Basal cell carcinoma

Summary

Basal cell carcinoma (MONDO:0020804) is a cancer with 75 cohort genes (708 GWAS associations across 25 studies; 15 CIViC-evidence somatic drivers; 3 ClinVar predisposition records) and 231 clinical trials. The dominant Reactome pathway is Melanin biosynthesis (3 cohort genes). Molecularly, PTCH1 Loss-of-function confers sensitivity to Vismodegib in Basal Cell Carcinoma (CIViC Level A); 24 further subtype–drug associations are mapped below. Top therapeutic interventions include vismodegib, sonidegib, and imiquimod.

At a glance

• Classification: Cancer
• Cohort genes: 75
• GWAS associations: 708
• ClinVar variants: 3
• Clinical trials: 231
• Precision-medicine evidence (CIViC): 25 subtype–drug associations

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	basal cell carcinoma
Mondo ID	MONDO:0020804
EFO	EFO:0004193
MeSH	D002280
NCIT	C156767, C7586
UMLS	C0007117
MedGen	2870
Is cancer (heuristic)	yes

Also known as: basal cell cancer · epithelioma, basal cell · malignant basal cell neoplasm

Data availability: 3 ClinVar variants · 708 GWAS associations (25 studies) · 31 intOGen driver records.

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 › basal cell carcinoma

Related subtypes (48): retroperitoneum carcinoma, head and neck carcinoma, peritoneal carcinoma, neuroendocrine carcinoma, laryngeal carcinoma, bone carcinoma, carcinoma ex pleomorphic adenoma, scrotal carcinoma, skin carcinoma, malignant myoepithelioma, trachea carcinoma, epithelial-myoepithelial carcinoma, lipid-rich carcinoma, comedocarcinoma, in situ carcinoma, adenocarcinoma, urinary bladder carcinoma, breast carcinoma, squamous cell carcinoma, lung carcinoma, prostate carcinoma, renal carcinoma, uterine carcinoma, vulvar carcinoma, large cell carcinoma, undifferentiated carcinoma, basaloid carcinoma, cribriform carcinoma, digestive system carcinoma, fallopian tube carcinoma, penile carcinoma, sarcomatoid carcinoma, thymic carcinoma, transitional cell carcinoma, ureter carcinoma, papillary carcinoma, Krebs 2 carcinoma, thyroid gland carcinoma, vaginal carcinoma, choroid plexus carcinoma, malignant epithelial tumor of ovary, mucin-producing carcinoma, carcinoma of urethra, combined carcinoid and adenocarcinoma, secondary carcinoma, invasive carcinoma, glycogen-rich carcinoma, lymph node carcinoma

Subtypes (1): skin basal cell carcinoma

Genetics & variants

GWAS landscape

708 GWAS associations across 25 studies. Top hits map to 29 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs12203592	6e-270	IRF4	T	1.41
rs62389423	1e-255	IRF4 - EXOC2	A	1.39
rs214793	1e-223	TGM3	T
rs10931936	1e-197	CASP8	C
rs730153	2e-195	RCC2	A
rs10830255	1e-182	TYR - NOX4	C
rs79134926	5e-175	LINC02676	T
rs2153271	4e-173	BNC2	T
rs3816659	6e-165	MIR4457 - CLPTM1L	G
rs1805007	2e-151	MC1R	C	0.35
rs6989943	1e-137	RGS22	A
rs11170164	8e-137	KRT5	T
rs12931267	1e-121	FANCA	G	1.33
rs10811645	2e-116	CDKN2B-AS1	A
rs8114927	1e-102	DLGAP4	C
rs214803	2e-102	TGM3	A	0.82
rs12122129	2e-99	RCC2 - ARHGEF10L	A	1.17
rs7498985	5e-97	GAS8	A
rs502803	2e-95	HLA-DRB1 - HLA-DQA1	A
rs35251485	9e-95	ZFHX4-AS1	A
rs61824911	2e-90	RHOU - LINC02814	G	1.18
rs117744081	2e-86	CPVL	G
rs7582362	2e-86	CASP8, FLACC1	G	0.86
rs73192661	1e-85	LPP	T
rs16891982	9e-81	SLC45A2	C	0.55
rs2849695	8e-80	PCSEAT - LINC00111	C
rs1126809	4e-79	TYR	G	0.16
rs6059655	7e-79	RALY	A	0.26
rs6743068	2e-78	CASP8, FLACC1	A	0.16
rs421284	4e-77	CLPTM1L	C	0.86

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90328132	Choquet H	2024	49,905	752,392	Multi-ancestry genome-wide meta-analysis identifies novel basal cell carcinoma loci and shared genetic effects with squamous cell carcinoma.
GCST90328134	Choquet H	2024	49,905	752,392	Multi-ancestry genome-wide meta-analysis identifies novel basal cell carcinoma loci and shared genetic effects with squamous cell carcinoma.
GCST008871	Liyanage UE	2019	31,787	619,351	Combined analysis of keratinocyte cancers identifies novel genome-wide loci.
GCST90475582	Verma A	2024	31,142	404,406	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90137411	Seviiri M	2022	20,791	286,893	A multi-phenotype analysis reveals 19 susceptibility loci for basal cell carcinoma and 15 for squamous cell carcinoma.
GCST90013410	Adolphe C	2021	17,416	375,455	Genetic and functional interaction network analysis reveals global enrichment of regulatory T cell genes influencing basal cell carcinoma susceptibility.
GCST004113	Lin Y	2017	17,187	287,054	Association between genetic variation within vitamin D receptor-DNA binding sites and risk of basal cell carcinoma.
GCST90077640	Backman JD	2021	4,723	34,891	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90081626	Backman JD	2021	4,723	34,891	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST002842	Stacey SN	2015	4,572	266,358	New basal cell carcinoma susceptibility loci.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	7
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	43

MAF distribution

Bucket	Variants
common (>=0.05)	49
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intron_variant	31
intergenic_variant	10
missense_variant	7
non_coding_transcript_exon_variant	1
unknown	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs12203592	6	396321	C>G,T	0.131	intron_variant	IRF4	6e-270	Tier 4: intronic/intergenic
rs62389423	6	421281	G>A,T	0.05	intergenic_variant	IRF4 - EXOC2	1e-255	Tier 4: intronic/intergenic
rs214793	20	2305059	C>G,T	0.05	intron_variant	TGM3	1e-223	Tier 4: intronic/intergenic
rs10931936	2	201279205	T>A,C,G	0.05	intron_variant	CASP8	1e-197	Tier 4: intronic/intergenic
rs730153	1	17423008	G>A,C	0.05	intron_variant	RCC2	2e-195	Tier 4: intronic/intergenic
rs10830255	11	89311357	A>C	0.05	intergenic_variant	TYR - NOX4	1e-182	Tier 4: intronic/intergenic
rs79134926	10	8923021	G>A,T	0.05	intron_variant	LINC02676	5e-175	Tier 4: intronic/intergenic
rs2153271	9	16864523	C>A,G,T	0.05	intron_variant	BNC2	4e-173	Tier 4: intronic/intergenic
rs3816659	5	1317705	A>C,G,T	0.05	intergenic_variant	MIR4457 - CLPTM1L	6e-165	Tier 4: intronic/intergenic
rs1805007	16	89919709	C>A,G,T	0.082	missense_variant	MC1R	2e-151	Tier 1: coding
rs6989943	8	100016011	G>A	0.05	intron_variant	RGS22	1e-137	Tier 4: intronic/intergenic
rs11170164	12	52519884	C>A,G,T	0.05	missense_variant	KRT5	8e-137	Tier 1: coding
rs12931267	16	89752324	C>G	0.05	intron_variant	FANCA	1e-121	Tier 4: intronic/intergenic
rs10811645	9	22049657	G>A,C	0.05	intron_variant	CDKN2B-AS1	2e-116	Tier 4: intronic/intergenic
rs8114927	20	36421920	T>A,C,G	0.05	intron_variant	DLGAP4	1e-102	Tier 4: intronic/intergenic
rs214803	20	2309687	C>A,G,T	0.05	missense_variant	TGM3	2e-102	Tier 1: coding
rs12122129	1	17445652	G>A,T	0.05	intergenic_variant	RCC2 - ARHGEF10L	2e-99	Tier 4: intronic/intergenic
rs7498985	16	90036709	G>A	0.05	intron_variant	GAS8	5e-97	Tier 4: intronic/intergenic
rs502803	6	32611181	G>A	0.05	intergenic_variant	HLA-DRB1 - HLA-DQA1	2e-95	Tier 4: intronic/intergenic
rs35251485	8	76571195	G>A,C	0.05	intron_variant	ZFHX4-AS1	9e-95	Tier 4: intronic/intergenic
rs61824911	1	228843990	A>G	0.05	intron_variant	RHOU - LINC02814	2e-90	Tier 4: intronic/intergenic
rs117744081	7	29092663	A>G	0.05	missense_variant	CPVL	2e-86	Tier 1: coding
rs7582362	2	201311571	A>G	0.05	intron_variant	CASP8, FLACC1	2e-86	Tier 4: intronic/intergenic
rs73192661	3	188411006	C>T	0.05	intron_variant	LPP	1e-85	Tier 4: intronic/intergenic
rs16891982	5	33951588	C>A,G	0.088	missense_variant	SLC45A2	9e-81	Tier 1: coding
rs2849695	21	41663383	T>C	0.05	intergenic_variant	PCSEAT - LINC00111	8e-80	Tier 4: intronic/intergenic
rs1126809	11	89284793	G>A	0.283	missense_variant	TYR	4e-79	Tier 1: coding
rs6059655	20	34077942	A>G	0.091	intron_variant	RALY	7e-79	Tier 4: intronic/intergenic
rs6743068	2	201289197	A>C,G,T	0.281	intron_variant	CASP8, FLACC1	2e-78	Tier 4: intronic/intergenic
rs421284	5	1325475	T>C,G	0.05	intron_variant	CLPTM1L	4e-77	Tier 4: intronic/intergenic

ClinVar germline variants

3 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
694603	NCBI36/hg18 9q22.32-22.33(chr9:95946863-99986314)x1		Pathogenic	no assertion criteria provided
187412	NM_024675.4(PALB2):c.1451T>A (p.Leu484Ter)	PALB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
560381	NM_000264.5(PTCH1):c.3836_3837del (p.Pro1279fs)	PTCH1	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 100 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 4

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

Gene	HGNC	Evidence routes
BRCA2	BRCA2	GWAS, Orphanet
TERT	TERT	GWAS, Orphanet
TP53	TP53	GWAS, Orphanet
CDKN2A	CDKN2A	GWAS, Orphanet

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
SMO	Act	BCC,GB,HCC,MBL,PAST,PLMESO,SKIN	CIViC #5365
RNASE1	Act	HNSC,MEL,SKCM	CIViC #4753
BRCA2	LoF	BLCA,BRCA,CESC,CHOL,HCC,HNSC,LUSC,MBL,OVT,PAAD,PRAD,PROSTATE,RCC,VULVA	CIViC #7
TERT	Act	PRCC	CIViC #79
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
TYR			CIViC #5972
BACH2			CIViC #14160
CASP8	LoF	BCC,BLCA,BRCA,CEAD,CESC,CSCC,HNSC,NHL,NPC,STAD,VULVA	CIViC #761
CDKN2A	LoF	ACYC,BLCA,BRCA,CHOL,COAD,COADREAD,CSCC,EGC,ESCA,ESCC,GBM,HCC,HNSC,LGGNOS,LUAD,LUSC,MEL,MLYM,NPC,NSCLC,OS,PAAD,PANCREAS,RCC,SKCM,SKIN,STAD,STOMACH,WDTC	CIViC #14
CDKN2B			CIViC #916
ZBTB7B	LoF	UCS
CTLA4			CIViC #1285
ARHGEF10L	LoF	BCC,CCRCC
CUX1	LoF	BRCA,GB,LUAD,LUSC,MEL,PAAD,WDTC
PALB2	LoF	OVT	CIViC #15013

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMO	Orphanet:1553	Curry-Jones syndrome
SMO	Orphanet:2495	Meningioma
SMO	Orphanet:388	Hirschsprung disease
BRCA2	Orphanet:1331	Familial prostate cancer
BRCA2	Orphanet:1333	Familial pancreatic carcinoma
BRCA2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRCA2	Orphanet:178	Chordoma
BRCA2	Orphanet:227535	Hereditary breast cancer
BRCA2	Orphanet:319462	Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations
BRCA2	Orphanet:440437	Familial colorectal cancer Type X
BRCA2	Orphanet:654	Nephroblastoma
BRCA2	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
BRCA2	Orphanet:694963	Inflammatory breast cancer
BRCA2	Orphanet:70567	Cholangiocarcinoma
BRCA2	Orphanet:84	Fanconi anemia
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
TGM3	Orphanet:1410	Uncombable hair syndrome
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
TRPS1	Orphanet:502	Trichorhinophalangeal syndrome type 2
TRPS1	Orphanet:77258	Trichorhinophalangeal syndrome type 1
TYR	Orphanet:352734	Minimal pigment oculocutaneous albinism type 1
TYR	Orphanet:352737	Temperature-sensitive oculocutaneous albinism type 1
TYR	Orphanet:79431	Oculocutaneous albinism type 1A

Cohort genes → proteins

75 cohort genes, 71 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	73
civic_only	1
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMO	HGNC:11119	ENSG00000128602	Q99835	Protein smoothened	civic_evidence
RNASE1	HGNC:10044	ENSG00000129538	P07998	Ribonuclease pancreatic	gwas
SNORD3P1	HGNC:10175	ENSG00000200318		small nucleolar RNA, C/D box 3 pseudogene 1	gwas
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	gwas
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	gwas
TGM3	HGNC:11779	ENSG00000125780	Q08188	Protein-glutamine gamma-glutamyltransferase E	gwas
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	gwas
TRPS1	HGNC:12340	ENSG00000104447	Q9UHF7	Zinc finger transcription factor Trps1	gwas
TYR	HGNC:12442	ENSG00000077498	P14679	Tyrosinase	gwas
LINC00111	HGNC:1262	ENSG00000227702		long intergenic non-protein coding RNA 111	gwas
VDR	HGNC:12679	ENSG00000111424	P11473	Vitamin D3 receptor	gwas
ATP11A	HGNC:13552	ENSG00000068650	P98196	Phospholipid-transporting ATPase IH	gwas
SMC2	HGNC:14011	ENSG00000136824	O95347	Structural maintenance of chromosomes protein 2	gwas
CSMD1	HGNC:14026	ENSG00000183117	Q96PZ7	CUB and sushi domain-containing protein 1	gwas
BACH2	HGNC:14078	ENSG00000112182	Q9BYV9	Transcription regulator protein BACH2	gwas
BCAS4	HGNC:14367	ENSG00000124243	Q8TDM0	Breast carcinoma-amplified sequence 4	gwas
CPVL	HGNC:14399	ENSG00000106066	Q9H3G5	Probable serine carboxypeptidase CPVL	gwas
FLACC1	HGNC:14439	ENSG00000155749	Q96Q35	Flagellum-associated coiled-coil domain-containing protein 1	gwas
SP6	HGNC:14530	ENSG00000189120	Q3SY56	Transcription factor Sp6	gwas
CASP10	HGNC:1500	ENSG00000003400	Q92851	Caspase-10	gwas
CASP8	HGNC:1509	ENSG00000064012	Q14790	Caspase-8	gwas
DHX35	HGNC:15861	ENSG00000101452	Q9H5Z1	Probable ATP-dependent RNA helicase DHX35	gwas
RALY	HGNC:15921	ENSG00000125970	Q9UKM9	RNA-binding protein Raly	gwas
CCR6	HGNC:1607	ENSG00000112486	P51684	C-C chemokine receptor type 6	gwas
BPIFB3	HGNC:16178	ENSG00000186190	P59826	BPI fold-containing family B member 3	gwas
TRPC4AP	HGNC:16181	ENSG00000100991	Q8TEL6	Short transient receptor potential channel 4-associated protein	gwas
STK35	HGNC:16254	ENSG00000125834	Q8TDR2	Serine/threonine-protein kinase 35	gwas
SLC45A2	HGNC:16472	ENSG00000164175	Q9UMX9	Membrane-associated transporter protein	gwas
RAET1M	HGNC:16799	ENSG00000216444		retinoic acid early transcript 1M (pseudogene)	gwas
PLIN3	HGNC:16893	ENSG00000105355	O60664	Perilipin-3	gwas
CEP43	HGNC:17012	ENSG00000213066	O95684	Centrosomal protein 43	gwas
JDP2	HGNC:17546	ENSG00000140044	Q8WYK2	Jun dimerization protein 2	gwas
RHOU	HGNC:17794	ENSG00000116574	Q7L0Q8	Rho-related GTP-binding protein RhoU	gwas
CDKN2A	HGNC:1787	ENSG00000147889	P42771	Cyclin-dependent kinase inhibitor 2A	gwas
CDKN2B	HGNC:1788	ENSG00000147883	P42772	Cyclin-dependent kinase 4 inhibitor B	gwas
ST3GAL6	HGNC:18080	ENSG00000064225	Q9Y274	Type 2 lactosamine alpha-2,3-sialyltransferase	gwas
ZNF365	HGNC:18194	ENSG00000138311	Q70YC4	Talanin	gwas
TICAM1	HGNC:18348	ENSG00000127666	Q8IUC6	TIR domain-containing adapter molecule 1	gwas
PADI4	HGNC:18368	ENSG00000159339	Q9UM07	Protein-arginine deiminase type-4	gwas
ZBTB7B	HGNC:18668	ENSG00000160685	O15156	Zinc finger and BTB domain-containing protein 7B	gwas
CFL1	HGNC:1874	ENSG00000172757	P23528	Cofilin-1	gwas
RHOBTB2	HGNC:18756	ENSG00000008853	Q9BYZ6	Rho-related BTB domain-containing protein 2	gwas
PADI6	HGNC:20449	ENSG00000276747	Q6TGC4	Inactive protein-arginine deiminase type-6	gwas
UBAC2	HGNC:20486	ENSG00000134882	Q8NBM4	Ubiquitin-associated domain-containing protein 2	gwas
CLPTM1	HGNC:2087	ENSG00000104853	O96005	Putative lipid scramblase CLPTM1	gwas
HAPLN3	HGNC:21446	ENSG00000140511	Q96S86	Hyaluronan and proteoglycan link protein 3	gwas
TNS3	HGNC:21616	ENSG00000136205	Q68CZ2	Tensin-3	gwas
SPMIP7	HGNC:22564	ENSG00000164500	A4D263	Protein SPMIP7	gwas
CLPTM1L	HGNC:24308	ENSG00000049656	Q96KA5	Lipid scramblase CLPTM1L	gwas
RGS22	HGNC:24499	ENSG00000132554	Q8NE09	Regulator of G-protein signaling 22	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMO	Protein smoothened	G protein-coupled receptor which associates with the patched protein (PTCH) to transduce hedgehog protein signaling.
RNASE1	Ribonuclease pancreatic	Endonuclease that catalyzes the cleavage of RNA on the 3’ side of pyrimidine nucleotides.
BRCA2	Breast cancer type 2 susceptibility protein	Involved in double-strand break repair and/or homologous recombination.
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
TGM3	Protein-glutamine gamma-glutamyltransferase E	Catalyzes the calcium-dependent formation of isopeptide cross-links between glutamine and lysine residues in various proteins, as well as the conjugation of polyamines to proteins.
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
TRPS1	Zinc finger transcription factor Trps1	Transcriptional repressor.
TYR	Tyrosinase	This is a copper-containing oxidase that functions in the formation of pigments such as melanins and other polyphenolic compounds.
VDR	Vitamin D3 receptor	Nuclear receptor for calcitriol, the active form of vitamin D3 which mediates the action of this vitamin on cells.
ATP11A	Phospholipid-transporting ATPase IH	Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of aminophospholipids, phosphatidylserines (PS) and phosphatidylethanolamines (PE), from the outer to the inner leaflet of t…
SMC2	Structural maintenance of chromosomes protein 2	Central component of the condensin complex, a complex required for conversion of interphase chromatin into mitotic-like condense chromosomes.
CSMD1	CUB and sushi domain-containing protein 1	Potential suppressor of squamous cell carcinomas.
BACH2	Transcription regulator protein BACH2	Transcriptional regulator that acts as a repressor or activator.
CPVL	Probable serine carboxypeptidase CPVL	May be involved in the digestion of phagocytosed particles in the lysosome, participation in an inflammatory protease cascade, and trimming of peptides for antigen presentation.
SP6	Transcription factor Sp6	Promotes cell proliferation.
CASP10	Caspase-10	Involved in the activation cascade of caspases responsible for apoptosis execution.
CASP8	Caspase-8	Thiol protease that plays a key role in programmed cell death by acting as a molecular switch for apoptosis, necroptosis and pyroptosis, and is required to prevent tissue damage during embryonic development and adulthood.
DHX35	Probable ATP-dependent RNA helicase DHX35	May be involved in pre-mRNA splicing.
RALY	RNA-binding protein Raly	RNA-binding protein that acts as a transcriptional cofactor for cholesterol biosynthetic genes in the liver.
CCR6	C-C chemokine receptor type 6	Receptor for the C-C type chemokine CCL20.
BPIFB3	BPI fold-containing family B member 3	May have the capacity to recognize and bind specific classes of odorants.
TRPC4AP	Short transient receptor potential channel 4-associated protein	Substrate-recognition component of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex required for cell cycle control.
SLC45A2	Membrane-associated transporter protein	Proton-associated glucose and sucrose transporter.
PLIN3	Perilipin-3	Structural component of lipid droplets, which is required for the formation and maintenance of lipid storage droplets.
CEP43	Centrosomal protein 43	Required for anchoring microtubules to the centrosomes.
JDP2	Jun dimerization protein 2	Component of the AP-1 transcription factor that represses transactivation mediated by the Jun family of proteins.
RHOU	Rho-related GTP-binding protein RhoU	Binds to and activates protein kinase PAK1.
CDKN2A	Cyclin-dependent kinase inhibitor 2A	Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6.
CDKN2B	Cyclin-dependent kinase 4 inhibitor B	Interacts strongly with CDK4 and CDK6.
ST3GAL6	Type 2 lactosamine alpha-2,3-sialyltransferase	Transfers the sialyl residue from CMP-N-acetyl-beta-neuraminate to the terminal galactose residue on sugar chains of glycoproteins and glycolipids.
ZNF365	Talanin	May play a role in uric acid excretion.
TICAM1	TIR domain-containing adapter molecule 1	Involved in innate immunity against invading pathogens.
PADI4	Protein-arginine deiminase type-4	Catalyzes the citrullination/deimination of arginine residues of proteins such as histones, thereby playing a key role in histone code and regulation of stem cell maintenance.
ZBTB7B	Zinc finger and BTB domain-containing protein 7B	Transcription regulator that acts as a key regulator of lineage commitment of immature T-cell precursors.
CFL1	Cofilin-1	Binds to F-actin and exhibits pH-sensitive F-actin depolymerizing activity.
RHOBTB2	Rho-related BTB domain-containing protein 2	Regulator of cell proliferation and apoptosis.
PADI6	Inactive protein-arginine deiminase type-6	Structural constituent of cytoplasmic lattices, which plays a key role in early embryonic development.
UBAC2	Ubiquitin-associated domain-containing protein 2	Restricts trafficking of FAF2 from the endoplasmic reticulum to lipid droplets.
CLPTM1	Putative lipid scramblase CLPTM1	Involved in GABAergic but not glutamatergic transmission.
HAPLN3	Hyaluronan and proteoglycan link protein 3	May function in hyaluronic acid binding.
TNS3	Tensin-3	May act as a protein phosphatase and/or a lipid phosphatase.
SPMIP7	Protein SPMIP7	Essential for normal spermatogenesis.
CLPTM1L	Lipid scramblase CLPTM1L	Scramblase that mediates the translocation of glucosaminylphosphatidylinositol (alpha-D-GlcN-(1-6)-(1,2-diacyl-sn-glycero-3-phospho)-1D-myo-inositol, GlcN-PI) across the endoplasmic reticulum (ER) membrane, from the cytosolic leaflet to th…
RGS22	Regulator of G-protein signaling 22	Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form.
GOLPH3L	Golgi phosphoprotein 3-like	Phosphatidylinositol-4-phosphate-binding protein that may antagonize the action of GOLPH3 which is required for the process of vesicle budding at the Golgi and anterograde transport to the plasma membrane.
EXOC2	Exocyst complex component 2	Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.
CTLA4	Cytotoxic T-lymphocyte protein 4	Inhibitory receptor acting as a major negative regulator of T-cell responses.
CTSH	Pro-cathepsin H	Important for the overall degradation of proteins in lysosomes.
CYRIA	CYFIP-related Rac1 interactor A	May negatively regulate RAC1 signaling and RAC1-driven cytoskeletal remodeling.
CTSS	Cathepsin S	Thiol protease.

Protein-family classification

Druggable: 20 · Difficult: 14 · Unknown: 41 · Druggable fraction: 0.27

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	5.2×	0.765
Complement	1	3.6×	0.765
Antibody/Immunoglobulin	4	1.6×	0.765
Protease	3	1.5×	0.765
Phosphatase	1	1.1×	0.765
Transcription factor	10	1.1×	0.765
Transporter	1	1.0×	0.765
Other/Unknown	41	1.0×	0.765
Enzyme (other)	6	1.0×	0.765
Scaffold/PPI	4	0.9×	0.765
GPCR	2	0.6×	0.902
Kinase	1	0.4×	0.937

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMO	GPCR	yes		Frizzled/Smoothened_7TM, Frizzled/SFRP, GPCR_2-like_7TM
RNASE1	Enzyme (other)	yes	4.6.1.18	RNaseA, RNaseA_AS, RNaseA_domain
SNORD3P1	Other/Unknown	no
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
TGM3	Antibody/Immunoglobulin	yes	2.3.2.13	Transglutaminase_N, Transglutaminase-like, Transglutaminase_C
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
TRPS1	Transcription factor	no		Znf_GATA, Znf_C2H2_type, Znf_NHR/GATA
TYR	Enzyme (other)	yes	1.14.18.1	Tyrosinase_Cu-bd, Di-copper_centre_dom_sf, Tyrosinase/Hemocyanin
LINC00111	Other/Unknown	no
VDR	Nuclear receptor	yes		VitD_rcpt, Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt
ATP11A	Transcription factor	no	7.6.2.1	P_typ_ATPase, P-type_ATPase_IV, ATPase_P-typ_transduc_dom_A_sf
SMC2	Other/Unknown	no		RecF/RecN/SMC_N, SMC_hinge, SMC
CSMD1	Complement	yes		Sushi_SCR_CCP_dom, CUB_dom, Sperma_CUB_dom_sf
BACH2	Transcription factor	no		BTB/POZ_dom, bZIP_Maf, bZIP
BCAS4	Other/Unknown	no		Cappuccino
CPVL	Protease	yes		Peptidase_S10, Ser_caboxypep_ser_AS, AB_hydrolase_fold
FLACC1	Other/Unknown	no		FLACC1
SP6	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
CASP10	Enzyme (other)	yes	3.4.22.63	Pept_C14_p20, DED_dom, Pept_C14_p10
CASP8	Enzyme (other)	yes	3.4.22.61	Pept_C14_p20, DED_dom, Pept_C14_p10
DHX35	Other/Unknown	no		Helicase_C-like, DNA/RNA_helicase_DEAH_CS, Helicase-assoc_dom
RALY	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, hnRNP_C
CCR6	GPCR	yes		GPCR_Rhodpsn, Chemokine_rcpt, Chemokine_CCR6
BPIFB3	Other/Unknown	no		Lipid-bd_serum_glycop_C, Lipid-bd_serum_glycop_N, Bactericidal_perm-incr_a/b_dom
TRPC4AP	Other/Unknown	no		ARM-type_fold, TRPC4AP
STK35	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
SLC45A2	Transporter	yes		MFS, MFS_trans_sf
RAET1M	Other/Unknown	no
PLIN3	Other/Unknown	no		Perilipin
CEP43	Other/Unknown	no		LisH, FOP_dimerisation-dom_N
JDP2	Other/Unknown	no		AP-1, bZIP, bZIP_sf
RHOU	Other/Unknown	no		Small_GTPase, Small_GTPase_Rho, Small_GTP-bd
CDKN2A	Scaffold/PPI	no		Ankyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor, Tumor_suppres_ARF
CDKN2B	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor
ST3GAL6	Other/Unknown	no		Glyco_trans_29, Sialyl_trans, GT29-like_sf
ZNF365	Transcription factor	no		GenomicStab_NeuMorph_Reg, FBX41/ZN365_Znf-C2H2
TICAM1	Other/Unknown	no		TIR_dom, TICAM1, RHIM
PADI4	Enzyme (other)	yes	3.5.3.15	PAD, Cupredoxin, PAD_C
ZBTB7B	Transcription factor	no		BTB/POZ_dom, SKP1/BTB/POZ_sf, Znf_C2H2_type
CFL1	Other/Unknown	no		ADF-H, ADF/Cofilin, ADF-H/Gelsolin-like_dom_sf
RHOBTB2	Other/Unknown	no		BTB/POZ_dom, Small_GTPase, Small_GTPase_Rho
PADI6	Enzyme (other)	yes	3.5.3.15	PAD, Cupredoxin, PAD_C
UBAC2	Other/Unknown	no		UBA-like_sf, UBA, Rhomboid-like_sf
CLPTM1	Other/Unknown	no		CLPTM1
HAPLN3	Antibody/Immunoglobulin	yes		Link_dom, Ig_sub, Ig-like_dom
TNS3	Phosphatase	yes		Tyr_Pase_dom, SH2, Tyr_Pase_cat
SPMIP7	Other/Unknown	no		SPATA48
CLPTM1L	Other/Unknown	no		CLPTM1
RGS22	Other/Unknown	no		RGS, RGS_sf, Rgs22

Expression context

Cohort genes with no expression data: 0.

65 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	1
moderate (6-20)	3
broad (>20)	71
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	8
lower esophagus mucosa	8
secondary oocyte	7
ventricular zone	6
ganglionic eminence	6
monocyte	6
sural nerve	5
granulocyte	5
buccal mucosa cell	5
esophagus mucosa	4
primordial germ cell in gonad	4
right hemisphere of cerebellum	4
left testis	3
right testis	3
calcaneal tendon	3
Brodmann (1909) area 23	3
middle temporal gyrus	3
cortical plate	3
endothelial cell	3
lymph node	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMO	225	ubiquitous	marker	ventricular zone, left ovary, right ovary
RNASE1	283	broad	marker	left testis, right testis, right lung
SNORD3P1	60		yes	liver, urinary bladder, body of stomach
BRCA2	184	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
TERT	105	broad	yes	stromal cell of endometrium, type B pancreatic cell, olfactory bulb
TGM3	120	tissue_specific	marker	lower esophagus mucosa, esophagus mucosa, skin of leg
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
TRPS1	284	ubiquitous	marker	mammary duct, epithelium of mammary gland, calcaneal tendon
TYR	59	tissue_specific	marker	pigmented layer of retina, male germ line stem cell (sensu Vertebrata) in testis, upper leg skin
LINC00111	56		yes	caudate nucleus, quadriceps femoris, cerebellar vermis
VDR	224	ubiquitous	marker	tibia, hair follicle, jejunal mucosa
ATP11A	268	ubiquitous	marker	germinal epithelium of ovary, visceral pleura, heart right ventricle
SMC2	265	ubiquitous	marker	ventricular zone, male germ line stem cell (sensu Vertebrata) in testis, ganglionic eminence
CSMD1	179	broad	marker	Brodmann (1909) area 23, middle temporal gyrus, primary visual cortex
BACH2	237	ubiquitous	marker	cortical plate, sural nerve, epithelium of nasopharynx
BCAS4	231	ubiquitous	marker	cerebellar vermis, lymph node, endothelial cell
CPVL	264	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
FLACC1	168	tissue_specific	marker	right uterine tube, bronchial epithelial cell, bronchus
SP6	140	broad	yes	lower esophagus mucosa, upper arm skin, placenta
CASP10	206	ubiquitous	marker	colonic epithelium, granulocyte, monocyte
CASP8	252	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
DHX35	216	ubiquitous	marker	lower esophagus muscularis layer, lower esophagus, esophagogastric junction muscularis propria
RALY	294	ubiquitous	marker	ganglionic eminence, granulocyte, ventricular zone
CCR6	103	broad	marker	lymph node, vermiform appendix, spleen
BPIFB3	13	tissue_specific	yes	olfactory segment of nasal mucosa, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
TRPC4AP	290	ubiquitous	marker	granulocyte, right adrenal gland cortex, adenohypophysis
STK35	256	ubiquitous	marker	secondary oocyte, oviduct epithelium, endothelial cell
SLC45A2	100	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, pigmented layer of retina, primordial germ cell in gonad
RAET1M	2		yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, colonic epithelium
PLIN3	288	ubiquitous	marker	pharyngeal mucosa, body of tongue, inferior vagus X ganglion

Protein interactions among cohort

Intra-cohort edges: 33.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
CDKN2A	9,311
TERT	5,717
PALB2	5,641
CFL1	5,350
CASP8	5,040
CTSS	4,897
BRCA2	4,839
SMC2	4,004
RHOU	3,874

Intra-cohort edges

A	B	Sources
ARHGEF10L	CFL1	biogrid_interaction
ATP11A	STN1	string_interaction
BACH2	CTSH	string_interaction
BRCA2	PALB2	biogrid_interaction, intact, string_interaction
BRCA2	TP53	string_interaction
CASP10	CASP8	biogrid_interaction, intact, string_interaction
CASP10	TP53	string_interaction
CASP8	FLACC1	string_interaction
CASP8	TICAM1	biogrid_interaction
CCR6	CEP43	string_interaction
CCR6	CLPTM1	intact
CDKN2A	CDKN2B	biogrid_interaction
CDKN2A	TP53	string_interaction
CDKN2B	TP53	string_interaction
CLPTM1	SLC45A2	biogrid_interaction
CLPTM1	TERT	string_interaction
CLPTM1	UBAC2	biogrid_interaction, string_interaction
CLPTM1L	SLC45A2	string_interaction
CLPTM1L	TERT	string_interaction
CPVL	UBAC2	string_interaction
CTSS	SEC16A	biogrid_interaction
CTSS	TP53	biogrid_interaction
DEF8	RALY	string_interaction
DEF8	SLC45A2	string_interaction
DEF8	SPIRE2	string_interaction
DHX35	STN1	string_interaction
FRMD4A	STK35	string_interaction
JDP2	TP53	biogrid_interaction
PADI4	TP53	string_interaction
PADI6	SLC45A2	string_interaction
PALB2	RHOBTB2	intact
PLIN3	RHOBTB2	string_interaction
SLC45A2	TYR	string_interaction

Structural data

PDB: 33 · AlphaFold-only: 38 · No structure: 4

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TP53	P04637	313
CTSS	P25774	62
VDR	P11473	52
CASP8	Q14790	36
PADI4	Q9UM07	28
TERT	O14746	23
CTLA4	P16410	22
CFL1	P23528	19
SMO	Q99835	15
BRCA2	P51587	14
RNASE1	P07998	12
TGM3	Q08188	11
TICAM1	Q8IUC6	8
STN1	Q9H668	8
CELF2	O95319	7
CDKN2A	P42771	5
PADI6	Q6TGC4	5
PALB2	Q86YC2	4
CUX1	P39880	3
SMC2	O95347	2
BACH2	Q9BYV9	2
CTSH	P09668	2
CYP1B1	Q16678	2
PPARGC1B	Q86YN6	2
TYR	P14679	1
CSMD1	Q96PZ7	1
RALY	Q9UKM9	1
CCR6	P51684	1
CEP43	O95684	1
RHOU	Q7L0Q8	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
THNSL2	Q86YJ6	95.48
CPVL	Q9H3G5	93.55
CYRIA	Q9H0Q0	92.68
ST3GAL6	Q9Y274	91.36
CDKN2B	P42772	90.12
HAPLN3	Q96S86	87.85
DHX35	Q9H5Z1	86.94
GOLPH3L	Q9H4A5	84.75
ATP11A	P98196	83.48
TRPC4AP	Q8TEL6	82.81
RHOBTB2	Q9BYZ6	81.89
BPIFB3	P59826	81.71
EXOC2	Q96KP1	80.82
CLPTM1L	Q96KA5	78.54
SLC45A2	Q9UMX9	77.96
JDP2	Q8WYK2	76.36
DEF8	Q6ZN54	76.04
FLACC1	Q96Q35	75.95
BCAS4	Q8TDM0	72.40
UBAC2	Q8NBM4	72.34
CLPTM1	O96005	70.90
CCDC88B	A6NC98	70.19
CASP10	Q92851	69.54
PLIN3	O60664	69.04
SBNO2	Q9Y2G9	68.13
STK35	Q8TDR2	67.52
ARHGEF10L	Q9HCE6	67.46
RGS22	Q8NE09	65.90
FRMD4A	Q9P2Q2	62.95
ZBTB7B	O15156	56.36

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 497. Enrichment computed across 122 evidence-associated genes (64 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 64 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Melanin biosynthesis	3	107.1×	8e-04	TYR, SLC45A2, OCA2
Endosomal/Vacuolar pathway	3	48.7×	0.007	CTSS, HLA-B, HLA-C
Developmental Lineage of Mammary Stem Cells	3	35.7×	0.012	FGF10, GATA3, KRT5
Signaling by cytosolic FGFR1 fusion mutants	3	29.7×	0.015	CEP43, CUX1, PIK3R1
Interferon gamma signaling	5	9.8×	0.015	HLA-B, HLA-C, HLA-DQA1, HLA-DQA2, IRF4
FasL/ CD95L signaling	2	71.4×	0.019	CASP10, CASP8
TLR3-mediated TICAM1-dependent programmed cell death	2	59.5×	0.019	CASP8, TICAM1
Impaired BRCA2 binding to PALB2	3	21.4×	0.019	BRCA2, PALB2, EXO1
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	3	19.8×	0.019	BRCA2, PALB2, EXO1
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	3	19.8×	0.019	BRCA2, PALB2, EXO1
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	3	19.8×	0.019	BRCA2, PALB2, EXO1
Interleukin-4 and Interleukin-13 signaling	5	8.0×	0.019	TP53, RHOU, GATA3, IRF4, PIK3R1
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	3	18.5×	0.021	BRCA2, PALB2, EXO1
Homologous DNA Pairing and Strand Exchange	3	17.8×	0.022	BRCA2, PALB2, EXO1
Caspase activation via extrinsic apoptotic signalling pathway	2	44.6×	0.026	CASP8, TICAM1
TRAIL signaling	2	44.6×	0.026	CASP10, CASP8
Oncogene Induced Senescence	3	15.7×	0.026	TP53, CDKN2A, CDKN2B
TRIF-mediated programmed cell death	2	39.6×	0.030	CASP8, TICAM1
Resolution of D-loop Structures through Holliday Junction Intermediates	3	14.1×	0.032	BRCA2, PALB2, EXO1
Signaling by FGFR1 in disease	3	13.7×	0.033	CEP43, CUX1, PIK3R1
TP53 Regulates Transcription of Caspase Activators and Caspases	2	29.7×	0.044	TP53, CASP10
Cell Cycle	7	3.9×	0.044	BRCA2, TERT, SMC2, CEP43, CDKN2A, CDKN2B, STN1
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	2	27.4×	0.049	CASP10, CASP8
MITF-M-regulated melanocyte development	4	7.1×	0.049	TERT, CDKN2A, IRF4, MC1R
Caspase activation via Death Receptors in the presence of ligand	2	23.8×	0.059	CASP8, TICAM1
Stabilization of p53	2	23.8×	0.059	TP53, CDKN2A
Innate Immune System	8	3.2×	0.062	ATP11A, CASP10, CASP8, CCR6, TICAM1, CTSH, CTSS, NEU1
Defective CYP1B1 causes Glaucoma	1	178.4×	0.069	CYP1B1
Evasion of Oncogene Induced Senescence Due to p14ARF Defects	1	178.4×	0.069	CDKN2A
Evasion of Oxidative Stress Induced Senescence Due to p14ARF Defects	1	178.4×	0.069	CDKN2A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 98 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
melanin biosynthetic process from tyrosine	3	129.0×	8e-04	TYR, SLC45A2, OCA2
negative regulation of mammary gland epithelial cell proliferation	3	103.2×	1e-03	BRCA2, CDKN2A, GATA3
negative regulation of stem cell proliferation	4	34.4×	0.002	TP53, FGF10, OVOL1, PTCH1
keratinocyte proliferation	4	23.7×	0.006	CDKN2A, FGF10, OVOL1, PTCH1
melanin biosynthetic process	3	39.7×	0.009	TYR, MC1R, OCA2
embryonic organ development	4	19.6×	0.009	TP53, PALB2, GATA3, PTCH1
apoptotic process involved in mammary gland involution	2	114.6×	0.014	VDR, CDKN2A
regulation of interleukin-12 production	2	86.0×	0.014	FOXP1, HLA-B
regulation of T-helper cell differentiation	2	86.0×	0.014	GATA3, IRF4
positive regulation of apoptotic process involved in mammary gland involution	2	86.0×	0.014	VDR, CDKN2A
mammary gland branching involved in pregnancy	2	86.0×	0.014	VDR, CSMD1
cellular response to interleukin-6	3	30.4×	0.014	ST3GAL6, CFL1, SBNO2
replicative senescence	3	30.4×	0.014	TERT, TP53, CDKN2A
positive regulation of execution phase of apoptosis	3	25.8×	0.014	TP53, CASP10, CASP8
adaptive immune response	7	6.0×	0.014	CTLA4, CTSH, CTSS, HLA-B, HLA-C, HLA-DQA1, HLA-DQA2
immune response	9	4.3×	0.015	CCR6, CTLA4, CTSH, CTSS, HLA-B, HLA-C, HLA-DQA1, HLA-DQA2 (+1 more)
stem cell proliferation	4	12.7×	0.016	TP53, FGF10, OVOL1, PTCH1
lysosomal lumen pH elevation	2	68.8×	0.017	SLC45A2, OCA2
negative regulation of keratinocyte proliferation	3	21.5×	0.017	VDR, OVOL1, PTCH1
cellular senescence	4	12.1×	0.017	BRCA2, TP53, CDKN2A, CDKN2B
positive regulation of miRNA transcription	4	11.9×	0.017	TERT, TP53, GATA3, MYCN
response to gamma radiation	3	17.8×	0.028	BRCA2, TP53, GATA3
protein import into nucleus	5	7.3×	0.028	SMO, TERT, TP53, CFL1, PIK3R1
lymphocyte migration	2	49.1×	0.029	CCR6, GATA3
antigen processing and presentation of exogenous peptide antigen via MHC class II	3	16.6×	0.031	CTSS, HLA-DQA1, HLA-DQA2
obsolete proteolysis involved in protein catabolic process	3	16.1×	0.033	CASP8, CTSH, CTSS
establishment of protein localization to telomere	2	43.0×	0.035	BRCA2, TERT
hair follicle morphogenesis	3	15.2×	0.037	SMO, TGM3, FGF10
positive regulation of focal adhesion disassembly	2	38.2×	0.040	RHOU, PIK3R1
negative regulation of transcription by RNA polymerase II	14	2.5×	0.040	SMO, TP53, TRPS1, VDR, BACH2, RALY, JDP2, CDKN2A (+6 more)

Therapeutics

Drugs indicated for this disease

4 approved, 4 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Cemiplimab	Approved (phase 4)
Fluorouracil	Approved (phase 4)
Imiquimod	Approved (phase 4)
Vismodegib	Approved (phase 4)
Calcium Chloride	Phase 3 (in late-stage trials)
Methyl Aminolevulinate	Phase 3 (in late-stage trials)
Tretinoin	Phase 3 (in late-stage trials)
Verteporfin	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Aminolevulinic Acid, Calcitriol, Diclofenac, Hydrogen Peroxide, Ingenol Mebutate, Ipilimumab, Itraconazole, Niacinamide, Nivolumab, Patidegib, Relatlimab, Sinecatechins, Sonidegib, Tirbanibulin.

Drug target analysis

Approved (phase 4): 12 · Phase ≥3: 12 · Phased (≥1): 16 · Undrugged: 59

Druggability breadth: 47 of 122 evidence-associated genes (39%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SMO	INFIGRATINIB
TERT	BERBERINE
TP53	NITROFURANTOIN
TYR	ASCORBIC ACID
VDR	CHOLECALCIFEROL
SMC2	SELUMETINIB
CASP8	PRIMAQUINE PHOSPHATE
CCR6	TEGASEROD MALEATE
STK35	NERATINIB
PADI4	CHLORTETRACYCLINE
CTSS	BOCEPREVIR
CYP1B1	PAZOPANIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
CYP1B1	22	4
STK35	18	4
CTSS	12	4
SMO	11	4
TERT	10	4
TYR	10	4
VDR	10	4
CCR6	3	4
PADI4	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
INFIGRATINIB	4	SMO
SONIDEGIB	4	SMO
SONIDEGIB PHOSPHATE	4	SMO
VISMODEGIB	4	SMO
BERBERINE	4	CYP1B1, TERT
DOXORUBICIN	4	TERT
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 10.

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

Symbol	Assays	Type breakdown
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
VDR	561	Binding:459, Functional:99, ADMET:3
CYP1B1	408	ADMET:281, Binding:127
TERT	391	Binding:389, Functional:2
CTSS	328	Binding:313, ADMET:9, Functional:5, Toxicity:1
TYR	211	Binding:209, ADMET:2
SMO	131	Binding:111, Functional:20
CASP8	116	Binding:106, Functional:10
STK35	94	Binding:94
PADI4	86	Binding:84, Functional:2
CCR6	60	Functional:33, Binding:27
CTSH	58	Binding:58
CASP10	22	Binding:21, Functional:1
RNASE1	17	Binding:16, ADMET:1
TGM3	15	Binding:15
CFL1	11	Binding:11
DHX35	8	Binding:8
RCC2	8	Binding:8
PLIN3	4	Binding:4
BACH2	3	Binding:3
SEC16A	3	Binding:3
SMC2	2	Binding:2
CEP43	2	Binding:2
CDKN2A	2	Binding:2
PADI6	1	Binding:1
CLPTM1	1	Binding:1
TNS3	1	Binding:1
CLPTM1L	1	Binding:1
CTLA4	1	Binding:1
CELF2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RNASE1	4.6.1.18	pancreatic ribonuclease
TGM3	2.3.2.13	protein-glutamine gamma-glutamyltransferase
TYR	1.14.18.1	tyrosinase
ATP11A	7.6.2.1	P-type phospholipid transporter
CASP10	3.4.22.63	caspase-10
CASP8	3.4.22.61	caspase-8
PADI4	3.5.3.15	protein-arginine deiminase
PADI6	3.5.3.15	protein-arginine deiminase
CTSH	3.4.22.16	cathepsin H
CTSS	3.4.22.27	cathepsin S

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SMO	131
TERT	391
TP53	869
TYR	211
VDR	561
CASP8	116
CTSS	328
CYP1B1	408

Pharmacogenomics

Cohort genes with a PharmGKB record: 72; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

28 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)
INFIGRATINIB	4	SMO
SONIDEGIB PHOSPHATE	4	SMO
BERBERINE	4	CYP1B1, TERT
DOXORUBICIN	4	TERT
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	12	SMO, TERT, TP53, TYR, VDR, SMC2, CASP8, CCR6, STK35, PADI4 (+2 more)
B	Phased (≥1) drug, not yet approved	4	TGM3, DHX35, CTSH, RCC2
C	Druggable family + PDB, no drug	5	RNASE1, CSMD1, PADI6, TNS3, CTLA4
D	Druggable family + AlphaFold only, no drug	5	CPVL, CASP10, SLC45A2, HAPLN3, EXOC2
E	Difficult family or no structure, no drug	49	SNORD3P1, BRCA2, TRPS1, LINC00111, ATP11A, BACH2, BCAS4, FLACC1, SP6, RALY (+39 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CASP10	22	CASP8
SLC45A2	0	TYR
CEP43	2	CCR6
CDKN2B	0	TP53
CLPTM1L	1	TERT
RNASE1	17	—
SNORD3P1	0	—
BRCA2	0	—
TRPS1	0	—
LINC00111	0	—
ATP11A	0	—
CSMD1	0	—
BACH2	3	—
BCAS4	0	—
CPVL	0	—
FLACC1	0	—
SP6	0	—
RALY	0	—
BPIFB3	0	—
TRPC4AP	0	—
RAET1M	0	—
PLIN3	4	—
JDP2	0	—
RHOU	0	—
CDKN2A	2	—
ST3GAL6	0	—
ZNF365	0	—
TICAM1	0	—
ZBTB7B	0	—
CFL1	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 231.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	126
PHASE2	51
PHASE1	23
PHASE3	14
PHASE1/PHASE2	8
EARLY_PHASE1	4
PHASE4	3
PHASE2/PHASE3	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00314756	PHASE4	COMPLETED	Treatment of Nodular Basal Cell Carcinoma (BCC) With Imiquimod 5% Cream After Curettage
NCT00581425	PHASE4	COMPLETED	Intron-A/Aldara Combination Therapy for Basal Cell Carcinoma (BCC)
NCT03610022	PHASE4	COMPLETED	Relationship Between Pharmacokinetics and Safety of Vismodegib - OPTIVISMO-1
NCT05078047	PHASE3	RECRUITING	Study Comparing the Standard Administration of IO Versus the Same IO Administered Each 3 Months in Patients in Response After 6 Months of Standard IO
NCT05212246	PHASE3	NOT_YET_RECRUITING	Basal Cell Carcinoma Chemoprevention Trial
NCT00049959	PHASE3	TERMINATED	Two Studies to Determine if Verteporfin PDT is Effective & Safe in Treating Multiple Basal Cell Carcinoma of the Skin.
NCT00129519	PHASE3	COMPLETED	A Study to Evaluate the Effectiveness of Imiquimod 5% Cream for Basal Cell Carcinoma Recurrence
NCT00189241	PHASE3	COMPLETED	A Study to Evaluate Effectiveness of Imiquimod 5% Cream in Superficial Basal Cell Carcinoma
NCT00472043	PHASE3	COMPLETED	PDT With Metvix 160 mg/g Cream Versus PDT With Placebo Cream in Participants With Primary Nodular Basal Call Carcinoma
NCT00472108	PHASE3	COMPLETED	Photodynamic Therapy (PDT) With Metvix Cream 160 mg/g Versus PDT With Placebo Cream in Participants With Primary Nodular Basal Cell Carcinoma
NCT00472459	PHASE3	COMPLETED	Photodynamic Therapy (PDT) With Metvix® 160 Milligrams/Gram Cream in Organ Transplant Participants With Non-melanoma Skin Cancer
NCT00473343	PHASE3	COMPLETED	Metvix PDT in Participant With High Risk Basal Cell Carcinoma
NCT00663650	PHASE3	UNKNOWN	Periocular Basal Cell Carcinoma (BCC): Permanent vs. Frozen Section Pathological Control
NCT01212549	PHASE3	COMPLETED	Comparison of Two Schemes of Cryosurgery and Imiquimod Combination Treatment for Basal Cell Carcinoma
NCT01260987	PHASE2/PHASE3	COMPLETED	Fractional CO2 Laser Assisted Photodynamic Therapy
NCT02144077	PHASE3	COMPLETED	Safety and Efficacy Study for the Treatment of Non-Aggressive Basal Cell Carcinoma With Photodynamic Therapy
NCT03070691	PHASE2/PHASE3	WITHDRAWN	Efficacy, Safety and Tolerability of Topically Applied LDE225 Cream (Hedgehog Pathway Inhibitor) in Adult Patients With Nevoid Basal Cell Carcinoma Syndrome (NBCCS)
NCT05046262	PHASE3	UNKNOWN	Calcium Electroporation for Basal Cell Carcinomas - Proof of Concept Study
NCT06150144	PHASE3	UNKNOWN	The Efficacy and Safety of Using Intralesional 5-fluorouracil for Basal Cell Carcinoma
NCT02834013	PHASE2	ACTIVE_NOT_RECRUITING	Nivolumab and Ipilimumab in Treating Patients With Rare Tumors
NCT03521830	PHASE2	RECRUITING	Nivolumab Alone or Plus Relatlimab or Ipilimumab for Patients With Locally-Advanced Unresectable or Metastatic Basal Cell Carcinoma
NCT04349436	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study to Investigate the Efficacy and Safety of RP1 in Adult Patients With Organ Transplants and Advanced Skin Malignancies
NCT04679480	PHASE2	ACTIVE_NOT_RECRUITING	Anti-PD1-antibody and Pulsed HHI for Advanced BCC
NCT04928222	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Placebo Microneedles in Healthy Volunteers (Part I) and Efficacy/Safety of Doxorubicin Microneedles in Basal Cell Cancer Subjects (Part II)
NCT05020912	PHASE2	RECRUITING	Alteration of the Immune Microenvironment in Basal Cell Carcinoma Following Photodynamic Therapy
NCT05086692	PHASE1/PHASE2	RECRUITING	A Beta-only IL-2 ImmunoTherapY Study
NCT05202860	PHASE2	ACTIVE_NOT_RECRUITING	Impact of Human Papillomavirus (HPV) Vaccination on Burden of Disease in Patients with Actinic Keratosis
NCT05294120	PHASE2	ACTIVE_NOT_RECRUITING	A Study on Radiation Therapy Guided by the Reflectance Confocal Microscopy (RCM)/Optical Coherence Tomography (OCT) Device in People With Basal Cell Carcinoma
NCT05561634	PHASE2	RECRUITING	Radiotherapy by Sonic Hedgehog Pathway Inhibitors in Basal Cell Carcinoma
NCT05896839	PHASE1/PHASE2	RECRUITING	Immunotherapy in Combination With Prednisone and Sirolimus for Kidney Transplant Recipients With Unresectable or Metastatic Skin Cancer
NCT05929664	PHASE2	RECRUITING	Cemiplimab Plus Fianlimab for the Treatment of Locally Advanced Head and Neck Basal Cell Carcinoma Before Surgery
NCT05969860	PHASE2	RECRUITING	At-Home Cancer Directed Therapy Versus in Clinic for the Treatment of Patients With Advanced Cancer
NCT06344052	PHASE2	RECRUITING	To Assess the Safety and Efficacy of SP-002 with Vismodegib for the Treatment of Locally Advanced Basal Cell Carcinoma
NCT06422936	PHASE2	ACTIVE_NOT_RECRUITING	Clinical Trial to Evaluate BO-112 in Patients With Basal Cell Carcinoma (BCC)
NCT06624475	PHASE2	RECRUITING	Neoadjuvant Nivolumab + Relatlimab (Opdualag) Versus Nivolumab for Resectable High-Risk Basal Cell Carcinoma
NCT06683846	PHASE2	RECRUITING	Ivonescimab in the Treatment of Multiple Advanced Tumors
NCT06981325	PHASE2	RECRUITING	Evaluation of Efficacy and Safety of Cemiplimab as First Line Treatment for Advanced Basal Cell Carcinoma (BCC) Patients
NCT07010692	PHASE1/PHASE2	RECRUITING	Treating Basal and Squamous Cell Carcinomas With Fractional Laser and Tirbanibulin Ointment
NCT07227350	PHASE2	NOT_YET_RECRUITING	L19IL2 or L19TNF or L19IL2/TNF in Patients With Basal Cell Carcinoma (BCC)
NCT07227870	PHASE2	NOT_YET_RECRUITING	L19IL2/TNF in Patients With Basal Cell Carcinoma

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
VISMODEGIB	4	18
SONIDEGIB	4	10
IMIQUIMOD	4	7
CEMIPLIMAB	4	2
INGENOL MEBUTATE	4	2
ITRACONAZOLE	4	2
AMINOLEVULINIC ACID	4	1
CALCITRIOL	4	1
CALCIUM CHLORIDE	4	1
GLATIRAMER ACETATE	4	1
HYDROGEN PEROXIDE	4	1
METHYL AMINOLEVULINATE	4	1
RELATLIMAB	4	1
L19IL2	3	2
ONFEKAFUSP ALFA	3	2
PATIDEGIB	3	2
ALANINE	3	1
FIANLIMAB	3	1
MAXACALCITOL	3	1
VUSOLIMOGENE ODERPAREPVEC	3	1
DARLEUKIN	2	2
BMS-833923	2	1
GUSACITINIB	2	1
HILTONOL	2	1
PROGRAMMED CELL DEATH 1 LIGAND 1	2	1
VIDUTOLIMOD	2	1
VUDALIMAB	2	1
HYOSCYAMINE	-1	2

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 25 predictive associations from 31 curated evidence items; also 2 diagnostic, 1 oncogenic.

Molecular subtype	Therapy	Effect	Level	CIViC
PTCH1 Loss-of-function	Vismodegib	Sensitivity/Response	CIViC A	EID11607
PTCH1 Loss-of-function	Sonidegib	Sensitivity/Response	CIViC A	EID11608
SMO Mutation	Vismodegib + Sonidegib	Resistance	CIViC B	EID1477
SMO Mutation	Vismodegib	Resistance	CIViC B	EID746
PTCH1 Q17X	Vismodegib	Sensitivity/Response	CIViC C	EID4684
PTCH1 Q787X	Vismodegib	Sensitivity/Response	CIViC C	EID4683
PTCH1 W170X	Vismodegib	Sensitivity/Response	CIViC C	EID4681
PTCH1 W712X	Vismodegib	Sensitivity/Response	CIViC C	EID4682
SMO L412F	Vismodegib	Resistance	CIViC C	EID4654 +2
SMO V321M	Vismodegib	Resistance	CIViC C	EID4660 +2
SMO W535L	Vismodegib	Resistance	CIViC C	EID3735 +1
SMO D473G	Vismodegib	Resistance	CIViC C	EID4634
SMO D473Y	Vismodegib	Resistance	CIViC C	EID4635
SMO G497W	Vismodegib	Resistance	CIViC C	EID4675
SMO S278I	Vismodegib	Resistance	CIViC C	EID4636
SMO W281L	Vismodegib	Resistance	CIViC C	EID4674
SMO Mutation	Arsenic Trioxide + PSI	Sensitivity/Response	CIViC D	EID747
SMO W281C	Vismodegib	Resistance	CIViC D	EID4637 +1
SMO A459V	Vismodegib	Resistance	CIViC D	EID4679
SMO C469Y	Vismodegib	Resistance	CIViC D	EID4677
SMO D473H	Vismodegib	Resistance	CIViC D	EID755
SMO I408V	Vismodegib	Resistance	CIViC D	EID4676
SMO Q477E	Vismodegib	Resistance	CIViC D	EID4639
SMO S533N	Vismodegib	Resistance	CIViC D	EID4680
SMO T241M	Vismodegib	Resistance	CIViC D	EID4678