descending thoracic aorta
EGF	215	broad	marker	renal medulla, body of pancreas, hindlimb stylopod muscle
MIR4787	6		yes	heart left ventricle, vagina, subcutaneous adipose tissue

Protein interactions among cohort

Intra-cohort edges: 31.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EGFR	18,421
HIF1A	9,734
ERBB2	9,659
CDKN2A	9,311
IL6	9,239
IL1B	8,564
EGF	8,267
BRAF	7,394
IL10	6,185
PTGS2	5,663

Intra-cohort edges

A	B	Sources
BRAF	CDKN2A	string_interaction
BRAF	EGFR	biogrid_interaction
BRAF	FGFR2	biogrid_interaction
CDKN2A	HIF1A	string_interaction
CISH	EGFR	intact
CISH	ERBB2	intact
CXCL8	CXCR1	string_interaction
CXCL8	IL1B	string_interaction
CXCL8	IL6	string_interaction
CXCL8	PTGS2	string_interaction
DCTN4	SMIM3	string_interaction
DOCK3	MAPKAPK3	string_interaction
EGF	EGFR	biogrid_interaction, intact, string_interaction
EGF	ERBB2	biogrid_interaction, string_interaction
EGF	ERRFI1	string_interaction
EGFR	ERBB2	intact, string_interaction
EGFR	ERRFI1	biogrid_interaction, intact, string_interaction
EGFR	PTGS2	string_interaction
ERBB2	ERRFI1	biogrid_interaction, intact, string_interaction
ERRFI1	FGFR2	biogrid_interaction
IL10	IL1B	string_interaction
IL10	IL6	string_interaction
IL1B	IL6	string_interaction
IL1B	PTGS2	string_interaction
IL6	PTGS2	string_interaction
IRGM	ZNF300	string_interaction
MYOZ3	SMIM3	string_interaction
PMP22	SMIM3	biogrid_interaction, intact
RBM22	SMIM3	string_interaction
SMIM3	ZNF300	string_interaction
SP140	SP140L	string_interaction

Structural data

PDB: 23 · AlphaFold-only: 15 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EGFR	P00533	388
BRAF	P15056	131
SP100	P23497	122
IL1B	P01584	64
ERBB2	P04626	63
FGFR2	P21802	63
IDH1	O75874	61
VEGFA	P15692	56
RBM22	Q9NW64	33
HIF1A	Q16665	25
CXCL8	P10145	22
IL6	P05231	17
EGF	P01133	13
IL10	P22301	9
ERRFI1	Q9UJM3	7
PTGS2	P35354	7
CDKN2A	P42771	5
SP140	Q13342	5
CXCR1	P25024	5
MAPKAPK3	Q16644	5
NDST1	P52848	5
DCTN4	Q9UJW0	2
ARID5B	Q14865	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PMP22	Q01453	89.87
FBXO36	Q8NEA4	89.64
HEMK1	Q9Y5R4	88.08
IRGM	A1A4Y4	84.60
CACNA2D2	Q9NY47	81.48
SLC16A14	Q7RTX9	79.82
CABCOCO1	Q8IVU9	77.74
SMIM3	Q9BZL3	76.75
DOCK3	Q8IZD9	75.52
CISH	Q9NSE2	73.91
SP140L	Q9H930	68.47
ZNF300	Q96RE9	68.40
C3orf18	Q9UK00	63.61
MYOZ3	Q8TDC0	61.56
SYNPO	Q8N3V7	50.70

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 277. Enrichment computed across 41 evidence-associated genes (26 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 26 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-4 and Interleukin-13 signaling	7	27.7×	1e-06	VEGFA, HIF1A, IL10, IL1B, IL6, CXCL8, PTGS2
PLCG1 events in ERBB2 signaling	3	329.4×	6e-06	EGFR, EGF, ERBB2
Interleukin-10 signaling	5	44.8×	7e-06	IL10, IL1B, IL6, CXCL8, PTGS2
ERBB2 Activates PTK6 Signaling	3	94.1×	2e-04	EGFR, EGF, ERBB2
TFAP2 (AP-2) family regulates transcription of growth factors and their receptors	3	87.8×	2e-04	EGFR, VEGFA, ERBB2
ERBB2 Regulates Cell Motility	3	82.4×	2e-04	EGFR, EGF, ERBB2
PI3K events in ERBB2 signaling	3	77.5×	2e-04	EGFR, EGF, ERBB2
Signaling by ERBB2 ECD mutants	3	77.5×	2e-04	EGFR, EGF, ERBB2
GRB2 events in ERBB2 signaling	3	73.2×	3e-04	EGFR, EGF, ERBB2
Developmental Lineage of Mammary Gland Myoepithelial Cells	3	62.8×	4e-04	EGFR, EGF, ERBB2
SHC1 events in ERBB2 signaling	3	54.9×	5e-04	EGFR, EGF, ERBB2
Signaling by ERBB2 TMD/JMD mutants	3	54.9×	5e-04	EGFR, EGF, ERBB2
Signaling by ERBB2 KD Mutants	3	48.8×	6e-04	EGFR, EGF, ERBB2
Downregulation of ERBB2 signaling	3	43.9×	8e-04	EGFR, EGF, ERBB2
Constitutive Signaling by Aberrant PI3K in Cancer	4	19.5×	9e-04	EGFR, EGF, ERBB2, FGFR2
Signaling by ERBB2	3	39.9×	9e-04	EGFR, EGF, ERBB2
RAF/MAP kinase cascade	5	11.7×	9e-04	EGFR, BRAF, EGF, ERBB2, FGFR2
PTK6 promotes HIF1A stabilization	2	125.5×	0.002	EGFR, HIF1A
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	4	14.9×	0.002	EGFR, EGF, ERBB2, FGFR2
Inhibition of Signaling by Overexpressed EGFR	2	97.6×	0.002	EGFR, EGF
EGFR interacts with phospholipase C-gamma	2	87.8×	0.003	EGFR, EGF
CD163 mediating an anti-inflammatory response	2	87.8×	0.003	IL10, IL6
Regulation of gene expression by Hypoxia-inducible Factor	2	73.2×	0.004	VEGFA, HIF1A
GRB2 events in EGFR signaling	2	58.6×	0.006	EGFR, EGF
SHC1 events in EGFR signaling	2	54.9×	0.006	EGFR, EGF
Constitutive Signaling by EGFRvIII	2	54.9×	0.006	EGFR, EGF
PIP3 activates AKT signaling	4	10.3×	0.006	EGFR, EGF, ERBB2, FGFR2
GAB1 signalosome	2	48.8×	0.007	EGFR, EGF
Signalling to ERKs	2	46.2×	0.008	BRAF, MAPKAPK3
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	2	43.9×	0.009	EGFR, EGF

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 32 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 MAPK cascade	8	20.2×	3e-06	EGFR, VEGFA, EGF, ERBB2, FGFR2, IL1B, IL6, NDST1
positive regulation of peptidyl-serine phosphorylation	4	95.8×	3e-05	EGFR, BRAF, IRGM, IL6
vascular endothelial growth factor production	3	225.7×	4e-05	HIF1A, IL1B, IL6
epidermal growth factor receptor signaling pathway	5	38.7×	4e-05	EGFR, BRAF, ERRFI1, EGF, ERBB2
positive regulation of vascular endothelial growth factor production	4	62.0×	7e-05	HIF1A, IL1B, IL6, PTGS2
ERBB2-EGFR signaling pathway	3	158.0×	9e-05	EGFR, EGF, ERBB2
positive regulation of miRNA transcription	4	36.3×	5e-04	EGFR, HIF1A, IL10, IL6
negative regulation of epidermal growth factor receptor signaling pathway	3	71.8×	8e-04	EGFR, ERRFI1, EGF
positive regulation of epithelial cell proliferation	4	30.5×	8e-04	EGFR, VEGFA, ERBB2, FGFR2
positive regulation of endothelial cell proliferation	4	28.9×	8e-04	VEGFA, EGF, HIF1A, IL10
positive regulation of gene expression	7	8.5×	1e-03	BRAF, VEGFA, EGF, HIF1A, IL1B, IL6, CXCL8
cellular response to lipopolysaccharide	5	15.3×	0.001	IRGM, IL10, IL1B, IL6, CXCL8
positive regulation of fever generation	2	263.3×	0.001	IL1B, PTGS2
regulation of ERK1 and ERK2 cascade	3	54.5×	0.001	ERBB2, FGFR2, IL1B
positive regulation of transcription by RNA polymerase II	10	4.7×	0.002	EGFR, SP100, VEGFA, ZNF300, CDKN2A, FGFR2, HIF1A, IL10 (+2 more)
positive regulation of ERK1 and ERK2 cascade	5	13.3×	0.002	EGFR, BRAF, VEGFA, FGFR2, IL1B
negative regulation of immature T cell proliferation in thymus	2	175.5×	0.002	CDKN2A, ERBB2
positive regulation of epithelial tube formation	2	175.5×	0.002	VEGFA, EGF
regulation of angiogenesis	3	39.5×	0.002	SP100, ERBB2, IL6
response to molecule of bacterial origin	2	131.7×	0.004	IL10, CXCL8
embryo implantation	3	32.9×	0.004	ERRFI1, IL1B, PTGS2
negative regulation of cell population proliferation	6	7.9×	0.004	CDKN2A, IL10, IL1B, IL6, CXCL8, PMP22
positive regulation of peptidyl-threonine phosphorylation	2	117.0×	0.004	IRGM, EGF
positive regulation of prostaglandin biosynthetic process	2	117.0×	0.004	IL1B, PTGS2
ubiquitin-dependent endocytosis	2	117.0×	0.004	EGFR, EGF
positive regulation of cell division	3	31.6×	0.004	VEGFA, FGFR2, IL1B
cellular response to epidermal growth factor stimulus	3	29.8×	0.004	EGFR, ERRFI1, ERBB2
epithelial cell proliferation	3	29.3×	0.004	EGFR, ERRFI1, EGF
cellular response to hypoxia	4	15.2×	0.004	VEGFA, FGFR2, HIF1A, PTGS2
angiogenesis	5	9.8×	0.004	VEGFA, EGF, FGFR2, HIF1A, CXCL8

Therapeutics

Drugs indicated for this disease

3 approved, 15 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Futibatinib	Approved (phase 4)
Ivosidenib	Approved (phase 4)
Pemigatinib	Approved (phase 4)
Capecitabine	Phase 3 (in late-stage trials)
Carboplatin	Phase 3 (in late-stage trials)
Cisplatin	Phase 3 (in late-stage trials)
Fluorouracil	Phase 3 (in late-stage trials)
Gemcitabine	Phase 3 (in late-stage trials)
Gimeracil	Phase 3 (in late-stage trials)
Infigratinib	Phase 3 (in late-stage trials)
Irinotecan	Phase 3 (in late-stage trials)
Lenvatinib	Phase 3 (in late-stage trials)
Oteracil	Phase 3 (in late-stage trials)
Oxaliplatin	Phase 3 (in late-stage trials)
Tegafur	Phase 3 (in late-stage trials)
Tinengotinib	Phase 3 (in late-stage trials)
Tislelizumab	Phase 3 (in late-stage trials)
Toripalimab	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Alectinib, Atezolizumab, Axatilimab, Bevacizumab, Bintrafusp Alfa, Calcitriol, Camrelizumab, Ceralasertib, Ceritinib, Cetuximab, Colchicine, Copanlisib, Dasatinib Anhydrous, Dexamethasone, Doxorubicin, Durvalumab, Everolimus, Floxuridine, Hydroxychloroquine, Ixabepilone, Milademetan, Mitomycin, Nibrozetone, Nivolumab, Olaparib, PEGINTERFERON ALFA-2B, Paclitaxel, Padeliporfin, Panitumumab, Pembrolizumab, Pevonedistat, Ramucirumab, Regorafenib, Rivoceranib, Selumetinib, Sintilimab, Sunitinib, Tipiracil, Trametinib, Trastuzumab, Tremelimumab, Trifluridine, Zimberelimab.

Drug target analysis

Approved (phase 4): 14 · Phase ≥3: 15 · Phased (≥1): 16 · Undrugged: 25

Druggability breadth: 23 of 41 evidence-associated genes (56%) 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
EGFR	LEVODOPA
BRAF	VEMURAFENIB
ERBB2	CLOTRIMAZOLE
FGFR2	PONATINIB
IDH1	ENASIDENIB
VEGFA	VADADUSTAT
CACNA2D2	NIMODIPINE
HIF1A	EMETINE
IL1B	POMALIDOMIDE
IL6	PREDNISOLONE
CXCL8	TOLMETIN
CXCR1	DEXIBUPROFEN
PMP22	PROGESTERONE
PTGS2	CELECOXIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HIF1A	255	4
PMP22	213	4
PTGS2	192	4
EGFR	175	4
ERBB2	83	4
FGFR2	59	4
BRAF	48	4
IDH1	10	4
CXCR1	9	4
VEGFA	5	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LEVODOPA	4	EGFR, HIF1A, PTGS2
CLOTRIMAZOLE	4	CXCR1, EGFR, ERBB2, HIF1A, PMP22, PTGS2
ERLOTINIB HYDROCHLORIDE	4	EGFR, ERBB2
CISPLATIN	4	EGFR
PONATINIB	4	BRAF, EGFR, ERBB2, FGFR2
AFATINIB	4	EGFR, ERBB2
CHROMIC CHLORIDE	4	EGFR
BACITRACIN	4	EGFR
ZINC CHLORIDE	4	EGFR
LAPATINIB DITOSYLATE	4	EGFR, ERBB2
VEMURAFENIB	4	BRAF, EGFR
FEDRATINIB	4	BRAF, EGFR, FGFR2
AXITINIB	4	EGFR, FGFR2
SORAFENIB	4	BRAF, EGFR, ERBB2, FGFR2, PTGS2
DASATINIB ANHYDROUS	4	BRAF, EGFR
NICLOSAMIDE	4	EGFR, HIF1A, PMP22
SELUMETINIB	4	EGFR
TERFENADINE	4	EGFR, HIF1A, PMP22
ALECTINIB	4	EGFR
NERATINIB	4	EGFR, ERBB2
IBRUTINIB	4	EGFR, ERBB2, FGFR2
AFATINIB DIMALEATE	4	EGFR, ERBB2
CABOZANTINIB	4	EGFR, ERBB2
DACOMITINIB	4	EGFR, ERBB2
DACOMITINIB ANHYDROUS	4	EGFR, ERBB2
CERITINIB	4	EGFR, FGFR2
VANDETANIB	4	EGFR, ERBB2, FGFR2
TRIBROMSALAN	4	EGFR, ERBB2
BOSUTINIB	4	EGFR, ERBB2
BITHIONOL	4	EGFR, ERBB2, HIF1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 8.

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

Symbol	Assays	Type breakdown
EGFR	6,531	Binding:6211, Functional:173, ADMET:138, Toxicity:9
PTGS2	1,548	Binding:1478, Functional:35, ADMET:34, Toxicity:1
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
ERBB2	1,221	Binding:1136, Functional:79, ADMET:6
FGFR2	966	Binding:940, Functional:22, ADMET:4
IDH1	488	Binding:475, Functional:12, ADMET:1
HIF1A	427	Binding:411, Functional:16
MAPKAPK3	239	Binding:232, Functional:7
CXCR1	120	Binding:85, Functional:35
VEGFA	64	Binding:64
IL1B	26	Binding:26
CACNA2D2	17	Binding:17
CXCL8	17	Functional:9, Binding:8
IL6	16	Binding:16
SP140	8	Binding:8
RBM22	6	Binding:6
EGF	5	Binding:5
SP140L	4	Binding:4
IRGM	3	Binding:3
CDKN2A	2	Binding:2
SP100	2	Binding:2
PMP22	1	Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EGFR	2.7.10.1	receptor protein-tyrosine kinase
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
ERBB2	2.7.10.1	receptor protein-tyrosine kinase
FGFR2	2.7.10.1	receptor protein-tyrosine kinase
IDH1	1.1.1.42	isocitrate dehydrogenase (NADP+)
HEMK1	2.1.1.297	peptide chain release factor N5-glutamine methyltransferase
NDST1	2.8.2.8	[heparan sulfate]-glucosamine N-sulfotransferase
PTGS2	1.14.99.1	prostaglandin-endoperoxide synthase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
EGFR	6,531
BRAF	1,442
ERBB2	1,221
FGFR2	966
IDH1	488
HIF1A	427
CXCR1	120
MAPKAPK3	239
PTGS2	1,548

Pharmacogenomics

Cohort genes with a PharmGKB record: 38; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

27 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)
LEVODOPA	4	EGFR, HIF1A, PTGS2
CLOTRIMAZOLE	4	CXCR1, EGFR, ERBB2, HIF1A, PMP22, PTGS2
ERLOTINIB HYDROCHLORIDE	4	EGFR, ERBB2
CISPLATIN	4	EGFR
PONATINIB	4	BRAF, EGFR, ERBB2, FGFR2
AFATINIB	4	EGFR, ERBB2
CHROMIC CHLORIDE	4	EGFR
BACITRACIN	4	EGFR
ZINC CHLORIDE	4	EGFR
LAPATINIB DITOSYLATE	4	EGFR, ERBB2
VEMURAFENIB	4	BRAF, EGFR
FEDRATINIB	4	BRAF, EGFR, FGFR2
AXITINIB	4	EGFR, FGFR2
SORAFENIB	4	BRAF, EGFR, ERBB2, FGFR2, PTGS2
DASATINIB ANHYDROUS	4	BRAF, EGFR
NICLOSAMIDE	4	EGFR, HIF1A, PMP22
SELUMETINIB	4	EGFR
TERFENADINE	4	EGFR, HIF1A, PMP22
NERATINIB	4	EGFR, ERBB2
IBRUTINIB	4	EGFR, ERBB2, FGFR2
AFATINIB DIMALEATE	4	EGFR, ERBB2
DACOMITINIB	4	EGFR, ERBB2
DACOMITINIB ANHYDROUS	4	EGFR, ERBB2
VANDETANIB	4	EGFR, ERBB2, FGFR2
TRIBROMSALAN	4	EGFR, ERBB2
BOSUTINIB	4	EGFR, ERBB2
BITHIONOL	4	EGFR, ERBB2, HIF1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	14	EGFR, BRAF, ERBB2, FGFR2, IDH1, VEGFA, CACNA2D2, HIF1A, IL1B, IL6 (+4 more)
B	Phased (≥1) drug, not yet approved	2	RBM22, MAPKAPK3
C	Druggable family + PDB, no drug	2	ERRFI1, NDST1
D	Druggable family + AlphaFold only, no drug	2	HEMK1, SLC16A14
E	Difficult family or no structure, no drug	21	CDKN2A, SP100, ZNF300, DCTN4, SP140, ARID5B, MYOZ3, CISH, C3orf18, SP140L (+11 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ERRFI1	0	ERBB2, EGFR
EGF	5	EGFR, ERBB2
IL10	0	IL6
CDKN2A	2	—
SP100	2	—
ZNF300	0	—
DCTN4	0	—
SP140	8	—
ARID5B	0	—
MYOZ3	0	—
CISH	0	—
C3orf18	0	—
HEMK1	0	—
SP140L	4	—
SLC16A14	0	—
FBXO36	0	—
ZNF300P1	0	—
CABCOCO1	0	—
IRGM	3	—
DOCK3	0	—
SMIM3	0	—
SYNPO	0	—
MIR4787	0	—
MIR548AV	0	—
NDST1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 520.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	217
PHASE2	143
PHASE1	79
PHASE1/PHASE2	38
PHASE3	21
PHASE2/PHASE3	11
PHASE4	10
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07486713	PHASE4	RECRUITING	Olutasidenib DDI Study in Patients With IDH1 Mutation Positive Malignancies
NCT00168987	PHASE4	COMPLETED	Influence of an Oral Nutritional Supplement Rich in Omega-3 Fatty Acids on Functional State and Quality of Life in Malnourished Patients With Gastroenterological Tumors
NCT00280709	PHASE4	COMPLETED	Biliary Metal Stent Study: Metal Stents for Management of Distal Malignant Biliary Obstruction
NCT00797121	PHASE4	UNKNOWN	Preoperative Biliary Drainage for Resectable Hilar Cholangiocarcinoma
NCT01111591	PHASE4	UNKNOWN	Cyclooxygenase-2 Inhibitor for Adjuvant Anticancer Effect in Patients With Biliary-pancreas Cancer
NCT01256034	PHASE4	COMPLETED	Effects of Preoperative Immunonutrition in Patients Undergoing Pancreaticoduodenectomy
NCT01256047	PHASE4	COMPLETED	Effects of Preoperative Immunonutrition in Patients Undergoing Hepatectomy
NCT01642875	PHASE4	UNKNOWN	Early Oral Versus Enteral Nutrition After Pancreatoduodenectomy
NCT02027311	PHASE4	COMPLETED	Etomidate vs. Midazolam for Sedation During ERCP
NCT02174575	PHASE4	WITHDRAWN	Anesthetic Agents and Acute Kidney Injury After Liver Resection Surgery
NCT02170090	PHASE3	ACTIVE_NOT_RECRUITING	Adjuvant Chemotherapy With Gemcitabine and Cisplatin Compared to Standard of Care After Curative Intent Resection of Biliary Tract Cancer
NCT02482454	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Radiofrquency Ablation Combined With Cytokine-induced Killer Cells for the Patients With Cholangiocarcinoma
NCT05506943	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Study of CTX-009 in Combination With Paclitaxel in Adult Patients With Unresectable Advanced, Metastatic or Recurrent Biliary Tract Cancers (COMPANION-002)
NCT05823311	PHASE3	RECRUITING	Lenvatinib, Tislelizumab Combined with Gemcitabine and Cisplatin (GPLET) in the Treatment of Advanced Cholangiocarcinoma
NCT05876754	PHASE3	RECRUITING	An Early Access Study of Ivosidenib in Patients With a Pretreated Locally Advanced or Metastatic Cholangiocarcinoma
NCT05948475	PHASE3	RECRUITING	Study of Tinengotinib VS. Physician’s Choice a Treatment of Subjects With FGFR-altered in Cholangiocarcinoma
NCT06037980	PHASE2/PHASE3	RECRUITING	CisPlatin plUs Gemcitabine and Nabpaclitaxel (GAP) as pReoperative Chemotherapy Versus Immediate Resection in patIents With resecTable BiliarY Tract Cancers (BTC) at High Risk for Recurrence
NCT06355427	PHASE2/PHASE3	RECRUITING	The Effect of [18F] F-FAPI PET-CT on Management in Patients With Proximal Cholangiocarcinoma
NCT06851663	PHASE2/PHASE3	RECRUITING	Trop2-targeted immunoPET Imaging of Solid Tumors
NCT07155525	PHASE3	RECRUITING	Tissue Adhesive Glue Modified Cyanoacrylate (Glubran® 2) in Soft Pancreas
NCT07328919	PHASE3	NOT_YET_RECRUITING	Efficacy and Safety of TT-00420 (Tinengotinib) Tablets Versus Chemotherapy in Patients With Advanced Intrahepatic Cholangiocarcinoma Harboring FGFR2 Fusions/Rearrangements or Mutations
NCT07598318	PHASE2/PHASE3	NOT_YET_RECRUITING	Study of Becotatug Vedotin Added to Standard Treatment for Advanced Bile Duct Cancer With EGFR Mutations
NCT00540735	PHASE3	TERMINATED	Efficiency Evaluation of Photodynamic Therapy With Photofrin® on Unresectable Type III or IV Cholangiocarcinomas
NCT00653978	PHASE3	UNKNOWN	Unilateral Versus Bilateral Stents for Bismuth Type II and III Malignant Hilar Strictures
NCT00809081	PHASE3	UNKNOWN	Early Enteral Feeding After Pylorus Preserving Pancreatoduodenectomy
NCT00869635	PHASE3	COMPLETED	S-1 and Photodynamic Therapy in Cholangiocarcinoma
NCT00907413	PHASE3	TERMINATED	Photodynamic Therapy (PDT) Trial for Palliation of Cholangiocarcinoma
NCT01739465	PHASE2/PHASE3	UNKNOWN	Comparison of Endoscopic Radiofrequency Ablation Versus Photodynamic Therapy for Inoperable Cholangiocarcinoma
NCT01755013	PHASE2/PHASE3	UNKNOWN	Photodynamic Therapy (PDT) for Palliation of Cholangiocarcinoma
NCT01926236	PHASE3	COMPLETED	Active Symptom Control Alone or With mFOLFOX Chemotherapy for Locally Advanced/ Metastatic Biliary Tract Cancers
NCT02548195	PHASE3	UNKNOWN	Oxaliplatin+Gemcitabine vs Capecitabine as Adjuvant Therapy for Intrahepatic Cholangiocarcinoma
NCT02591030	PHASE2/PHASE3	COMPLETED	Safety and Efficacy of Modified Folfirinox Versus Gemcis in Bile Duct Tumours
NCT02773485	PHASE3	UNKNOWN	Chemo Alone or in Combination With Radiation in Unresectable Cholangiocarcinoma
NCT02853474	PHASE3	COMPLETED	Early Palliative Care in Patients With Metastatic Upper Gastrointestinal Cancers Treated With First-line Chemotherapy
NCT02989857	PHASE3	COMPLETED	Study of AG-120 in Previously Treated Advanced Cholangiocarcinoma With IDH1 Mutations (ClarIDHy)
NCT03086993	PHASE2/PHASE3	UNKNOWN	Percutaneous Hepatic Perfusion vs. Cisplatin/Gemcitabine in Patients With Intrahepatic Cholangiocarcinoma
NCT03656536	PHASE3	TERMINATED	A Study to Evaluate the Efficacy and Safety of Pemigatinib Versus Chemotherapy in Unresectable or Metastatic Cholangiocarcinoma
NCT03773302	PHASE3	TERMINATED	Phase 3 Study of BGJ398 (Oral Infigratinib) in First Line Cholangiocarcinoma With FGFR2 Gene Fusions/Translocations
NCT03779035	PHASE3	UNKNOWN	Adjuvant Chemotherapy for Biliary Tract Cancer After Curative Resection
NCT04066491	PHASE2/PHASE3	TERMINATED	Gemcitabine Plus Cisplatin With or Without Bintrafusp Alfa (M7824) in Participants With 1L BTC

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PEMIGATINIB	4	8
IVOSIDENIB	4	6
FLOXURIDINE	4	5
FUTIBATINIB	4	4
INFIGRATINIB	4	4
TIVOZANIB	4	4
PANITUMUMAB	4	3
TIPIRACIL	4	3
TRASTUZUMAB	4	3
TRIFLURIDINE	4	3
CERITINIB	4	2
NIRAPARIB	4	2
TREMELIMUMAB	4	2
ABEMACICLIB	4	1
ALECTINIB	4	1
AVELUMAB	4	1
CABOZANTINIB	4	1
COBIMETINIB	4	1
COPANLISIB	4	1
DESFLURANE	4	1
DOSTARLIMAB	4	1
ENTRECTINIB	4	1
ETOMIDATE	4	1
GEMCITABINE HYDROCHLORIDE	4	1
LEVOLEUCOVORIN	4	1
MARGETUXIMAB	4	1
MELPHALAN	4	1
MEPERIDINE	4	1
MIDAZOLAM	4	1
OLUTASIDENIB	4	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 35 predictive associations from 41 curated evidence items; also 2 prognostic, 2 diagnostic.

Molecular subtype	Therapy	Effect	Level	CIViC
FGFR2::v Fusion OR FGFR2::? Fusion	Infigratinib	Sensitivity/Response	CIViC A	EID11230 +2
IDH1 R132	Ivosidenib	Sensitivity/Response	CIViC A	EID10886
BRAF V600E	Dabrafenib + Trametinib	Sensitivity/Response	CIViC B	EID7453 +1
FGFR2 Mutation	Infigratinib	Sensitivity/Response	CIViC B	EID5912 +1
FGFR2::v Fusion	Futibatinib	Sensitivity/Response	CIViC B	EID12489 +1
BRAF V600	Vemurafenib	Sensitivity/Response	CIViC B	EID5905
CDKN2A Mutation	Palbociclib	Sensitivity/Response	CIViC B	EID7300
FGFR2::? Fusion	Erdafitinib	Sensitivity/Response	CIViC B	EID10406
IDH1 Mutation	Ivosidenib	Sensitivity/Response	CIViC B	EID7447
FGFR2 Mutation	Erdafitinib	Sensitivity/Response	CIViC C	EID10375 +1
ATP1B1::NRG1 Fusion	Afatinib	Sensitivity/Response	CIViC C	EID5858
BRAF V600E	Vemurafenib + Irinotecan + Panitumumab	Sensitivity/Response	CIViC C	EID5906
ERBB2 Amplification	Pertuzumab + Trastuzumab	Sensitivity/Response	CIViC C	EID7638
ERRFI1 E384*	Erlotinib	Sensitivity/Response	CIViC C	EID1724
FGFR2 Amplification AND FGFR2::? Fusion	Futibatinib	Sensitivity/Response	CIViC C	EID11642
FGFR2 C383R	Futibatinib	Sensitivity/Response	CIViC C	EID11631
FGFR2 Mutation AND CDH1 MUTATION AND CDKN2A Mutation AND CDKN2B Mutation	Pazopanib + Crizotinib + Palbociclib Regimen	Sensitivity/Response	CIViC C	EID12777
FGFR2 W290C	Futibatinib	Sensitivity/Response	CIViC C	EID11633
FGFR2::BICC1 Fusion	Futibatinib	Sensitivity/Response	CIViC C	EID11629
FGFR2::CCDC6 Fusion	Futibatinib	Sensitivity/Response	CIViC C	EID11646
FGFR2::DBP Fusion	Futibatinib	Sensitivity/Response	CIViC C	EID11628
FGFR2::FILIP1 Fusion	Futibatinib	Sensitivity/Response	CIViC C	EID11630
FGFR2::KIAA1217 Fusion	Futibatinib	Sensitivity/Response	CIViC C	EID11647
FGFR2::NRAP Fusion	Futibatinib	Sensitivity/Response	CIViC C	EID11641
FGFR2::OGA Fusion	Ponatinib	Sensitivity/Response	CIViC C	EID295
FGFR2::POC1B Fusion	Futibatinib	Sensitivity/Response	CIViC C	EID11627
FGFR2::TACC3 Fusion	Ponatinib + Pazopanib	Sensitivity/Response	CIViC C	EID296
FGFR2::TNS1 Fusion	Futibatinib	Sensitivity/Response	CIViC C	EID11644
FGFR2::TTC28 Fusion	Futibatinib	Sensitivity/Response	CIViC C	EID11645
FGFR2::WAC Fusion	Futibatinib	Sensitivity/Response	CIViC C	EID11643

+5 more predictive associations (showing top 30 by evidence level).