Carcinoma of esophagus

Summary

Carcinoma of esophagus (MONDO:0019086) is a cancer (an umbrella term covering 5 Mondo subtypes) with 35 cohort genes (49 GWAS associations across 17 studies; 11 CIViC-evidence somatic drivers; 4 ClinVar predisposition records) and 1,300 clinical trials. The dominant Reactome pathway is Ethanol oxidation (4 cohort genes). Molecularly, TP53 Wildtype confers sensitivity to Chemotherapy in Esophageal Carcinoma (CIViC Level B); 11 further subtype–drug associations are mapped below. Top therapeutic interventions include irinotecan, epirubicin, and cisplatin.

At a glance

• Classification: Cancer
• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 35
• GWAS associations: 49
• ClinVar variants: 4
• Clinical trials: 1,300
• Precision-medicine evidence (CIViC): 12 subtype–drug associations

Clinical features

Epidemiology

Prevalence records

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

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	7	Worldwide	Validated
Point prevalence	1-9 / 100 000	9.8	Worldwide	Validated
Annual incidence	1-9 / 100 000	6.67	Europe	Validated
Lifetime Prevalence	1-5 / 10 000	12.2	Europe	Validated
Point prevalence	1-9 / 100 000	7.1	Europe	Validated
Annual incidence	1-9 / 100 000	5.5	United States	Validated
Annual incidence	1-9 / 100 000	6.873	France	Validated
Annual incidence	1-5 / 10 000	10.82	United Kingdom	Validated
Annual incidence	1-9 / 100 000	3.9	India	Validated
Annual incidence	1-5 / 10 000	20	China	Validated
Annual incidence	1-9 / 100 000	2.3	Africa	Validated
Annual incidence	1-9 / 100 000	9	Japan	Validated
Annual incidence	1-9 / 100 000	8	Russian Federation	Validated
Annual incidence	1-5 / 10 000	13	Latin America	Validated
Annual incidence	1-9 / 100 000	3.293	Austria	Validated
Annual incidence	1-9 / 100 000	7.892	Belgium	Validated
Annual incidence	1-9 / 100 000	1.194	Bulgaria	Validated
Annual incidence	1-9 / 100 000	3.281	Croatia	Validated
Annual incidence	1-9 / 100 000	3.718	Czech Republic	Validated
Annual incidence	1-9 / 100 000	3.473	Estonia	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	carcinoma of esophagus
Mondo ID	MONDO:0019086
EFO	EFO:0002916
Orphanet	70482
DOID	DOID:1107
NCIT	C3513
SNOMED CT	372138000
UMLS	C0152018
MedGen	56256
GARD	0006383
MedDRA	10030155
Anatomy (UBERON)	UBERON:0001043
Is cancer (heuristic)	yes

Also known as: cancer of esophagus · cancer of oesophagus · cancer of the esophagus · cancer of the oesophagus · carcinoma of esophagus · carcinoma of the esophagus · carcinoma of the oesophagus · esophageal cancer · esophageal cancer, NOS · esophageal carcinoma · esophagus carcinoma · oesophagus carcinoma

Data availability: 4 ClinVar variants · 49 GWAS associations (17 studies) · 6 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › digestive system disorder › digestive system cancer › digestive system carcinoma › carcinoma of esophagus

Related subtypes (15): maxillary sinus carcinoma, gastroesophageal junction adenocarcinoma, gallbladder carcinoma, intestine carcinoma in situ, gastric carcinoma, exocrine pancreatic carcinoma, small intestine carcinoma, pancreatic endocrine carcinoma, ameloblastic carcinoma, digestive system mixed adenoneuroendocrine carcinoma, carcinoma of liver and intrahepatic biliary tract, carcinoma of floor of mouth, carcinoma of pharynx, colorectal carcinoma, oral cavity carcinoma

Subtypes (5): esophageal small cell neuroendocrine carcinoma, esophagus carcinoma in situ, esophageal adenocarcinoma, esophageal squamous cell carcinoma, carcinoma of esophagus, salivary gland type

Genetics & variants

GWAS landscape

49 GWAS associations across 17 studies. Top hits map to 26 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1229984	2e-46	ADH1B	C	0.71
rs2074356	2e-31	HECTD4	T	1.56
rs4646776	1e-25	ALDH2	C	0.48
rs671	3e-24	ALDH2	A	1.67
rs4822983	2e-22	CHEK2	T	1.27
rs2014300	8e-22	RUNX1	G	1.43
rs11066015	7e-21	ACAD10	A	1.38
rs4785204	2e-20	HEATR3	T	1.24
rs2274223	4e-20	PLCE1	G	1.34
rs10052657	2e-19	PDE4D	C	1.49
rs6503659	3e-16	HAP1 - JUP	A	1.27
rs11066280	2e-15	HECTD4	A	1.3
rs2239815	4e-15	XBP1	T	1.18
rs2239612	6e-14	ST6GAL1	T	1.21
rs10484761	7e-12	LRFN2 - UNC5CL	G	1.33
rs8030672	1e-11	CARS1P1 - ANP32A	A	1.56
rs17761864	2e-11	SMG6	A	1.21
rs2847281	2e-11	PTPN2	C	1.2
rs9288520	4e-11	PSMB3P2 - IGFBP2	?	1.33
rs3765524	2e-09	PLCE1	T	1.35
rs10058728	5e-09	CSNK1A1	T	2.04
rs738722	1e-08	CHEK2	T	1.3
rs75460256	1e-08	ECRG4	G	1.87
rs117121174	1e-08	IFT81 - ATP2A2	A	0.38
rs10201587	1e-08	FLACC1, CASP8	G	0.23
rs76954182	3e-08	RASSF10 - BMAL1	C	4.96
rs1050631	4e-08	SLC39A6	T	1.3
rs2834617	4e-08	LINC00160 - LINC01426	C	3.75
rs17450420	5e-08	ATP6V1G1P7 - RPL7P45	?	1.7
rs11877682	5e-08	SIGLEC15, EPG5	T	5.03

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90432134	Jiang Y	2023	116,382	213,325	A cross-disorder study to identify causal relationships, shared genetic variants, and genes across 21 digestive disorders.
GCST001672	Wu C	2012	2,031	2,044	Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions.
GCST001674	Wu C	2012	2,031	2,044	Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions.
GCST001089	Wu C	2011	2,031	2,044	Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations.
GCST000777	Abnet CC	2010	1,625	2,100	A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma.
GCST90018621	Sakaue S	2021	1,388	159,201	A cross-population atlas of genetic associations for 220 human phenotypes.
GCST002010	Wu C	2013	1,331	0	Genome-wide association study identifies common variants in SLC39A6 associated with length of survival in esophageal squamous-cell carcinoma.
GCST90013699	Ishigaki K	2020	1,300	195,745	Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.
GCST90013738	Ishigaki K	2020	1,132	97,655	Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.
GCST90011807	Rashkin SR	2020	1,091	410,350	Pan-cancer study detects genetic risk variants and shared genetic basis in two large cohorts.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	4
Tier 2: splice/UTR	1
Tier 3: regulatory	0
Tier 4: intronic/intergenic	38

MAF distribution

Bucket	Variants
common (>=0.05)	31
low_freq (0.01-0.05)	9
rare (<0.01)	0
unknown	3

Functional consequences

Consequence	Count
intron_variant	27
intergenic_variant	9
missense_variant	4
synonymous_variant	1
3_prime_UTR_variant	1
non_coding_transcript_exon_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1229984	4	99318162	T>A,C,G	0.245	missense_variant	ADH1B	2e-46	Tier 1: coding
rs2074356	12	112207597	G>A,C,T	0.13	intron_variant	HECTD4	2e-31	Tier 4: intronic/intergenic
rs4646776	12	111792215	G>A,C	0.245	intron_variant	ALDH2	1e-25	Tier 4: intronic/intergenic
rs671	12	111803962	G>A	0.05	missense_variant	ALDH2	3e-24	Tier 1: coding
rs4822983	22	28719078	C>T	0.2	intron_variant	CHEK2	2e-22	Tier 4: intronic/intergenic
rs2014300	21	34985564	A>C,G,T	0.17	intron_variant	RUNX1	8e-22	Tier 4: intronic/intergenic
rs11066015	12	111730205	G>A	0.19	intron_variant	ACAD10	7e-21	Tier 4: intronic/intergenic
rs4785204	16	50069823	C>T	0.26	intron_variant	HEATR3	2e-20	Tier 4: intronic/intergenic
rs2274223	10	94306584	A>C,G,T	0.21	missense_variant	PLCE1	4e-20	Tier 1: coding
rs10052657	5	59111944	C>A	0.22	intron_variant	PDE4D	2e-19	Tier 4: intronic/intergenic
rs6503659	17	41741012	A>C,G,T	0.13	intergenic_variant	HAP1 - JUP	3e-16	Tier 4: intronic/intergenic
rs11066280	12	112379979	T>A,G	0.21	intron_variant	HECTD4	2e-15	Tier 4: intronic/intergenic
rs2239815	22	28796682	T>A,C,G	0.37	intron_variant	XBP1	4e-15	Tier 4: intronic/intergenic
rs2239612	3	187075454	G>A,C,T	0.19	intron_variant	ST6GAL1	6e-14	Tier 4: intronic/intergenic
rs10484761	6	40834522	T>C	0.09	intergenic_variant	LRFN2 - UNC5CL	7e-12	Tier 4: intronic/intergenic
rs8030672	15	68766745	T>A	0.03	intron_variant	CARS1P1 - ANP32A	1e-11	Tier 4: intronic/intergenic
rs17761864	17	2268343	C>A,T	0.14	intron_variant	SMG6	2e-11	Tier 4: intronic/intergenic
rs2847281	18	12821594	A>C,G,T	0.16	intron_variant	PTPN2	2e-11	Tier 4: intronic/intergenic
rs9288520	2	216616548	G>A	0.34	intergenic_variant	PSMB3P2 - IGFBP2	4e-11	Tier 4: intronic/intergenic
rs3765524	10	94298541	C>A,T	0.207	missense_variant	PLCE1	2e-09	Tier 1: coding
rs10058728	5	149524529	A>T	0.02	intron_variant	CSNK1A1	5e-09	Tier 4: intronic/intergenic
rs738722	22	28734024	T>C,G	0.25	intron_variant	CHEK2	1e-08	Tier 4: intronic/intergenic
rs75460256	2	106071382	A>G,T	0.024	intron_variant	ECRG4	1e-08	Tier 4: intronic/intergenic
rs117121174	12	110259525	G>A	0.126	intron_variant	IFT81 - ATP2A2	1e-08	Tier 4: intronic/intergenic
rs10201587	2	201338068	A>G,T	0.343	intron_variant	FLACC1, CASP8	1e-08	Tier 4: intronic/intergenic
rs76954182	11	13206905	T>C		intergenic_variant	RASSF10 - BMAL1	3e-08	Tier 4: intronic/intergenic
rs1050631	18	36114157	G>A,C,T	0.18	synonymous_variant	SLC39A6	4e-08	Tier 4: intronic/intergenic
rs2834617	21	34743557	T>C,G	0.012	intergenic_variant	LINC00160 - LINC01426	4e-08	Tier 4: intronic/intergenic
rs17450420	13	104386796	A>G	0.04	intergenic_variant	ATP6V1G1P7 - RPL7P45	5e-08	Tier 4: intronic/intergenic
rs11877682	18	45831894	C>T	0.05	intron_variant	SIGLEC15, EPG5	5e-08	Tier 4: intronic/intergenic

ClinVar germline variants

4 retrieved; paginated sample, class counts are floors:

2 likely pathogenic, 1 uncertain significance, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4526862	NM_138715.3(MSR1):c.31C>T (p.Gln11Ter)	MSR1	Likely pathogenic	criteria provided, single submitter
4526863	NM_138715.3:c.688_1356del	MSR1	Likely pathogenic	criteria provided, single submitter
4345075	NM_138715.3(MSR1):c.-4-1G>A	MSR1	Uncertain significance	criteria provided, single submitter
51465	NM_000059.4(BRCA2):c.3445A>G (p.Met1149Val)	BRCA2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 69 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
TP53	LoF	ACC,ALL,AML,ANGS,ANSC,BCC,BL,BLADDER,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,CHRCC,CLLSLL,COAD,COADREAD,CSCC,DLBCLNOS,EGC,ES,ESCA,ESCC,GB,GBC,GBM,GIST,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LMS,LNM,LUAD,LUSC,MBL,MEL,MLYM,MT,NBL,NETNOS,NHL,NPC,NSCLC,OS,OVT,PAAD,PANCREAS,PAST,PCM,PLMESO,PRAD,PRCC,PROSTATE,RCC,READ,SACA,SARCNOS,SCLC,SIC,SKCM,SKIN,SOFT_TISSUE,STAD,STOMACH,THYM,UCEC,UCS,UTUC,VULVA,WDTC,WT	CIViC #45
SLTM	Act	CCRCC,LGGNOS,LUAD,NSCLC,OS,PRCC,RCC	CIViC #52
ERBB2	Act	BLCA,BRCA,CESC,CHOL,COADREAD,EGC,ESCA,ESCC,LMS,LUAD,NSCLC,OVT,PRCC,READ,STAD,UCEC	CIViC #20
GNAS	Act	BRCA,COADREAD,ESCA,HCC,LUAD,MBL,PAAD,PANCREAS	CIViC #2319
IL6			CIViC #2970
NTRK1	Act	BRCA	CIViC #3983
RUNX1	LoF	ACYC,ALL,AML,BRCA,GBM	CIViC #43
BRCA2	LoF	BLCA,BRCA,CESC,CHOL,HCC,HNSC,LUSC,MBL,OVT,PAAD,PRAD,PROSTATE,RCC,VULVA	CIViC #7
CHEK2	Act	BRCA	CIViC #8950
TBL1XR1	Act	ALL,BL,BRCA,DLBCLNOS,MLYM,NHL,PLMESO	CIViC #15004
ALDH2	Act	OS

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TP53	Orphanet:1333	Familial pancreatic carcinoma
TP53	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
TP53	Orphanet:1501	Adrenocortical carcinoma
TP53	Orphanet:210159	Adult hepatocellular carcinoma
TP53	Orphanet:251576	Gliosarcoma
TP53	Orphanet:251579	Giant cell glioblastoma
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
TP53	Orphanet:668	Osteosarcoma
TP53	Orphanet:67038	B-cell chronic lymphocytic leukemia
TP53	Orphanet:70573	Small cell lung cancer
TP53	Orphanet:96253	Cushing disease
TP53	Orphanet:99756	Alveolar rhabdomyosarcoma
TP53	Orphanet:99757	Embryonal rhabdomyosarcoma
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
GNAS	Orphanet:189427	Cushing syndrome due to bilateral macronodular adrenocortical disease
GNAS	Orphanet:2762	Progressive osseous heteroplasia
GNAS	Orphanet:562	McCune-Albright syndrome
GNAS	Orphanet:57782	Mazabraud syndrome
GNAS	Orphanet:79443	Pseudohypoparathyroidism type 1A
GNAS	Orphanet:79444	Pseudohypoparathyroidism type 1C
GNAS	Orphanet:79445	Pseudopseudohypoparathyroidism
GNAS	Orphanet:93276	Polyostotic fibrous dysplasia
GNAS	Orphanet:93277	Monostotic fibrous dysplasia
GNAS	Orphanet:94089	Pseudohypoparathyroidism type 1B
IL6	Orphanet:85414	Systemic-onset juvenile idiopathic arthritis
NTRK1	Orphanet:146	Differentiated thyroid carcinoma
NTRK1	Orphanet:642	Hereditary sensory and autonomic neuropathy type 4
NTRK1	Orphanet:64752	Hereditary sensory and autonomic neuropathy type 5
NTRK1	Orphanet:99361	Isolated familial medullary thyroid carcinoma
RUNX1	Orphanet:102724	Acute myeloid leukemia with t(8;21)(q22;q22) translocation
RUNX1	Orphanet:521	Chronic myeloid leukemia
RUNX1	Orphanet:71290	Familial platelet disorder with associated myeloid malignancy
RUNX1	Orphanet:98850	Aggressive systemic mastocytosis
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

Cohort genes → proteins

35 cohort genes, 35 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	27
civic_only	6
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	civic_evidence
SLTM	HGNC:20709	ENSG00000137776	Q9NWH9	SAFB-like transcription modulator	civic_evidence
ERBB2	HGNC:3430	ENSG00000141736	P04626	Receptor tyrosine-protein kinase erbB-2	civic_evidence
GNAS	HGNC:4392	ENSG00000087460	O95467	Neuroendocrine secretory protein 55	civic_evidence
IL6	HGNC:6018	ENSG00000136244	P05231	Interleukin-6	civic_evidence
NTRK1	HGNC:8031	ENSG00000198400	P04629	High affinity nerve growth factor receptor	civic_evidence
RPL6	HGNC:10362	ENSG00000089009	Q02878	Large ribosomal subunit protein eL6	gwas
RUNX1	HGNC:10471	ENSG00000159216	Q01196	Runt-related transcription factor 1	gwas
SEMA5B	HGNC:10737	ENSG00000082684	Q9P283	Semaphorin-5B	gwas
ST6GAL1	HGNC:10860	ENSG00000073849	P15907	Beta-galactoside alpha-2,6-sialyltransferase 1	gwas
SLC10A2	HGNC:10906	ENSG00000125255	Q12908	Ileal sodium/bile acid cotransporter	gwas
BRAP	HGNC:1099	ENSG00000089234	Q7Z569	BRCA1-associated protein	gwas
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	clinvar
XBP1	HGNC:12801	ENSG00000100219	P17861	X-box-binding protein 1	gwas
ANP32A	HGNC:13233	ENSG00000140350	P39687	Acidic leucine-rich nuclear phosphoprotein 32 family member A	gwas
CHEK2	HGNC:16627	ENSG00000183765	O96017	Serine/threonine-protein kinase Chk2	gwas
PLCE1	HGNC:17175	ENSG00000138193	Q9P212	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1	gwas
SMG6	HGNC:17809	ENSG00000070366	Q86US8	Telomerase-binding protein EST1A	gwas
SLC39A6	HGNC:18607	ENSG00000141424	Q13433	Zinc transporter ZIP6	gwas
UNC5CL	HGNC:21203	ENSG00000124602	Q8IV45	UNC5C-like protein	gwas
ACAD10	HGNC:21597	ENSG00000111271	Q6JQN1	Acyl-CoA dehydrogenase family member 10	gwas
NOC3L	HGNC:24034	ENSG00000173145	Q8WTT2	Nucleolar complex protein 3 homolog	gwas
CSNK1A1	HGNC:2451	ENSG00000113712	P48729	Casein kinase I isoform alpha	gwas
ADH1B	HGNC:250	ENSG00000196616	P00325	All-trans-retinol dehydrogenase [NAD(+)] ADH1B	gwas
ADH4	HGNC:252	ENSG00000198099	P08319	All-trans-retinol dehydrogenase [NAD(+)] ADH4	gwas
ADH6	HGNC:255	ENSG00000172955	P28332	Alcohol dehydrogenase 6	gwas
HEATR3	HGNC:26087	ENSG00000155393	Q7Z4Q2	HEAT repeat-containing protein 3	gwas
HECTD4	HGNC:26611	ENSG00000173064	Q9Y4D8	Probable E3 ubiquitin-protein ligase HECTD4	gwas
HSCB	HGNC:28913	ENSG00000100209	Q8IWL3	Iron-sulfur cluster co-chaperone protein HscB	gwas
TBL1XR1	HGNC:29529	ENSG00000177565	Q9BZK7	F-box-like/WD repeat-containing protein TBL1XR1	gwas
ALDH2	HGNC:404	ENSG00000111275	P05091	Aldehyde dehydrogenase, mitochondrial	gwas
APEX1	HGNC:587	ENSG00000100823	P27695	DNA repair nuclease/redox regulator APEX1	gwas
MSR1	HGNC:7376	ENSG00000038945	P21757	Macrophage scavenger receptor types I and II	clinvar
PDE4D	HGNC:8783	ENSG00000113448	Q08499	3’,5’-cyclic-AMP phosphodiesterase 4D	gwas
PTPN2	HGNC:9650	ENSG00000175354	P17706	Tyrosine-protein phosphatase non-receptor type 2	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
SLTM	SAFB-like transcription modulator	When overexpressed, acts as a general inhibitor of transcription that eventually leads to apoptosis.
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.
IL6	Interleukin-6	Cytokine with a wide variety of biological functions in immunity, tissue regeneration, and metabolism.
NTRK1	High affinity nerve growth factor receptor	Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons.
RPL6	Large ribosomal subunit protein eL6	Component of the large ribosomal subunit.
RUNX1	Runt-related transcription factor 1	Forms the heterodimeric complex core-binding factor (CBF) with CBFB.
SEMA5B	Semaphorin-5B	May act as a positive axonal guidance cue.
ST6GAL1	Beta-galactoside alpha-2,6-sialyltransferase 1	Transfers sialic acid from CMP-sialic acid to galactose-containing acceptor substrates.
SLC10A2	Ileal sodium/bile acid cotransporter	Plays a critical role in the sodium-dependent reabsorption of bile acids from the lumen of the small intestine.
BRAP	BRCA1-associated protein	Negatively regulates MAP kinase activation by limiting the formation of Raf/MEK complexes probably by inactivation of the KSR1 scaffold protein.
BRCA2	Breast cancer type 2 susceptibility protein	Involved in double-strand break repair and/or homologous recombination.
XBP1	X-box-binding protein 1	Functions as a transcription factor during endoplasmic reticulum (ER) stress by regulating the unfolded protein response (UPR).
ANP32A	Acidic leucine-rich nuclear phosphoprotein 32 family member A	Multifunctional protein that is involved in the regulation of many processes including tumor suppression, apoptosis, cell cycle progression or transcription.
CHEK2	Serine/threonine-protein kinase Chk2	Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks.
PLCE1	1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1	The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes.
SMG6	Telomerase-binding protein EST1A	Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini.
SLC39A6	Zinc transporter ZIP6	Zinc-influx transporter which plays a role in zinc homeostasis and in the induction of epithelial-to-mesenchymal transition (EMT).
UNC5CL	UNC5C-like protein	Inhibits NF-kappa-B-dependent transcription by impairing NF-kappa-B binding to its targets.
ACAD10	Acyl-CoA dehydrogenase family member 10	Acyl-CoA dehydrogenase only active with R- and S-2-methyl-C15-CoA.
NOC3L	Nucleolar complex protein 3 homolog	May be required for adipogenesis.
CSNK1A1	Casein kinase I isoform alpha	Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates.
ADH1B	All-trans-retinol dehydrogenase [NAD(+)] ADH1B	Catalyzes the NAD-dependent oxidation of all-trans-retinol and its derivatives such as all-trans-4-hydroxyretinol and may participate in retinoid metabolism.
ADH4	All-trans-retinol dehydrogenase [NAD(+)] ADH4	Catalyzes the NAD-dependent oxidation of either all-trans-retinol or 9-cis-retinol.
ADH6	Alcohol dehydrogenase 6	Alcohol dehydrogenase.
HEATR3	HEAT repeat-containing protein 3	Plays a role in ribosome biogenesis and in nuclear import of the 60S ribosomal protein L5/large ribosomal subunit protein uL18 (RPL5).
HECTD4	Probable E3 ubiquitin-protein ligase HECTD4	E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.
HSCB	Iron-sulfur cluster co-chaperone protein HscB	Acts as a co-chaperone in iron-sulfur cluster assembly in mitochondria.
TBL1XR1	F-box-like/WD repeat-containing protein TBL1XR1	F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units.
ALDH2	Aldehyde dehydrogenase, mitochondrial	Required for clearance of cellular formaldehyde, a cytotoxic and carcinogenic metabolite that induces DNA damage.
APEX1	DNA repair nuclease/redox regulator APEX1	Multifunctional protein that plays a central role in the cellular response to oxidative stress.
MSR1	Macrophage scavenger receptor types I and II	Membrane glycoproteins implicated in the pathologic deposition of cholesterol in arterial walls during atherogenesis.
PDE4D	3’,5’-cyclic-AMP phosphodiesterase 4D	Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
PTPN2	Tyrosine-protein phosphatase non-receptor type 2	Non-receptor type tyrosine-specific phosphatase that dephosphorylates receptor protein tyrosine kinases including INSR, EGFR, CSF1R, PDGFR.

Protein-family classification

Druggable: 13 · Difficult: 7 · Unknown: 15 · Druggable fraction: 0.37

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	5	4.0×	0.056
Phosphatase	2	4.8×	0.228
Enzyme (other)	5	1.7×	0.381
Transporter	1	2.2×	0.510
Scaffold/PPI	3	1.5×	0.510
Transcription factor	4	0.9×	0.731
Other/Unknown	15	0.8×	0.956

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
SLTM	Other/Unknown	no		RRM_dom, SAP_dom, Nucleotide-bd_a/b_plait_sf
ERBB2	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
GNAS	Other/Unknown	no		NESP55, Gprotein_alpha_S, Gprotein_alpha_su
IL6	Other/Unknown	no		IL-6-like, 4_helix_cytokine-like_core, IL6/GCSF/MGF_CS
NTRK1	Kinase	yes	2.7.10.1	Cys-rich_flank_reg_C, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
RPL6	Scaffold/PPI	no		60S_ribosomal_eL6, Ribosomal_uL6_N, Translation_prot_SH3-like_sf
RUNX1	Transcription factor	no		AML1_Runt, p53-like_TF_DNA-bd_sf, p53/RUNT-type_TF_DNA-bd_sf
SEMA5B	Scaffold/PPI	no		TSP1_rpt, Semap_dom, Plexin_repeat
ST6GAL1	Enzyme (other)	yes	2.4.99.1	Glyco_trans_29, Sialyl_trans, GT29-like_sf
SLC10A2	Other/Unknown	no		BilAc:Na_symport/Acr3, Bilac:Na_transpt, Na+/solute_symporter_sf
BRAP	Transcription factor	no		Znf_UBP, Znf_RING, BRAP2/ETP1_RRM
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
XBP1	Transcription factor	no		bZIP, bZIP_sf, ER_Stress-Reg_TF
ANP32A	Other/Unknown	no		Leu-rich_rpt, U2A’_phosphoprotein32A_C, LRR_dom_sf
CHEK2	Kinase	yes	2.7.11.1	FHA_dom, Prot_kinase_dom, Ser/Thr_kinase_AS
PLCE1	Enzyme (other)	yes	3.1.4.11	C2_dom, RA_dom, PLipase_C_PInositol-sp_X_dom
SMG6	Other/Unknown	no		PIN_dom, TPR-like_helical_dom_sf, DNA/RNA-bd_Est1-type
SLC39A6	Transporter	yes		ZIP, ZIP_Transporter
UNC5CL	Other/Unknown	no		Death_dom, ZU5_dom, DEATH-like_dom_sf
ACAD10	Kinase	yes		Aminoglycoside_PTrfase, AcylCoA_DH/ox_M, HAD-SF_hydro_IA
NOC3L	Other/Unknown	no		CCAAT-binding_factor, Noc3_N, ARM-type_fold
CSNK1A1	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
ADH1B	Other/Unknown	no		ADH_Zn_CS, GroES-like_sf, ADH-like_C
ADH4	Enzyme (other)	yes	1.1.1.1	ADH_Zn_CS, GroES-like_sf, ADH-like_C
ADH6	Other/Unknown	no		ADH_Zn_CS, GroES-like_sf, ADH-like_C
HEATR3	Other/Unknown	no		ARM-like, ARM-type_fold, SYO1-like
HECTD4	Other/Unknown	no		HECT_dom, SPRY_HECTD4, Hect_E3_ubiquitin_ligase
HSCB	Other/Unknown	no		HscB, HscB_oligo_C, HscB_C_sf
TBL1XR1	Scaffold/PPI	no		WD40_rpt, LisH, WD40/YVTN_repeat-like_dom_sf
ALDH2	Enzyme (other)	yes	1.2.1.3	Aldehyde_DH_dom, Ald_DH_CS_CYS, Ald_DH/histidinol_DH
APEX1	Phosphatase	yes	4.2.99.18	AP_endonuc_1, Endo/exonuclease/phosphatase, AP_endonuclease_F1_BS
MSR1	Other/Unknown	no		SRCR, SR-AI/II, Collagen
PDE4D	Enzyme (other)	yes	3.1.4.53	PDEase_catalytic_dom, PDEase, PDEase_CS
PTPN2	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat

Expression context

Cohort genes with no expression data: 0.

33 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)	35
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	7
ganglionic eminence	5
ventricular zone	5
male germ line stem cell (sensu Vertebrata) in testis	4
liver	4
calcaneal tendon	3
cortical plate	3
embryo	3
jejunal mucosa	3
secondary oocyte	3
tendon of biceps brachii	2
sural nerve	2
tibia	2
lower esophagus mucosa	2
apex of heart	2
right testis	2
stromal cell of endometrium	2
parotid gland	2
lower lobe of lung	2
monocyte	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
SLTM	291	ubiquitous	marker	calcaneal tendon, sural nerve, tibia
ERBB2	276	ubiquitous	marker	lower esophagus mucosa, right uterine tube, sural nerve
GNAS	312	ubiquitous	marker	type B pancreatic cell, postcentral gyrus, Brodmann (1909) area 46
IL6	200	ubiquitous	marker	cartilage tissue, vena cava, gall bladder
NTRK1	160	broad	marker	dorsal root ganglion, apex of heart, male germ line stem cell (sensu Vertebrata) in testis
RPL6	154	ubiquitous	marker	cortical plate, ganglionic eminence, embryo
RUNX1	253	ubiquitous	marker	olfactory segment of nasal mucosa, epithelium of bronchus, mucosa of paranasal sinus
SEMA5B	164	broad	yes	ventricular zone, ganglionic eminence, tibialis anterior
ST6GAL1	294	ubiquitous	marker	liver, right lobe of liver, renal medulla
SLC10A2	49	tissue_specific	marker	ileal mucosa, jejunal mucosa, duodenum
BRAP	286	ubiquitous	marker	left testis, right testis, testis
BRCA2	184	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
XBP1	167	broad	marker	body of pancreas, trachea, pancreas
ANP32A	295	ubiquitous	marker	ganglionic eminence, cortical plate, embryo
CHEK2	183	ubiquitous	marker	primordial germ cell in gonad, lower esophagus mucosa, male germ line stem cell (sensu Vertebrata) in testis
PLCE1	271	broad	marker	renal glomerulus, metanephric glomerulus, ventricular zone
SMG6	201	ubiquitous	marker	stromal cell of endometrium, left ovary, right testis
SLC39A6	300	ubiquitous	marker	secondary oocyte, choroid plexus epithelium, pigmented layer of retina
UNC5CL	180	tissue_specific	yes	epithelial cell of pancreas, pancreatic ductal cell, kidney epithelium
ACAD10	271	ubiquitous	marker	apex of heart, right lobe of liver, parotid gland
NOC3L	276	ubiquitous	marker	secondary oocyte, calcaneal tendon, male germ line stem cell (sensu Vertebrata) in testis
CSNK1A1	294	ubiquitous	marker	stromal cell of endometrium, cortical plate, adrenal tissue
ADH1B	244	broad	marker	right lobe of liver, right coronary artery, lower lobe of lung
ADH4	200	tissue_specific	marker	jejunal mucosa, right lobe of liver, liver
ADH6	178	tissue_specific	marker	right lobe of liver, liver, jejunal mucosa
HEATR3	248	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
HECTD4	293	ubiquitous	marker	right hemisphere of cerebellum, cerebellar cortex, cerebellar hemisphere
HSCB	253	ubiquitous	marker	parotid gland, buccal mucosa cell, right lobe of liver
TBL1XR1	284	ubiquitous	marker	calcaneal tendon, nipple, tibia

Protein interactions among cohort

Intra-cohort edges: 17.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
ERBB2	9,659
IL6	9,239
NTRK1	9,181
APEX1	5,100
RPL6	5,038
RUNX1	4,994
BRCA2	4,839
CHEK2	4,795
ALDH2	4,554

Intra-cohort edges

A	B	Sources
ACAD10	ALDH2	string_interaction
ACAD10	HECTD4	string_interaction
ADH1B	ALDH2	string_interaction
ADH4	ALDH2	string_interaction
ADH6	ALDH2	string_interaction
ALDH2	HECTD4	string_interaction
ALDH2	HSCB	intact
ANP32A	APEX1	string_interaction
APEX1	TP53	string_interaction
BRCA2	CHEK2	string_interaction
BRCA2	TP53	string_interaction
CHEK2	TP53	intact, string_interaction
CSNK1A1	PLCE1	intact
HEATR3	ST6GAL1	biogrid_interaction
NOC3L	PLCE1	string_interaction
PLCE1	TP53	biogrid_interaction
PLCE1	UNC5CL	string_interaction

Structural data

PDB: 25 · AlphaFold-only: 10 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNAS	O95467	490
TP53	P04637	313
RPL6	Q02878	196
PDE4D	Q08499	122
APEX1	P27695	67
NTRK1	P04629	65
ERBB2	P04626	63
CHEK2	O96017	38
ALDH2	P05091	29
IL6	P05231	17
BRCA2	P51587	14
PTPN2	P17706	14
ANP32A	P39687	9
ADH1B	P00325	9
RUNX1	Q01196	5
XBP1	P17861	5
SMG6	Q86US8	5
CSNK1A1	P48729	5
ST6GAL1	P15907	4
NOC3L	Q8WTT2	4
PLCE1	Q9P212	3
ADH4	P08319	1
HSCB	Q8IWL3	1
TBL1XR1	Q9BZK7	1
MSR1	P21757	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADH6	P28332	95.87
ACAD10	Q6JQN1	86.83
HEATR3	Q7Z4Q2	83.07
SLC10A2	Q12908	82.88
UNC5CL	Q8IV45	80.18
BRAP	Q7Z569	76.92
SEMA5B	Q9P283	75.50
SLC39A6	Q13433	60.04
SLTM	Q9NWH9	52.38
HECTD4	Q9Y4D8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 351. Enrichment computed across 35 evidence-associated genes (30 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 30 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Ethanol oxidation	4	126.9×	7e-06	ADH1B, ADH4, ADH6, ALDH2
Phase I - Functionalization of compounds	4	29.3×	0.002	ADH1B, ADH4, ADH6, ALDH2
Biological oxidations	4	17.3×	0.009	ADH1B, ADH4, ADH6, ALDH2
Stabilization of p53	2	50.8×	0.060	TP53, CHEK2
Regulation of TP53 Activity through Methylation	2	36.2×	0.095	TP53, CHEK2
Loss of function of TP53 in cancer due to loss of tetramerization ability	1	380.7×	0.099	TP53
TRKA activation by NGF	1	190.3×	0.099	NTRK1
Metabolism of serotonin	1	190.3×	0.099	ALDH2
Regulation of TP53 Expression	1	190.3×	0.099	TP53
PLC-gamma1 signalling	1	126.9×	0.099	NTRK1
Signalling to STAT3	1	126.9×	0.099	NTRK1
Abasic sugar-phosphate removal via the single-nucleotide replacement pathway	1	126.9×	0.099	APEX1
RUNX3 regulates RUNX1-mediated transcription	1	126.9×	0.099	RUNX1
Impaired BRCA2 translocation to the nucleus	1	126.9×	0.099	BRCA2
Impaired BRCA2 binding to SEM1 (DSS1)	1	126.9×	0.099	BRCA2
Resolution of AP sites via the multiple-nucleotide patch replacement pathway	1	95.2×	0.099	APEX1
PLCG1 events in ERBB2 signaling	1	95.2×	0.099	ERBB2
Serotonin clearance from the synaptic cleft	1	95.2×	0.099	ALDH2
Transcriptional activation of cell cycle inhibitor p21	1	95.2×	0.099	TP53
Drug-mediated inhibition of ERBB2 signaling	1	95.2×	0.099	ERBB2
Resistance of ERBB2 KD mutants to trastuzumab	1	95.2×	0.099	ERBB2
Resistance of ERBB2 KD mutants to sapitinib	1	95.2×	0.099	ERBB2
Resistance of ERBB2 KD mutants to tesevatinib	1	95.2×	0.099	ERBB2
Resistance of ERBB2 KD mutants to neratinib	1	95.2×	0.099	ERBB2
Resistance of ERBB2 KD mutants to osimertinib	1	95.2×	0.099	ERBB2
Resistance of ERBB2 KD mutants to afatinib	1	95.2×	0.099	ERBB2
Resistance of ERBB2 KD mutants to AEE788	1	95.2×	0.099	ERBB2
Resistance of ERBB2 KD mutants to lapatinib	1	95.2×	0.099	ERBB2
Drug resistance in ERBB2 TMD/JMD mutants	1	95.2×	0.099	ERBB2
Translation of Structural Proteins	2	27.2×	0.099	ST6GAL1, CSNK1A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 35 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ethanol metabolic process	2	481.5×	0.002	ADH4, ALDH2
retinol metabolic process	3	42.5×	0.009	ADH1B, ADH4, ADH6
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	3	42.5×	0.009	BRCA2, TP53, CHEK2
alcohol metabolic process	2	137.6×	0.012	ADH4, ALDH2
cellular response to nutrient	2	120.4×	0.012	XBP1, CSNK1A1
DNA damage response, signal transduction by p53 class mediator	3	30.7×	0.012	BRCA2, TP53, CHEK2
negative regulation of lipid storage	2	87.5×	0.019	IL6, PTPN2
thymocyte apoptotic process	2	80.2×	0.020	TP53, CHEK2
replicative senescence	2	56.6×	0.034	TP53, CHEK2
response to X-ray	2	50.7×	0.034	BRCA2, TP53
Ras protein signal transduction	3	17.6×	0.034	BRAP, TP53, PLCE1
double-strand break repair	3	17.4×	0.034	BRCA2, TP53, CHEK2
nitroglycerin metabolic process	1	481.5×	0.035	ALDH2
alcohol catabolic process	1	481.5×	0.035	ADH4
negative regulation of helicase activity	1	481.5×	0.035	TP53
epithelial cell maturation involved in salivary gland development	1	481.5×	0.035	XBP1
cellular response to actinomycin D	1	481.5×	0.035	TP53
quinone metabolic process	1	481.5×	0.035	ADH4
negative regulation of interleukin-2-mediated signaling pathway	1	481.5×	0.035	PTPN2
negative regulation of positive thymic T cell selection	1	481.5×	0.035	PTPN2
regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	481.5×	0.035	TP53
regulation of dopamine biosynthetic process	1	481.5×	0.035	ALDH2
negative regulation of G1 to G0 transition	1	481.5×	0.035	TP53
regulation of connective tissue replacement	1	481.5×	0.035	RUNX1
regulation of serotonin biosynthetic process	1	481.5×	0.035	ALDH2
retinoic acid metabolic process	2	45.9×	0.035	ADH1B, ADH6
hematopoietic stem cell proliferation	2	37.0×	0.035	RUNX1, BRCA2
cellular response to gamma radiation	2	34.4×	0.035	TP53, CHEK2
response to gamma radiation	2	33.2×	0.035	BRCA2, TP53
positive regulation of Rho protein signal transduction	2	33.2×	0.035	CSNK1A1, ERBB2

Therapeutics

Drugs indicated for this disease

0 approved, 25 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Atezolizumab	Phase 3 (in late-stage trials)
Camrelizumab	Phase 3 (in late-stage trials)
Capecitabine	Phase 3 (in late-stage trials)
Carboplatin	Phase 3 (in late-stage trials)
Cetuximab	Phase 3 (in late-stage trials)
Cisplatin	Phase 3 (in late-stage trials)
Fluorouracil	Phase 3 (in late-stage trials)
Gimeracil	Phase 3 (in late-stage trials)
Irinotecan	Phase 3 (in late-stage trials)
Lobaplatin	Phase 3 (in late-stage trials)
Nedaplatin	Phase 3 (in late-stage trials)
Nimotuzumab	Phase 3 (in late-stage trials)
Nivolumab	Phase 3 (in late-stage trials)
Oteracil	Phase 3 (in late-stage trials)
Oxaliplatin	Phase 3 (in late-stage trials)
Paclitaxel	Phase 3 (in late-stage trials)
Pembrolizumab	Phase 3 (in late-stage trials)
Pertuzumab	Phase 3 (in late-stage trials)
Rivoceranib	Phase 3 (in late-stage trials)
Serplulimab	Phase 3 (in late-stage trials)
Sintilimab	Phase 3 (in late-stage trials)
Tegafur	Phase 3 (in late-stage trials)
Tiragolumab	Phase 3 (in late-stage trials)
Toripalimab	Phase 3 (in late-stage trials)
Trastuzumab	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Benmelstobart, Bevacizumab, Bintrafusp Alfa, Enoxaparin Sodium, Erlotinib, Ipilimumab, Onabotulinumtoxina, Panitumumab, Pemetrexed, Ramucirumab.

Drug target analysis

Approved (phase 4): 15 · Phase ≥3: 15 · Phased (≥1): 16 · Undrugged: 19

Druggability breadth: 26 of 35 evidence-associated genes (74%) 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
TP53	NITROFURANTOIN
SLTM	CABOZANTINIB
ERBB2	CLOTRIMAZOLE
IL6	PREDNISOLONE
NTRK1	PONATINIB
RPL6	GENTAMICIN SULFATE
RUNX1	APOMORPHINE HYDROCHLORIDE
SLC10A2	URSODIOL
XBP1	TERFENADINE
CHEK2	NERATINIB
ACAD10	GEFITINIB
CSNK1A1	PYRVINIUM
ALDH2	DISULFIRAM
APEX1	CEFOTAXIME SODIUM
PDE4D	INAMRINONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDE4D	269	4
TP53	196	4
ERBB2	83	4
NTRK1	66	4
APEX1	53	4
CHEK2	30	4
CSNK1A1	29	4
SLC10A2	9	4
ACAD10	7	4
XBP1	4	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	PDE4D, TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	ERBB2, TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	PDE4D, 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
MECHLORETHAMINE HYDROCHLORIDE	4	TP53
ECONAZOLE NITRATE	4	TP53
TRIFLUPROMAZINE HYDROCHLORIDE	4	TP53
PROCHLORPERAZINE EDISYLATE	4	TP53
DEQUALINIUM CHLORIDE	4	APEX1, TP53

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 11.

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

Symbol	Assays	Type breakdown
ERBB2	1,221	Binding:1136, Functional:79, ADMET:6
NTRK1	1,194	Binding:1182, ADMET:7, Functional:5
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
PDE4D	863	Binding:805, Functional:33, ADMET:23, Toxicity:2
CHEK2	690	Binding:687, Functional:2, ADMET:1
CSNK1A1	518	Binding:514, Functional:4
PTPN2	250	Binding:246, ADMET:4
RPL6	90	Binding:90
ALDH2	71	Binding:66, Functional:5
APEX1	49	Binding:45, Functional:4
SLC10A2	47	Binding:28, Functional:19
ST6GAL1	27	Binding:27
RUNX1	20	Binding:17, Functional:3
IL6	16	Binding:16
SLTM	14	Binding:14
ADH1B	13	Binding:13
ADH4	13	Binding:13
ADH6	11	Binding:11
XBP1	7	Binding:6, Functional:1
ANP32A	3	Binding:3
ACAD10	3	Binding:3
BRAP	2	Binding:2
TBL1XR1	2	Binding:2
MSR1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ERBB2	2.7.10.1	receptor protein-tyrosine kinase
NTRK1	2.7.10.1	receptor protein-tyrosine kinase
ST6GAL1	2.4.99.1	beta-galactoside alpha-(2,6)-sialyltransferase
CHEK2	2.7.11.1	non-specific serine/threonine protein kinase
PLCE1	3.1.4.11	phosphoinositide phospholipase C
CSNK1A1	2.7.11.1	non-specific serine/threonine protein kinase
ADH4	1.1.1.1	alcohol dehydrogenase
ALDH2	1.2.1.3	aldehyde dehydrogenase (NAD+)
APEX1	4.2.99.18	DNA-(apurinic or apyrimidinic site) lyase
PDE4D	3.1.4.53	3’,5’-cyclic-AMP phosphodiesterase
PTPN2	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TP53	869
ERBB2	1,221
NTRK1	1,194
CHEK2	690
CSNK1A1	518
PDE4D	863
PTPN2	250

Pharmacogenomics

Cohort genes with a PharmGKB record: 35; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

29 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Compound	Max phase	Cohort target (bioactivity)
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	PDE4D, TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	ERBB2, TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	PDE4D, 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
MECHLORETHAMINE HYDROCHLORIDE	4	TP53
ECONAZOLE NITRATE	4	TP53
TRIFLUPROMAZINE HYDROCHLORIDE	4	TP53
PROCHLORPERAZINE EDISYLATE	4	TP53
DEQUALINIUM CHLORIDE	4	APEX1, TP53

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	15	TP53, SLTM, ERBB2, IL6, NTRK1, RPL6, RUNX1, SLC10A2, XBP1, CHEK2 (+5 more)
B	Phased (≥1) drug, not yet approved	1	PTPN2
C	Druggable family + PDB, no drug	3	ST6GAL1, PLCE1, ADH4
D	Druggable family + AlphaFold only, no drug	1	SLC39A6
E	Difficult family or no structure, no drug	15	GNAS, SEMA5B, BRAP, BRCA2, ANP32A, SMG6, UNC5CL, NOC3L, ADH1B, ADH6 (+5 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ANP32A	3	APEX1
ADH1B	13	ALDH2
ADH4	13	ALDH2
ADH6	11	ALDH2
HECTD4	0	ALDH2, ACAD10
GNAS	0	—
SEMA5B	0	—
ST6GAL1	27	—
BRAP	2	—
BRCA2	0	—
PLCE1	0	—
SMG6	0	—
SLC39A6	0	—
UNC5CL	0	—
NOC3L	0	—
HEATR3	0	—
HSCB	0	—
TBL1XR1	2	—
MSR1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1,300.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	392
PHASE2	322
PHASE1	162
PHASE1/PHASE2	95
PHASE3	84
PHASE4	20
PHASE2/PHASE3	16
EARLY_PHASE1	9

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05183126	PHASE4	RECRUITING	Pharmacokinetic Study of Skeletal Muscle Area-based Paclitaxel Infusion in Patients With Cancer
NCT06437288	PHASE4	ENROLLING_BY_INVITATION	Hematoporphyrin Photodynamic Therapy for Esophageal Cancer
NCT07124351	PHASE4	RECRUITING	Intraoperative Imaging of Gastrointestinal Malignancies Using Pafolacianine (CYTALUX™)
NCT00333099	PHASE4	COMPLETED	INEC Study: Immuno-modulating Enteral Nutrition in Cancer
NCT00365508	PHASE4	COMPLETED	Counseling and Nicotine Replacement Therapy in Helping Adult Smokers Quit Smoking
NCT00642239	PHASE4	UNKNOWN	A Clinical Trial of a Radiation Sensitizer in Radiochemotherapy for Thoracic Esophageal Squamous Carcinoma
NCT00666978	PHASE4	COMPLETED	Health Education Counseling With or Without Bupropion in Helping African Americans Stop Smoking
NCT00754468	PHASE4	COMPLETED	Study of CryoSpray Ablation(TM)to Determine Treatment Effect, Depth of Injury, and Side Effects in the Esophagus.
NCT00790140	PHASE4	UNKNOWN	Trial of Enteral Nutrition Enriched With Eicosapentaenoic Acid (EPA) in Upper Gastrointestinal Cancer Surgery
NCT00911092	PHASE4	COMPLETED	Predictive Proteomic Factors of the Response to Concomitant Radiochemotherapy in Esophageal Cancer
NCT01038154	PHASE4	UNKNOWN	Study to Evaluate the Efficacy of Pravastatin on Survival and Recurrence of Advanced Gastroesophageal Cancer
NCT01416077	PHASE4	COMPLETED	Decreasing Postoperative Complications by Goal-Directed Fluid Therapy During Esophageal Resection
NCT01927328	PHASE4	UNKNOWN	Iron Replacement in Oesophagogastric Neoplasia
NCT01962272	PHASE4	COMPLETED	The Effect of Nutritional Counseling for Cancer Patients
NCT02042313	PHASE4	UNKNOWN	Postoperative Pain Management After Minimally Invasive Esophagectomy
NCT02320734	PHASE4	COMPLETED	Deep Neuromuscular Relaxation in Patients for Thoraco-laparoscopic Esophagectomy
NCT03384511	PHASE4	COMPLETED	The Use of 18F-ALF-NOTA-PRGD2 PET/CT Scan to Predict the Efficacy and Adverse Events of Apatinib in Malignancies.
NCT03413436	PHASE4	COMPLETED	Lobaplation or Cisplatin in Adjuvant Chemotherapy for Esophageal Carcinoma
NCT03642093	PHASE4	UNKNOWN	HOPE - A Study to Evaluate the Effect of a Prehabilitation Program on GI Cancer Patients Planning to Undergo Surgery
NCT04269369	PHASE4	UNKNOWN	Implementation of Pre-emptive Geno- and Phenotyping in 5-Fluorouracil- or Capecitabine-treated Patients
NCT03731442	PHASE3	RECRUITING	Salvage Chemoradiation Therapy for Recurrence After Radical Surgery or Palliative Surgery in Esophageal Cancer Patients
NCT04135664	PHASE3	RECRUITING	Comparison of Esophagectomy and Chemoradiation for Patients With cN0-pT1b Stage Esophageal Squamous Cell Carcinoma
NCT04280822	PHASE3	RECRUITING	Neo-adjuvant Immunochemotheray Versus Neo-adjuvant Chemotherapy for Resectable Esophageal Carcinoma
NCT04415853	PHASE3	RECRUITING	Study of Larotinib in Unresectable Advanced or Recurrent Esophageal Cancer
NCT04513808	PHASE3	RECRUITING	Total Intravenous Anesthesia and Recurrence Free Survival
NCT04821843	PHASE3	RECRUITING	Neoadjuvant Treatment Modalities in Esophageal Cancer
NCT04871412	PHASE3	RECRUITING	The Thoracic Peri-Operative Integrative Surgical Care Evaluation Trial - Stage III
NCT05055648	PHASE3	RECRUITING	PROton Versus Photon Therapy for Esophageal Cancer - a Trimodality Strategy
NCT05188313	PHASE3	RECRUITING	TRAstuzumab and Pertuzumab for HER2+ Resectable Oesophageal Cancer
NCT05357846	PHASE3	RECRUITING	PD-1 Inhibitor Combined With Neoadjuvant Chemoradiotherapy Plus Surgery for Locally Advanced ESCC (NEOCRTEC2101)
NCT05504265	PHASE2/PHASE3	RECRUITING	Perioperative Analgesia Modes in Minimally Invasive Esophagectomy
NCT05547529	PHASE3	RECRUITING	The Efficacy of Neoadjuvant Chemoradiotherapy in Comparison With Neoadjuvant Chemotherapy in Patients With Resectable Squamous Cell Esophageal Cancer
NCT05865743	PHASE3	RECRUITING	Perioperative SDD to Prevent Infectious Complications After Esophagectomy
NCT06115629	PHASE3	NOT_YET_RECRUITING	Surveillance After Resection of Oesophageal aNd Gastric Cancer (SARONG-II) Trial
NCT06339060	PHASE3	RECRUITING	An Organ Preservation Strategies After Chemoradiotherapy Combined With Immunotherapy for Esophageal Cancer (PALACE3).
NCT06501664	PHASE3	NOT_YET_RECRUITING	Liposomal Irinotecan and 5-FU as Second-line Therapy for Patients With ESCC
NCT06676449	PHASE3	RECRUITING	TDLN-sparing RT Plus Immunotherapy and Chemotherapy in Locally Advanced ESCC
NCT06782412	PHASE2/PHASE3	RECRUITING	Multicenter Validation Trial of [18F]AlF-FAPI-74 for PET Imaging of Cancer-associated Fibroblasts Through Fibroblast Activation Protein Inhibitors (FAPI) in Different Tumor Types
NCT06914011	PHASE3	NOT_YET_RECRUITING	Circulating Tumor DNA MRD-Guided Adjuvant Therapy for Curatively Resected Locally Advanced Esophageal Squamous Cell Carcinoma
NCT06964568	PHASE3	RECRUITING	CCRT Followed by PD-1 Inhibitor Maintenance Therapy in Locally Advanced ESCC

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
IRINOTECAN	4	19
EPIRUBICIN	4	8
CISPLATIN	4	6
FLUOROURACIL	4	6
AFATINIB	4	4
ERLOTINIB HYDROCHLORIDE	4	4
INDOCYANINE GREEN ACID FORM	4	4
PANITUMUMAB	4	4
SUNITINIB MALATE	4	4
CETUXIMAB	4	3
FLOXURIDINE	4	3
HYDROXYUREA	4	3
NICOTINE	4	3
TORIPALIMAB	4	3
EFLORNITHINE	4	2
FERUMOXYTOL	4	2
FLUDEOXYGLUCOSE F 18	4	2
IXABEPILONE	4	2
NIRAPARIB	4	2
PEMBROLIZUMAB	4	2
RAMUCIRUMAB	4	2
RELATLIMAB	4	2
SARGRAMOSTIM	4	2
TEGAFUR	4	2
TRASTUZUMAB EMTANSINE	4	2
TREMELIMUMAB	4	2
VANDETANIB	4	2
VINORELBINE	4	2
ALDESLEUKIN	4	1
AMIODARONE HYDROCHLORIDE	4	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 12 predictive associations from 12 curated evidence items; also 1 prognostic.

Molecular subtype	Therapy	Effect	Level	CIViC
TP53 Wildtype	Chemotherapy	Sensitivity/Response	CIViC B	EID906
GNAS c.393T>C	Cisplatin + Fluorouracil	Resistance	CIViC B	EID2895
NTRK1 Amplification	Larotrectinib	Sensitivity/Response	CIViC C	EID12120
CDK9 Overexpression	Alvocidib + CAN508	Sensitivity/Response	CIViC D	EID9311
ERBB2 Amplification	Ibrutinib	Sensitivity/Response	CIViC D	EID6929
HDAC6 Overexpression	Panobinostat + Trichostatin A + Vorinostat	Sensitivity/Response	CIViC D	EID9856
HDAC9 Overexpression	HDAC Inhibitor REC-2282	Sensitivity/Response	CIViC D	EID9855
MYC Amplification	Ibrutinib	Sensitivity/Response	CIViC D	EID6928
YAP1 Overexpression	Verteporfin	Sensitivity/Response	CIViC D	EID1983
YAP1 Overexpression	Docetaxel + Verteporfin	Sensitivity/Response	CIViC D	EID9329
IL6 Overexpression	Cisplatin	Resistance	CIViC D	EID7851
YAP1 Overexpression	Docetaxel + Fluorouracil	Resistance	CIViC D	EID1982