Estrogen-receptor negative breast cancer

disease

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Also known as ER- breast cancer

Summary

Estrogen-receptor negative breast cancer (MONDO:0006513) is a cancer with 61 cohort genes (186 GWAS associations across 25 studies; 14 CIViC-evidence somatic drivers) and 22 clinical trials. The dominant Reactome pathway is Cell Cycle (7 cohort genes). Molecularly, RET Overexpression confers sensitivity to Vandetanib in Estrogen-receptor Negative Breast Cancer (CIViC Level D). Top therapeutic interventions include carboplatin, aldesleukin, and busulfan.

At a glance

Classification: Cancer
Cohort genes: 61
GWAS associations: 186
Clinical trials: 22
Precision-medicine evidence (CIViC): 1 subtype–drug association

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	estrogen-receptor negative breast cancer
Mondo ID	MONDO:0006513
EFO	EFO:1000650
DOID	DOID:0060076
Is cancer (heuristic)	yes

Also known as: ER- breast cancer

Data availability: 186 GWAS associations (25 studies).

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › cancer › carcinoma › breast carcinoma › breast carcinoma by gene expression profile › estrogen-receptor negative breast cancer

Subtypes (1): triple-negative breast carcinoma

Genetics & variants

GWAS landscape

186 GWAS associations across 25 studies. Top hits map to 25 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs2242652	9e-43	TERT	A
rs9397437	3e-40	CCDC170 - ESR1	A	1.32
rs67397200	3e-37	ANKLE1 - ABHD8	G	1.17
rs78378222	4e-36	TP53	T
rs10069690	2e-35	TERT	T	1.18
rs11200014	8e-35	FGFR2	A
rs149934734	3e-32	C11orf65	T
rs3757322	3e-31	CCDC170	G	1.15
rs1421085	9e-30	FTO	T
rs12601991	7e-28	HNF1B	T
rs4784227	2e-26	CASC16	T	1.14
rs7297051	9e-25	PTHLH - CCDC91	C	1.15
rs4245739	3e-23	MDM4	C	1.14
rs61494113	3e-21	ANKLE1 - ABHD8	A	1.26
rs3215401	6e-21	TERT - MIR4457	A	1.14
rs56069439	8e-19	ANKLE1	?	1.16
rs2747652	2e-18	ESR1	C	1.1
rs616488	4e-18	PEX14	A	1.12
rs143521471	4e-18	TNRC6B	T
rs7710703	5e-18	TERT	T
rs7713218	5e-18	TERT	A
rs11155804	8e-18	CCDC170 - ESR1	?	1.16
rs72993806	8e-16	POGLUT3	C
rs73110464	2e-15	KRT8	T
rs12662670	9e-15	CCDC170	?	1.2
rs56345976	2e-14	TERT	A
rs10789665	3e-14	POGLUT3	T
rs7931342	4e-14	SMIM38 - MYEOV	G
rs11571833	2e-13	BRCA2	T	1.58
rs10771399	4e-13	PTHLH - CCDC91	?	1.27

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90319501	Tang M	2023	53,386	183,232	Epidemiological and Genetic Analyses of Schizophrenia and Breast Cancer.
GCST90134422	Wu X	2022	35,474	373,479	Investigating the shared genetic architecture of uterine leiomyoma and breast cancer: A genome-wide cross-trait analysis.
GCST002861	Guo Q	2015	23,059	0	Identification of novel genetic markers of breast cancer survival.
GCST90651106	Wu X	2023	21,468	105,974	Using human genetics to understand the phenotypic association between chronotype and breast cancer.
GCST90026469	Adedokun B	2021	21,468	105,974	Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women.
GCST005076	Milne RL	2017	14,135	58,126	Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.
GCST003587	Fehringer G	2016	5,020	61,820	Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations.
GCST003588	Fehringer G	2016	5,020	61,820	Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations.
GCST003842	Couch FJ	2016	4,939	14,352	Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer.
GCST90296721	Jia G	2024	4,924	17,058	Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	2
Tier 2: splice/UTR	5
Tier 3: regulatory	2
Tier 4: intronic/intergenic	41

MAF distribution

Bucket	Variants
common (>=0.05)	46
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	3

Functional consequences

Consequence	Count
intron_variant	33
intergenic_variant	5
3_prime_UTR_variant	4
regulatory_region_variant	2
non_coding_transcript_exon_variant	2
stop_gained	1
synonymous_variant	1
missense_variant	1
splice_polypyrimidine_tract_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs2242652	5	1279913	G>A	0.05	intron_variant	TERT	9e-43	Tier 4: intronic/intergenic
rs9397437	6	151631197	G>A	0.07	intergenic_variant	CCDC170 - ESR1	3e-40	Tier 4: intronic/intergenic
rs67397200	19	17290595	C>G	0.32	intergenic_variant	ANKLE1 - ABHD8	3e-37	Tier 4: intronic/intergenic
rs78378222	17	7668434	T>A,G		3_prime_UTR_variant	TP53	4e-36	Tier 2: splice/UTR
rs10069690	5	1279675	C>T	0.26	intron_variant	TERT	2e-35	Tier 4: intronic/intergenic
rs11200014	10	121575416	G>A,T	0.05	intron_variant	FGFR2	8e-35	Tier 4: intronic/intergenic
rs149934734	11	108444879	C>T	0.05	intron_variant	C11orf65	3e-32	Tier 4: intronic/intergenic
rs3757322	6	151621059	T>A,G	0.32	3_prime_UTR_variant	CCDC170	3e-31	Tier 2: splice/UTR
rs1421085	16	53767042	T>C	0.05	intron_variant	FTO	9e-30	Tier 4: intronic/intergenic
rs12601991	17	37741642	T>A,G	0.05	intron_variant	HNF1B	7e-28	Tier 4: intronic/intergenic
rs4784227	16	52565276	C>A,T	0.24	intron_variant	CASC16	2e-26	Tier 4: intronic/intergenic
rs7297051	12	28021884	C>G,T	0.24	regulatory_region_variant	PTHLH - CCDC91	9e-25	Tier 3: regulatory
rs4245739	1	204549714	C>A,G,T	0.26	3_prime_UTR_variant	MDM4	3e-23	Tier 2: splice/UTR
rs61494113	19	17291050	G>A	0.41	intergenic_variant	ANKLE1 - ABHD8	3e-21	Tier 4: intronic/intergenic
rs3215401	5	1296141	A>AG	0.31	non_coding_transcript_exon_variant	TERT - MIR4457	6e-21	Tier 4: intronic/intergenic
rs56069439	19	17283116	C>A	0.3	intron_variant	ANKLE1	8e-19	Tier 4: intronic/intergenic
rs2747652	6	152115881	T>C,G	0.48	intron_variant	ESR1	2e-18	Tier 4: intronic/intergenic
rs616488	1	10506158	A>C,G,T	0.33	intron_variant	PEX14	4e-18	Tier 4: intronic/intergenic
rs143521471	22	40243702	C>A,G,T	0.05	intron_variant	TNRC6B	4e-18	Tier 4: intronic/intergenic
rs7710703	5	1287390	T>A,C	0.05	intron_variant	TERT	5e-18	Tier 4: intronic/intergenic
rs7713218	5	1283197	A>C,G,T	0.05	intron_variant	TERT	5e-18	Tier 4: intronic/intergenic
rs11155804	6	151625017	T>A,G	0.34	intergenic_variant	CCDC170 - ESR1	8e-18	Tier 4: intronic/intergenic
rs72993806	11	108488962	C>G	0.05	intron_variant	POGLUT3	8e-16	Tier 4: intronic/intergenic
rs73110464	12	52918828	C>A,T	0.05	intron_variant	KRT8	2e-15	Tier 4: intronic/intergenic
rs12662670	6	151597721	T>C,G	0.08	intron_variant	CCDC170	9e-15	Tier 4: intronic/intergenic
rs56345976	5	1276758	G>A	0.05	intron_variant	TERT	2e-14	Tier 4: intronic/intergenic
rs10789665	11	108485953	T>C	0.05	intron_variant	POGLUT3	3e-14	Tier 4: intronic/intergenic
rs7931342	11	69227030	T>G	0.05	intron_variant	SMIM38 - MYEOV	4e-14	Tier 4: intronic/intergenic
rs11571833	13	32398489	A>T	0.01	stop_gained	BRCA2	2e-13	Tier 1: coding
rs10771399	12	28002147	A>G	0.12	intergenic_variant	PTHLH - CCDC91	4e-13	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 77 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 2

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
BRCA2	BRCA2	GWAS, Orphanet
ESR1	ESR1	GWAS, Orphanet

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
RET	Act	ANGS,MEL,NSCLC,PGNG,SOFT_TISSUE,WDTC	CIViC #42
BRCA2	LoF	BLCA,BRCA,CESC,CHOL,HCC,HNSC,LUSC,MBL,OVT,PAAD,PRAD,PROSTATE,RCC,VULVA	CIViC #7
TERT	Act	PRCC	CIViC #79
CCNE1			CIViC #11
CDKN2B			CIViC #916
ROBO4			CIViC #12367
CHEK1			CIViC #981
SH2B3	Act	MDS	CIViC #7954
ESR1	Act	BRCA,LUSC,MEL,UCEC	CIViC #21
FGFR2	Act	BRCA,CHOL,LUSC,SACA,UCEC	CIViC #22
HLA-C	LoF	DLBCLNOS	CIViC #2608
KLF5	Act	BLCA,CESC,LUSC	CIViC #634
MDM4			CIViC #3466
RAD51B			CIViC #4763

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RET	Orphanet:146	Differentiated thyroid carcinoma
RET	Orphanet:1848	Renal agenesis, bilateral
RET	Orphanet:247698	Multiple endocrine neoplasia type 2A
RET	Orphanet:247709	Multiple endocrine neoplasia type 2B
RET	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
RET	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
RET	Orphanet:388	Hirschsprung disease
RET	Orphanet:93100	Renal agenesis, unilateral
RET	Orphanet:99361	Isolated familial medullary thyroid carcinoma
RET	Orphanet:99803	Haddad syndrome
BRCA2	Orphanet:1331	Familial prostate cancer
BRCA2	Orphanet:1333	Familial pancreatic carcinoma
BRCA2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRCA2	Orphanet:178	Chordoma
BRCA2	Orphanet:227535	Hereditary breast cancer
BRCA2	Orphanet:319462	Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations
BRCA2	Orphanet:440437	Familial colorectal cancer Type X
BRCA2	Orphanet:654	Nephroblastoma
BRCA2	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
BRCA2	Orphanet:694963	Inflammatory breast cancer
BRCA2	Orphanet:70567	Cholangiocarcinoma
BRCA2	Orphanet:84	Fanconi anemia
HNF1B	Orphanet:1309	Medullary sponge kidney
HNF1B	Orphanet:1331	Familial prostate cancer
HNF1B	Orphanet:2578	Mayer-Rokitansky-Küster-Hauser syndrome type 2
HNF1B	Orphanet:261265	17q12 microdeletion syndrome
HNF1B	Orphanet:93111	HNF1B-related autosomal dominant tubulointerstitial kidney disease
HNF1B	Orphanet:93172	Renal dysplasia, unilateral
HNF1B	Orphanet:93173	Renal dysplasia, bilateral
HNF1B	Orphanet:97363	Unilateral multicystic dysplastic kidney
HNF1B	Orphanet:97364	Bilateral multicystic dysplastic kidney
TERT	Orphanet:146	Differentiated thyroid carcinoma
TERT	Orphanet:1501	Adrenocortical carcinoma
TERT	Orphanet:1775	Dyskeratosis congenita
TERT	Orphanet:2032	Idiopathic pulmonary fibrosis
TERT	Orphanet:2495	Meningioma
TERT	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
TERT	Orphanet:457246	Clear cell sarcoma of kidney
TERT	Orphanet:618	Familial melanoma
TERT	Orphanet:88	Idiopathic aplastic anemia
CDH2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
CDKN2B	Orphanet:618	Familial melanoma
CDKN2B	Orphanet:652	Multiple endocrine neoplasia type 1
ROBO4	Orphanet:402075	Familial bicuspid aortic valve
ZNF365	Orphanet:2073	Narcolepsy type 1
ZNF365	Orphanet:83465	Narcolepsy type 2
NEK10	Orphanet:244	Primary ciliary dyskinesia
FTO	Orphanet:210144	Lethal polymalformative syndrome, Boissel type
HEPACAM	Orphanet:210548	Macrocephaly-intellectual disability-autism syndrome
HEPACAM	Orphanet:2478	Megalencephalic leukoencephalopathy with subcortical cysts

Cohort genes → proteins

61 cohort genes, 58 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	60
civic_only	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RET	HGNC:9967	ENSG00000165731	P07949	Proto-oncogene tyrosine-protein kinase receptor Ret	civic_evidence
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	gwas
HNF1B	HGNC:11630	ENSG00000275410	P35680	Hepatocyte nuclear factor 1-beta	gwas
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	gwas
TNFSF10	HGNC:11925	ENSG00000121858	P50591	Tumor necrosis factor ligand superfamily member 10	gwas
TOX3	HGNC:11972	ENSG00000103460	O15405	TOX high mobility group box family member 3	gwas
ACRV1	HGNC:127	ENSG00000134940	P26436	Acrosomal protein SP-10	gwas
CCNE1	HGNC:1589	ENSG00000105173	P24864	G1/S-specific cyclin-E1	gwas
RALY	HGNC:15921	ENSG00000125970	Q9UKM9	RNA-binding protein Raly	gwas
PKNOX2	HGNC:16714	ENSG00000165495	Q96KN3	Homeobox protein PKNOX2	gwas
CDH2	HGNC:1759	ENSG00000170558	P19022	Cadherin-2	gwas
CDKN2B	HGNC:1788	ENSG00000147883	P42772	Cyclin-dependent kinase 4 inhibitor B	gwas
ROBO4	HGNC:17985	ENSG00000154133	Q8WZ75	Roundabout homolog 4	gwas
ZNF365	HGNC:18194	ENSG00000138311	Q70YC4	Talanin	gwas
NEK10	HGNC:18592	ENSG00000163491	Q6ZWH5	Serine/threonine-protein kinase Nek10	gwas
CHEK1	HGNC:1925	ENSG00000149554	O14757	Serine/threonine-protein kinase Chk1	gwas
LGR6	HGNC:19719	ENSG00000133067	Q9HBX8	Leucine-rich repeat-containing G-protein coupled receptor 6	gwas
FRY	HGNC:20367	ENSG00000073910	Q5TBA9	Protein furry homolog	gwas
SLC37A2	HGNC:20644	ENSG00000134955	Q8TED4	Glucose-6-phosphate exchanger SLC37A2	gwas
CLK1	HGNC:2068	ENSG00000013441	P49759	Dual specificity protein kinase CLK1	gwas
TUBA1C	HGNC:20768	ENSG00000167553	Q9BQE3	Tubulin alpha-1C chain	gwas
L3MBTL3	HGNC:23035	ENSG00000198945	Q96JM7	Lethal(3)malignant brain tumor-like protein 3	gwas
ADCY9	HGNC:240	ENSG00000162104	O60503	Adenylate cyclase type 9	gwas
PATE1	HGNC:24664	ENSG00000171053	Q8WXA2	Prostate and testis expressed protein 1	gwas
FTO	HGNC:24678	ENSG00000140718	Q9C0B1	Alpha-ketoglutarate-dependent dioxygenase FTO	gwas
BABAM1	HGNC:25008	ENSG00000105393	Q9NWV8	BRISC and BRCA1-A complex member 1	gwas
CCDC15	HGNC:25798	ENSG00000149548	Q0P6D6	Coiled-coil domain-containing protein 15	gwas
HEPACAM	HGNC:26361	ENSG00000165478	Q14CZ8	Hepatic and glial cell adhesion molecule	gwas
HYLS1	HGNC:26558	ENSG00000198331	Q96M11	Centriolar and ciliogenesis-associated protein HYLS1	gwas
ANKLE1	HGNC:26812	ENSG00000160117	Q8NAG6	Structure-specific endonuclease ANKLE1	gwas
TMEM218	HGNC:27344	ENSG00000150433	A2RU14	Transmembrane protein 218	gwas
POGLUT3	HGNC:28496	ENSG00000178202	Q7Z4H8	Protein O-glucosyltransferase 3	gwas
HYCC2	HGNC:28593	ENSG00000155744	Q8IXS8	Hyccin 2	gwas
WDR43	HGNC:28945	ENSG00000163811	Q15061	WD repeat-containing protein 43	gwas
SH2B3	HGNC:29605	ENSG00000111252	Q9UQQ2	SH2B adapter protein 3	gwas
PATE2	HGNC:32249	ENSG00000196844	Q6UY27	Prostate and testis expressed protein 2	gwas
HEPN1	HGNC:34400	ENSG00000221932	Q6WQI6	Protein HEPN1	gwas
ESR1	HGNC:3467	ENSG00000091831	P03372	Estrogen receptor	gwas
PATE3	HGNC:35426	ENSG00000236027	B3GLJ2	Prostate and testis expressed protein 3	gwas
PATE4	HGNC:35427	ENSG00000237353	P0C8F1	Prostate and testis expressed protein 4	gwas
RPL23AP53	HGNC:35921	ENSG00000223508		ribosomal protein L23a pseudogene 53	gwas
FEZ1	HGNC:3659	ENSG00000149557	Q99689	Fasciculation and elongation protein zeta-1	gwas
FGFR2	HGNC:3689	ENSG00000066468	P21802	Fibroblast growth factor receptor 2	gwas
MIR4757	HGNC:41746	ENSG00000266738		microRNA 4757	gwas
GBA1LP	HGNC:4178	ENSG00000160766		glucosylceramidase beta 1 like, pseudogene	gwas
HLA-C	HGNC:4933	ENSG00000204525	P10321	HLA class I histocompatibility antigen, C alpha chain	gwas
ANXA13	HGNC:536	ENSG00000104537	P27216	Annexin A13	gwas
INHBB	HGNC:6067	ENSG00000163083	P09529	Inhibin beta B chain	gwas
STT3A	HGNC:6172	ENSG00000134910	P46977	Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit STT3A	gwas
KCNH1	HGNC:6250	ENSG00000143473	O95259	Voltage-gated delayed rectifier potassium channel KCNH1	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RET	Proto-oncogene tyrosine-protein kinase receptor Ret	Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN,…
BRCA2	Breast cancer type 2 susceptibility protein	Involved in double-strand break repair and/or homologous recombination.
HNF1B	Hepatocyte nuclear factor 1-beta	Transcription factor that binds to the inverted palindrome 5’-GTTAATNATTAAC-3'.
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
TNFSF10	Tumor necrosis factor ligand superfamily member 10	Cytokine that binds to TNFRSF10A/TRAILR1, TNFRSF10B/TRAILR2, TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4 and possibly also to TNFRSF11B/OPG.
TOX3	TOX high mobility group box family member 3	Transcriptional coactivator of the p300/CBP-mediated transcription complex.
CCNE1	G1/S-specific cyclin-E1	Essential for the control of the cell cycle at the G1/S (start) transition.
RALY	RNA-binding protein Raly	RNA-binding protein that acts as a transcriptional cofactor for cholesterol biosynthetic genes in the liver.
CDH2	Cadherin-2	Calcium-dependent cell adhesion protein; preferentially mediates homotypic cell-cell adhesion by dimerization with a CDH2 chain from another cell.
CDKN2B	Cyclin-dependent kinase 4 inhibitor B	Interacts strongly with CDK4 and CDK6.
ROBO4	Roundabout homolog 4	Receptor for Slit proteins, at least for SLIT2, and seems to be involved in angiogenesis and vascular patterning.
ZNF365	Talanin	May play a role in uric acid excretion.
NEK10	Serine/threonine-protein kinase Nek10	Plays a role in the cellular response to UV irradiation.
CHEK1	Serine/threonine-protein kinase Chk1	Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA.
LGR6	Leucine-rich repeat-containing G-protein coupled receptor 6	Receptor for R-spondins that potentiates the canonical Wnt signaling pathway and acts as a marker of multipotent stem cells in the epidermis.
FRY	Protein furry homolog	Plays a crucial role in the structural integrity of mitotic centrosomes and in the maintenance of spindle bipolarity by promoting PLK1 activity at the spindle poles in early mitosis.
SLC37A2	Glucose-6-phosphate exchanger SLC37A2	Inorganic phosphate and glucose-6-phosphate antiporter.
CLK1	Dual specificity protein kinase CLK1	Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates.
TUBA1C	Tubulin alpha-1C chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
L3MBTL3	Lethal(3)malignant brain tumor-like protein 3	Is a negative regulator of Notch target genes expression, required for RBPJ-mediated transcriptional repression.
ADCY9	Adenylate cyclase type 9	Adenylyl cyclase that catalyzes the formation of the signaling molecule cAMP in response to activation of G protein-coupled receptors.
FTO	Alpha-ketoglutarate-dependent dioxygenase FTO	RNA demethylase that mediates oxidative demethylation of different RNA species, such as mRNAs, tRNAs and snRNAs, and acts as a regulator of fat mass, adipogenesis and energy homeostasis.
BABAM1	BRISC and BRCA1-A complex member 1	Component of the BRCA1-A complex, a complex that specifically recognizes ‘Lys-63’-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks…
CCDC15	Coiled-coil domain-containing protein 15	Plays an important role in primary cilium assembly, maintenance, and length regulation.
HEPACAM	Hepatic and glial cell adhesion molecule	Involved in regulating cell motility and cell-matrix interactions.
HYLS1	Centriolar and ciliogenesis-associated protein HYLS1	Plays a role in ciliogenesis.
ANKLE1	Structure-specific endonuclease ANKLE1	Structure-selective DNA endonuclease that specifically cleaves branched DNA.
TMEM218	Transmembrane protein 218	May be involved in ciliary biogenesis or function.
POGLUT3	Protein O-glucosyltransferase 3	Protein glucosyltransferase that catalyzes the transfer of glucose from UDP-glucose to a serine residue within the consensus sequence peptide C-X-N-T-X-G-S-F-X-C.
HYCC2	Hyccin 2	Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane.
WDR43	WD repeat-containing protein 43	Ribosome biogenesis factor that coordinates hyperactive transcription and ribogenesis.
SH2B3	SH2B adapter protein 3	Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.
ESR1	Estrogen receptor	Nuclear hormone receptor.
PATE4	Prostate and testis expressed protein 4	May modulate the function of nicotinic acetylcholine receptors.
FEZ1	Fasciculation and elongation protein zeta-1	May be involved in axonal outgrowth as component of the network of molecules that regulate cellular morphology and axon guidance machinery.
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…
HLA-C	HLA class I histocompatibility antigen, C alpha chain	Antigen-presenting major histocompatibility complex class I (MHCI) molecule with an important role in reproduction and antiviral immunity.
ANXA13	Annexin A13	Binds to membranes enriched in phosphatidylserine or phosphatidylglycerol in a calcium-dependent manner.
INHBB	Inhibin beta B chain	Inhibins and activins inhibit and activate, respectively, the secretion of follitropin by the pituitary gland.
STT3A	Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit STT3A	Catalytic subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within a…
KCNH1	Voltage-gated delayed rectifier potassium channel KCNH1	Pore-forming (alpha) subunit of a voltage-gated delayed rectifier potassium channel that mediates outward-rectifying potassium currents which, on depolarization, reaches a steady-state level and do not inactivate.
KLF12	Krueppel-like factor 12	Confers strong transcriptional repression to the AP-2-alpha gene.
KLF5	Krueppel-like factor 5	Transcription factor that binds to GC box promoter elements.
KRT8	Keratin, type II cytoskeletal 8	Required for the formation of KRT8/KRT18 filaments that are involved in ARHGEF40-mediated actin stress fiber formation and tensional force-induced stress fiber formation and reinforcement.
LSP1	Lymphocyte-specific protein 1	May play a role in mediating neutrophil activation and chemotaxis.
MDM4	Protein Mdm4	Contributes to p53/TP53 regulation.
MTX1	Metaxin-1	Involved in transport of proteins into the mitochondrion.
NDUFB3	NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3	Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis.
PEX14	Peroxisomal membrane protein PEX14	Component of the PEX13-PEX14 docking complex, a translocon channel that specifically mediates the import of peroxisomal cargo proteins bound to PEX5 receptor.
PPIL3	Peptidyl-prolyl cis-trans isomerase-like 3	PPIases accelerate the folding of proteins.

Protein-family classification

Druggable: 16 · Difficult: 11 · Unknown: 34 · Druggable fraction: 0.26

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
Nuclear receptor	1	6.3×	0.520
Kinase	5	2.3×	0.520
Antibody/Immunoglobulin	4	1.9×	0.520
Ion channel	1	1.8×	0.774
Transporter	1	1.3×	0.774
Scaffold/PPI	4	1.1×	0.774
Other/Unknown	34	1.0×	0.774
Transcription factor	7	0.9×	0.774
Enzyme (other)	3	0.6×	0.926
GPCR	1	0.4×	0.926

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Cadherin-like_dom
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
HNF1B	Transcription factor	no		HD, HNF1b_C, HNF-1_N
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
TNFSF10	Other/Unknown	no		TNF_dom, Tumour_necrosis_fac-like_dom, TNF_ligand_10/11
TOX3	Other/Unknown	no		HMG_box_dom, HMG_box_dom_sf, TOX_HMG-box_domain
ACRV1	Other/Unknown	no		LY6_UPA_recep-like, Acrosomal_SP-10-like
CCNE1	Other/Unknown	no		Cyclin_C-dom, Cyclin_N, Cyclin-like_dom
RALY	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, hnRNP_C
PKNOX2	Transcription factor	no		HD, KN_HD, Homeodomain-like_sf
CDH2	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin_pro_dom
CDKN2B	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor
ROBO4	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
ZNF365	Transcription factor	no		GenomicStab_NeuMorph_Reg, FBX41/ZN365_Znf-C2H2
NEK10	Kinase	yes		Prot_kinase_dom, Tyr_kinase_AS, Kinase-like_dom_sf
CHEK1	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
LGR6	GPCR	yes		GPCR_Rhodpsn, LRRNT, Leu-rich_rpt
FRY	Other/Unknown	no		Cell_Morphogen_C, Cell_morpho_N, MOR2-PAG1_mid
SLC37A2	Transporter	yes		Sugar_P_transporter, MFS, MFS_dom
CLK1	Kinase	yes	2.7.12.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
TUBA1C	Other/Unknown	no		Tubulin, Alpha_tubulin, Tubulin_FtsZ_GTPase
L3MBTL3	Transcription factor	no		SAM, Znf_C2H2C, Mbt
ADCY9	Other/Unknown	no		A/G_cyclase, A/G_cyclase_CS, Nucleotide_cyclase
PATE1	Other/Unknown	no		LY6_UPA_recep-like
FTO	Enzyme (other)	yes	1.14.11.53	FTO_C, FTO_cat_dom, FTO
BABAM1	Other/Unknown	no		BABAM1, vWFA_dom_sf
CCDC15	Other/Unknown	no		CCDC15
HEPACAM	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
HYLS1	Other/Unknown	no		HYLS1, HYLS1_C_dom, Centriolar_ciliogenesis_assoc
ANKLE1	Scaffold/PPI	no		GIY-YIG_endonuc, Ankyrin_rpt, LEM_dom
TMEM218	Other/Unknown	no		Tmem218, TMEM218_N
POGLUT3	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, CAP10, Ig-like_fold
HYCC2	Other/Unknown	no		Hyccin
WDR43	Scaffold/PPI	no		WD40_rpt, SSU_processome_Utp12, WD40/YVTN_repeat-like_dom_sf
SH2B3	Scaffold/PPI	no		SH2, PH_domain, PH-like_dom_sf
PATE2	Other/Unknown	no		LY6_UPA_recep-like, PATE2, PATE2-like_ECD_3FTx
HEPN1	Other/Unknown	no
ESR1	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Estr_rcpt, Znf_hrmn_rcpt
PATE3	Other/Unknown	no		LY6_UPA_recep-like
PATE4	Other/Unknown	no		LY6_UPA_recep-like, Snake_toxin-like_sf
RPL23AP53	Other/Unknown	no
FEZ1	Other/Unknown	no		FEZ
FGFR2	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
MIR4757	Other/Unknown	no
GBA1LP	Other/Unknown	no
HLA-C	Antibody/Immunoglobulin	yes		MHC_I_a_a1/a2, Ig_C1-set, Ig-like_dom
ANXA13	Other/Unknown	no		Annexin, ANX13, Annexin_repeat_CS
INHBB	Other/Unknown	no		INHBB_C, TGF-b_propeptide, TGF-b_C
STT3A	Enzyme (other)	yes	2.4.99.18	Oligo_trans_STT3, STT3_N, AglB-like_core
KCNH1	Ion channel	yes		PAS, cNMP-bd_dom, PAS-assoc_C

Expression context

Cohort genes with no expression data: 0.

52 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)	1
broad (>20)	60
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	8
secondary oocyte	7
oocyte	6
ventricular zone	5
stromal cell of endometrium	5
left testis	4
granulocyte	4
sural nerve	4
monocyte	3
testis	3
right frontal lobe	3
right uterine tube	3
primordial germ cell in gonad	3
calcaneal tendon	3
corpus epididymis	3
buccal mucosa cell	3
substantia nigra pars reticulata	2
colonic mucosa	2
right testis	2
adrenal tissue	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RET	193	broad	marker	substantia nigra pars reticulata, dorsal root ganglion, substantia nigra pars compacta
BRCA2	184	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
HNF1B	74	broad	marker	metanephros cortex, adult mammalian kidney, kidney
TERT	105	broad	yes	stromal cell of endometrium, type B pancreatic cell, olfactory bulb
TNFSF10	285	ubiquitous	marker	nasal cavity epithelium, urethra, monocyte
TOX3	220	broad	marker	mucosa of sigmoid colon, pancreatic ductal cell, colonic mucosa
ACRV1	145	tissue_specific	marker	left testis, right testis, testis
CCNE1	201	ubiquitous	marker	secondary oocyte, oocyte, adrenal tissue
RALY	294	ubiquitous	marker	ganglionic eminence, granulocyte, ventricular zone
PKNOX2	236	broad	yes	pigmented layer of retina, sural nerve, right frontal lobe
CDH2	233	ubiquitous	marker	heart right ventricle, ventricular zone, stromal cell of endometrium
CDKN2B	219	ubiquitous	marker	jejunal mucosa, colonic mucosa, lower esophagus mucosa
ROBO4	254	broad	marker	lower lobe of lung, apex of heart, omental fat pad
ZNF365	206	broad	yes	middle temporal gyrus, lateral nuclear group of thalamus, Brodmann (1909) area 23
NEK10	178	broad	marker	olfactory segment of nasal mucosa, right uterine tube, left testis
CHEK1	210	ubiquitous	marker	secondary oocyte, oocyte, primordial germ cell in gonad
LGR6	201	broad	marker	right coronary artery, descending thoracic aorta, thoracic aorta
FRY	288	ubiquitous	marker	blood vessel layer, popliteal artery, tibial artery
SLC37A2	199	broad	marker	right adrenal gland, left adrenal gland, right adrenal gland cortex
CLK1	294	ubiquitous	marker	granulocyte, right uterine tube, right ovary
TUBA1C	288	ubiquitous	marker	secondary oocyte, Brodmann (1909) area 46, oocyte
L3MBTL3	213	ubiquitous	marker	calcaneal tendon, male germ line stem cell (sensu Vertebrata) in testis, stromal cell of endometrium
ADCY9	296	ubiquitous	marker	secondary oocyte, choroid plexus epithelium, vastus lateralis
PATE1	23	tissue_specific	marker	corpus epididymis, seminal vesicle, cauda epididymis
FTO	294	ubiquitous	marker	cortical plate, bronchial epithelial cell, Brodmann (1909) area 10
BABAM1	278	ubiquitous	marker	prefrontal cortex, right frontal lobe, anterior cingulate cortex
CCDC15	188	ubiquitous	yes	oocyte, secondary oocyte, sperm
HEPACAM	167	broad	marker	lateral globus pallidus, substantia nigra pars reticulata, medial globus pallidus
HYLS1	205	ubiquitous	yes	oocyte, secondary oocyte, sperm
ANKLE1	160	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, bone marrow, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 27.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ESR1	12,382
TUBA1C	6,155
TERT	5,717
CDH2	5,623
CHEK1	4,939
BRCA2	4,839
RET	4,203
KRT8	3,915
CCNE1	3,811
RALY	3,651

Intra-cohort edges

A	B	Sources
ACRV1	PATE3	string_interaction
ACRV1	PATE4	string_interaction
ANKLE1	BABAM1	string_interaction
BABAM1	BRCA2	string_interaction
BRCA2	LSP1	string_interaction
BRCA2	RAD51B	string_interaction
BRCA2	TOX3	string_interaction
ESR1	PPIL3	intact
ESR1	WDR43	intact
HEPACAM	HEPN1	string_interaction
HYCC2	NDUFB3	string_interaction
HYCC2	PPIL3	string_interaction
HYLS1	PKNOX2	string_interaction
LSP1	NEK10	string_interaction
LSP1	RAD51B	string_interaction
LSP1	TOX3	string_interaction
NDUFB3	PPIL3	string_interaction
NEK10	RAD51B	string_interaction
NEK10	TOX3	string_interaction
PATE1	PATE2	string_interaction
PATE1	PATE3	string_interaction
PATE1	PATE4	string_interaction
PATE2	PATE3	string_interaction
PATE2	PATE4	string_interaction
PATE3	PATE4	string_interaction
PKNOX2	SLC37A2	string_interaction
RAD51B	TOX3	string_interaction

Structural data

PDB: 32 · AlphaFold-only: 26 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ESR1	P03372	478
CHEK1	O14757	164
FGFR2	P21802	63
MDM4	O15151	39
CLK1	P49759	38
RET	P07949	34
FTO	Q9C0B1	28
TERT	O14746	23
CCNE1	P24864	22
BRCA2	P51587	14
HLA-C	P10321	13
PTHLH	P12272	11
L3MBTL3	Q96JM7	9
TNFSF10	P50591	7
NDUFB3	O43676	7
ADCY9	O60503	6
STT3A	P46977	5
RAD51B	O15315	5
SLC37A2	Q8TED4	4
PEX14	O75381	4
PPIL3	Q9H2H8	4
HNF1B	P35680	3
BABAM1	Q9NWV8	3
WDR43	Q15061	3
KRT8	P05787	3
LSP1	P33241	3
RALY	Q9UKM9	1
HEPACAM	Q14CZ8	1
ANXA13	P27216	1
INHBB	P09529	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
POGLUT3	Q7Z4H8	93.16
TUBA1C	Q9BQE3	91.70
PATE4	P0C8F1	90.73
PATE3	B3GLJ2	90.23
CDKN2B	P42772	90.12
TMEM218	A2RU14	87.79
PATE2	Q6UY27	86.09
PATE1	Q8WXA2	80.46
CDH2	P19022	79.68
LGR6	Q9HBX8	77.94
MTX1	Q13505	71.83
NEK10	Q6ZWH5	70.23
ANKLE1	Q8NAG6	70.14
HYCC2	Q8IXS8	69.27
FEZ1	Q99689	67.83
HYLS1	Q96M11	66.11
SH2B3	Q9UQQ2	63.45
ACRV1	P26436	62.66
PKNOX2	Q96KN3	61.38
TOX3	O15405	60.22
ROBO4	Q8WZ75	57.67
HEPN1	Q6WQI6	54.42
KLF12	Q9Y4X4	51.57
CCDC15	Q0P6D6	50.02
ZNF365	Q70YC4	30.21
FRY	Q5TBA9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 331. Enrichment computed across 61 evidence-associated genes (32 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 32 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cell Cycle	7	7.9×	0.007	BRCA2, TERT, CCNE1, CDKN2B, TUBA1C, BABAM1, MDM4
Presynaptic phase of homologous DNA pairing and strand exchange	3	25.5×	0.035	BRCA2, CHEK1, RAD51B
Signaling by FGFR2 amplification mutants	1	356.9×	0.055	FGFR2
Signaling by FGFR2 fusions	1	356.9×	0.055	FGFR2
p53-Dependent G1 DNA Damage Response	2	44.6×	0.055	CCNE1, MDM4
p53-Dependent G1/S DNA damage checkpoint	2	44.6×	0.055	CCNE1, MDM4
G1/S DNA Damage Checkpoints	2	42.0×	0.055	CCNE1, MDM4
Developmental Lineage of Mammary Gland Alveolar Cells	2	39.6×	0.055	ESR1, KRT8
Impaired BRCA2 binding to PALB2	2	28.6×	0.055	BRCA2, RAD51B
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	2	28.6×	0.055	ESR1, KRT8
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	2	26.4×	0.055	BRCA2, RAD51B
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	2	26.4×	0.055	BRCA2, RAD51B
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	2	26.4×	0.055	BRCA2, RAD51B
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	2	24.6×	0.055	BRCA2, RAD51B
G1 Phase	2	24.6×	0.055	CCNE1, CDKN2B
Homologous DNA Pairing and Strand Exchange	2	23.8×	0.055	BRCA2, RAD51B
Cellular Senescence	3	12.9×	0.055	CCNE1, CDKN2B, MDM4
Cellular responses to stimuli	5	4.9×	0.055	CCNE1, CDKN2B, TUBA1C, ADCY9, MDM4
Signal Transduction	9	2.9×	0.055	TERT, CCNE1, CDKN2B, LGR6, TUBA1C, ADCY9, SH2B3, INHBB (+1 more)
Oncogene Induced Senescence	2	21.0×	0.067	CDKN2B, MDM4
Homology Directed Repair	2	19.3×	0.069	BRCA2, BABAM1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	2	19.3×	0.069	BRCA2, BABAM1
Chaperonin-mediated protein folding	2	18.8×	0.069	CCNE1, TUBA1C
Resolution of D-loop Structures through Holliday Junction Intermediates	2	18.8×	0.069	BRCA2, RAD51B
Cell Cycle Checkpoints	3	8.3×	0.073	CCNE1, BABAM1, MDM4
Protein folding	2	16.2×	0.085	CCNE1, TUBA1C
Signaling by SCF-KIT	2	15.5×	0.086	CHEK1, SH2B3
DNA Double-Strand Break Repair	2	15.5×	0.086	BRCA2, BABAM1
Impaired BRCA2 translocation to the nucleus	1	119.0×	0.090	BRCA2
Impaired BRCA2 binding to SEM1 (DSS1)	1	119.0×	0.090	BRCA2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 53 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
prostate epithelial cord elongation	2	212.0×	0.015	ESR1, FGFR2
prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis	2	90.8×	0.047	ESR1, FGFR2
establishment of protein localization to telomere	2	79.5×	0.047	BRCA2, TERT
positive regulation of Wnt signaling pathway	3	21.7×	0.047	TERT, LGR6, FGFR2
RNA-templated transcription	1	318.0×	0.047	TERT
cerebellar molecular layer morphogenesis	1	318.0×	0.047	ZNF365
DNA strand elongation	1	318.0×	0.047	TERT
negative regulation of hepatocyte growth factor production	1	318.0×	0.047	INHBB
regulation of pronephros size	1	318.0×	0.047	HNF1B
fibroblast growth factor receptor signaling pathway involved in negative regulation of apoptotic process in bone marrow cell	1	318.0×	0.047	FGFR2
fibroblast growth factor receptor signaling pathway involved in hemopoiesis	1	318.0×	0.047	FGFR2
fibroblast growth factor receptor signaling pathway involved in positive regulation of cell proliferation in bone marrow	1	318.0×	0.047	FGFR2
peroxisome transport along microtubule	1	318.0×	0.047	PEX14
pronephric nephron tubule development	1	318.0×	0.047	HNF1B
lateral sprouting from an epithelium	1	318.0×	0.047	FGFR2
ureteric bud elongation	1	318.0×	0.047	HNF1B
obsolete negative regulation of mesenchymal cell apoptotic process involved in mesonephric nephron morphogenesis	1	318.0×	0.047	HNF1B
positive regulation of anterograde axonal transport of mitochondrion	1	318.0×	0.047	FEZ1
regulation of white fat cell proliferation	1	318.0×	0.047	FTO
regulation of DNA strand resection involved in replication fork processing	1	318.0×	0.047	ZNF365
siRNA transcription	1	318.0×	0.047	TERT
mesenchymal cell apoptotic process involved in metanephros development	1	318.0×	0.047	HNF1B
positive regulation of transdifferentiation	1	318.0×	0.047	TERT
regulation of epithelial cell apoptotic process	1	318.0×	0.047	ESR1
regulation of lymphoid progenitor cell differentiation	1	318.0×	0.047	ANKLE1
telomere maintenance via recombination	2	57.8×	0.047	BRCA2, TERT
inner cell mass cell proliferation	2	37.4×	0.047	BRCA2, CHEK1
regulation of double-strand break repair via homologous recombination	2	37.4×	0.047	ZNF365, CHEK1
replicative senescence	2	37.4×	0.047	TERT, CHEK1
embryonic digestive tract morphogenesis	2	35.3×	0.047	HNF1B, FGFR2

Therapeutics

Drug target analysis

Approved (phase 4): 11 · Phase ≥3: 12 · Phased (≥1): 12 · Undrugged: 49

Druggability breadth: 25 of 61 evidence-associated genes (41%) 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
RET	PONATINIB
TERT	BERBERINE
CCNE1	PALBOCICLIB
CHEK1	FEDRATINIB
CLK1	MOMELOTINIB
TUBA1C	COLCHICINE
L3MBTL3	CHLORPHENIRAMINE
FTO	FLUORESCEIN
ESR1	CANDESARTAN CILEXETIL
FGFR2	PONATINIB
MDM4	DIOSMIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ESR1	162	4
RET	135	4
CLK1	67	4
FGFR2	59	4
CCNE1	38	4
CHEK1	36	4
TUBA1C	21	4
FTO	18	4
TERT	10	4
MDM4	7	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	FGFR2, RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	CHEK1, CLK1, FGFR2, RET
TIVOZANIB	4	RET
LENVATINIB	4	ESR1, FGFR2, RET
AXITINIB	4	FGFR2, RET
SORAFENIB	4	CLK1, FGFR2, RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	CLK1, ESR1, RET
RUXOLITINIB	4	CLK1, RET
INFIGRATINIB PHOSPHATE	4	FGFR2, RET
INFIGRATINIB	4	FGFR2, RET
IBRUTINIB	4	FGFR2, RET
PALBOCICLIB	4	CCNE1, CHEK1, CLK1, RET
REGORAFENIB	4	CLK1, RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	CLK1, RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	CLK1, RET
CERITINIB	4	CLK1, FGFR2, RET
VANDETANIB	4	FGFR2, RET
NILOTINIB	4	CLK1, RET
BOSUTINIB	4	CHEK1, CLK1, RET
GILTERITINIB	4	CCNE1, RET
BRIGATINIB	4	CHEK1, CLK1, FGFR2, RET
UPADACITINIB	4	RET

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
ESR1	2,435	Binding:2037, Functional:363, ADMET:35
TUBA1C	1,689	Binding:1648, Functional:35, ADMET:6
RET	1,586	Binding:1573, Functional:10, ADMET:3
CHEK1	1,086	Binding:1039, Functional:44, ADMET:3
FGFR2	966	Binding:940, Functional:22, ADMET:4
CCNE1	691	Binding:690, ADMET:1
CLK1	553	Binding:547, Functional:4, ADMET:2
TERT	391	Binding:389, Functional:2
FTO	153	Binding:153
MDM4	149	Binding:148, Functional:1
L3MBTL3	50	Binding:49, Functional:1
NEK10	40	Binding:40
KCNH1	24	Binding:23, Toxicity:1
ADCY9	18	Binding:16, Functional:2
ANXA13	6	Binding:6
CDH2	4	Binding:3, Functional:1
NDUFB3	4	Binding:4
TNFSF10	3	Functional:2, Binding:1
KLF5	3	Binding:2, Functional:1
STT3A	2	Binding:2
LGR6	1	Binding:1
HLA-C	1	Binding:1
MTX1	1	Binding:1
PEX14	1	ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RET	2.7.10.1	receptor protein-tyrosine kinase
CHEK1	2.7.11.1	non-specific serine/threonine protein kinase
CLK1	2.7.12.1	dual-specificity kinase
FTO	1.14.11.53	mRNA N6-methyladenine demethylase
FGFR2	2.7.10.1	receptor protein-tyrosine kinase
STT3A	2.4.99.18	dolichyl-diphosphooligosaccharide-protein glycotransferase
PPIL3	5.2.1.8	peptidylprolyl isomerase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RET	1,586
TERT	391
CCNE1	691
CHEK1	1,086
CLK1	553
TUBA1C	1,689
FTO	153
ESR1	2,435
FGFR2	966
MDM4	149

Pharmacogenomics

Cohort genes with a PharmGKB record: 59; 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)
PONATINIB	4	FGFR2, RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	CHEK1, CLK1, FGFR2, RET
TIVOZANIB	4	RET
LENVATINIB	4	ESR1, FGFR2, RET
AXITINIB	4	FGFR2, RET
SORAFENIB	4	CLK1, FGFR2, RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	CLK1, ESR1, RET
RUXOLITINIB	4	CLK1, RET
INFIGRATINIB PHOSPHATE	4	FGFR2, RET
INFIGRATINIB	4	FGFR2, RET
IBRUTINIB	4	FGFR2, RET
REGORAFENIB	4	CLK1, RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	CLK1, RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	CLK1, RET
CERITINIB	4	CLK1, FGFR2, RET
VANDETANIB	4	FGFR2, RET
NILOTINIB	4	CLK1, RET
BOSUTINIB	4	CHEK1, CLK1, RET
GILTERITINIB	4	CCNE1, RET
BRIGATINIB	4	CHEK1, CLK1, FGFR2, RET
UPADACITINIB	4	RET

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	11	RET, TERT, CCNE1, CHEK1, CLK1, TUBA1C, L3MBTL3, FTO, ESR1, FGFR2 (+1 more)
B	Phased (≥1) drug, not yet approved	1	NEK10
C	Druggable family + PDB, no drug	6	SLC37A2, HEPACAM, HLA-C, STT3A, KCNH1, PPIL3
D	Druggable family + AlphaFold only, no drug	3	ROBO4, LGR6, POGLUT3
E	Difficult family or no structure, no drug	40	BRCA2, HNF1B, TNFSF10, TOX3, ACRV1, RALY, PKNOX2, CDH2, CDKN2B, ZNF365 (+30 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BRCA2	0	—
HNF1B	0	—
TNFSF10	3	—
TOX3	0	—
ACRV1	0	—
RALY	0	—
PKNOX2	0	—
CDH2	4	—
CDKN2B	0	—
ROBO4	0	—
ZNF365	0	—
LGR6	1	—
FRY	0	—
SLC37A2	0	—
ADCY9	18	—
PATE1	0	—
BABAM1	0	—
CCDC15	0	—
HEPACAM	0	—
HYLS1	0	—
ANKLE1	0	—
TMEM218	0	—
POGLUT3	0	—
HYCC2	0	—
WDR43	0	—
SH2B3	0	—
PATE2	0	—
HEPN1	0	—
PATE3	0	—
PATE4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 22.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	15
PHASE1	3
PHASE3	1
PHASE2/PHASE3	1
PHASE1/PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01805076	PHASE3	COMPLETED	MRI and Mammography Before Surgery in Patients With Stage I-II Breast Cancer
NCT01881230	PHASE2/PHASE3	COMPLETED	Evaluate Risk/Benefit of Nab Paclitaxel in Combination With Gemcitabine and Carboplatin Compared to Gemcitabine and Carboplatin in Triple Negative Metastatic Breast Cancer (or Metastatic Triple Negative Breast Cancer)
NCT02315196	PHASE2	ACTIVE_NOT_RECRUITING	Pegylated Liposomal Doxorubicin Hydrochloride and Carboplatin Followed by Surgery and Paclitaxel in Treating Patients With Triple Negative Stage II-III Breast Cancer
NCT02957968	PHASE2	ACTIVE_NOT_RECRUITING	Neoadjuvant Pembrolizumab + Decitabine Followed by Std Neoadj Chemo for Locally Advanced HER2- Breast Ca
NCT00003199	PHASE2	COMPLETED	Combination Chemotherapy and Peripheral Blood Stem Cell Transplant Followed By Aldesleukin and Sargramostim in Treating Patients With Inflammatory Stage IIIB or Metastatic Stage IV Breast Cancer
NCT00194779	PHASE2	COMPLETED	Combination Chemotherapy and Filgrastim Before Surgery in Treating Patients With HER2-Positive Breast Cancer That Can Be Removed By Surgery
NCT00559507	PHASE2	COMPLETED	Saracatinib in Treating Patients With Metastatic or Locally Advanced Breast Cancer That Cannot Be Removed By Surgery
NCT00577122	PHASE2	COMPLETED	Medroxyprogesterone +/- Cyclophosphamide & Methotrexate in Hormone Receptor-Negative Recurrent/Metastatic Breast Cancer
NCT00733408	PHASE2	COMPLETED	Nab-Paclitaxel and Bevacizumab Followed By Bevacizumab and Erlotinib in Metastatic Breast Cancer
NCT01037790	PHASE2	COMPLETED	Phase II Trial of the Cyclin-Dependent Kinase Inhibitor PD 0332991 in Patients With Cancer
NCT01100489	PHASE2	WITHDRAWN	Breast-Conserving Surgery Followed by Radiation Therapy With MRI-Detected Stage I or Stage II Breast Cancer
NCT01151449	PHASE2	TERMINATED	Gamma-secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced, Metastatic, or Recurrent Triple Negative Invasive Breast Cancer
NCT01173497	PHASE2	COMPLETED	A Study Evaluating INIPARIB in Combination With Chemotherapy to Treat Triple Negative Breast Cancer Brain Metastasis
NCT01234532	PHASE2	TERMINATED	Entinostat and Anastrozole in Treating Postmenopausal Women With TNBC That Can Be Removed by Surgery
NCT01372579	PHASE2	UNKNOWN	Carboplatin and Eribulin Mesylate in Triple Negative Breast Cancer Patients
NCT01818063	PHASE2	COMPLETED	Carboplatin and Combination Chemotherapy With or Without Veliparib in Treating Patients With Stage IIB-IIIC Breast Cancer
NCT01918306	PHASE1/PHASE2	TERMINATED	GDC-0941 and Cisplatin in Treating Patients With Androgen Receptor-Negative Triple Negative Metastatic Breast Cancer
NCT04504916	PHASE2	TERMINATED	A Study of Zilovertamab Vedotin (MK-2140/VLS-101) in Participants With Solid Tumors (MK-2140-002)
NCT00031681	PHASE1	COMPLETED	7-Hydroxystaurosporine and Irinotecan Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors or Triple Negative Breast Cancer (Currently Accruing Only Triple-negative Breast Cancer Patients Since 6/8/2007)
NCT00516243	PHASE1	COMPLETED	Defined Green Tea Catechin Extract in Treating Women With Hormone Receptor Negative Stage I-III Breast Cancer
NCT01104259	PHASE1	COMPLETED	Veliparib, Cisplatin, and Vinorelbine Ditartrate in Treating Patients With Recurrent and/or Metastatic Breast Cancer
NCT05541367	Not specified	RECRUITING	Estrogen Receptor (ER) PET/CT Imaging in Breast Cancer

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CARBOPLATIN	4	5
ALDESLEUKIN	4	1
BUSULFAN	4	1
EPIRUBICIN HYDROCHLORIDE	4	1
ERIBULIN MESYLATE	4	1
PALBOCICLIB	4	1
SARGRAMOSTIM	4	1
THIOTEPA	4	1
VINORELBINE TARTRATE	4	1
VELIPARIB	3	4
CIRMTUZUMAB	3	1
ENTINOSTAT	3	1
INIPARIB	3	1
SARACATINIB	3	1
UCN-01	2	1
VEDOTIN	2	1
CHEMBL4438584	0	1
CHEMBL1236539	0	1

Precision-medicine subtype map (CIViC)

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

Molecular subtype	Therapy	Effect	Level	CIViC
RET Overexpression	Vandetanib	Sensitivity/Response	CIViC D	EID2992

Cohort genes: RET, BRCA2, TERT, CCNE1, CDKN2B, ROBO4, CHEK1, SH2B3, ESR1, FGFR2, HLA-C, KLF5, MDM4, RAD51B, HNF1B, TNFSF10, TOX3, ACRV1, RALY, PKNOX2, CDH2, ZNF365, NEK10, LGR6, FRY, SLC37A2, CLK1, TUBA1C, L3MBTL3, ADCY9, PATE1, FTO, BABAM1, CCDC15, HEPACAM, HYLS1, ANKLE1, TMEM218, POGLUT3, HYCC2, WDR43, PATE2, HEPN1, PATE3, PATE4, FEZ1, MIR4757, ANXA13, INHBB, STT3A, KCNH1, KLF12, KRT8, LSP1, MTX1, NDUFB3, PEX14, PPIL3, PTHLH
Drugs: Carboplatin, Aldesleukin, Busulfan, Epirubicin, Eribulin, Palbociclib, Sargramostim, Thiotepa, Vinorelbine Tartrate, Veliparib, Cirmtuzumab, Entinostat, Iniparib, Saracatinib, Vandetanib