Urinary bladder cancer

Summary

Urinary bladder cancer (MONDO:0001187) is a cancer (an umbrella term covering 9 Mondo subtypes) with 27 cohort genes (162 GWAS associations across 52 studies; 22 CIViC-evidence somatic drivers; 421 ClinVar predisposition records) and 42 clinical trials. The dominant Reactome pathway is Signaling by ERBB2 KD Mutants (6 cohort genes). Molecularly, ERBB2 G292R confers sensitivity to Neratinib in Urinary Bladder Cancer (CIViC Level B); 3 further subtype–drug associations are mapped below. Top therapeutic interventions include mitomycin and oportuzumab monatox.

At a glance

• Classification: Cancer
• Umbrella term: 9 Mondo subtypes
• Cohort genes: 27
• GWAS associations: 162
• ClinVar variants: 421
• Clinical trials: 42
• Precision-medicine evidence (CIViC): 4 subtype–drug associations

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	urinary bladder cancer
Mondo ID	MONDO:0001187
OMIM	109800
Orphanet	157980
DOID	DOID:11054
ICD-10-CM	C67
ICD-11	1244512758
NCIT	C9334
SNOMED CT	399326009
UMLS	C0005684
MedGen	14150
Anatomy (UBERON)	UBERON:0001255
Is cancer (heuristic)	yes

Also known as: bladder cancer, somatic · cancer of urinary bladder · malignant bladder neoplasm · malignant bladder tumor · malignant bladder tumour · malignant neoplasm of bladder · malignant neoplasm of the bladder · malignant neoplasm of the urinary bladder · malignant neoplasm of urinary bladder · malignant neoplasm, bladder · malignant neoplasm, urinary bladder · malignant tumor of bladder · malignant tumor of the bladder · malignant tumor of the urinary bladder · malignant tumor of urinary bladder · malignant tumor, urinary bladder · malignant tumour of bladder · malignant tumour of the bladder · malignant tumour of the urinary bladder · malignant tumour of urinary bladder (+9 more)

Data availability: 421 ClinVar variants · 162 GWAS associations (52 studies).

Disease family

An umbrella term covering 9 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › urinary system disorder › urinary bladder disorder › urinary bladder neoplasm › urinary bladder cancer

Related subtypes (5): bladder benign neoplasm, urinary bladder villous adenoma, bladder papillary urothelial neoplasm, bladder flat intraepithelial lesion, bladder inflammatory myofibroblastic tumor

Subtypes (9): bladder lateral wall cancer, bladder neck cancer, urinary bladder posterior wall cancer, bladder sarcoma, urinary bladder anterior wall cancer, urachus cancer, bladder dome cancer, bladder lymphoma, urinary bladder carcinoma

Genetics & variants

GWAS landscape

162 GWAS associations across 52 studies. Top hits map to 19 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs2920295	1e-45	PSCA - LY6K	A	0.2
rs2978982	1e-44	PSCA	T	0.19
rs2585181	1e-41	PSCA - LY6K	C	0.18
rs10094872	4e-38	CASC11	A	0.19
rs9642880	7e-29	CASC11	T	1.2
chr1:110229772	9e-23		G	1.2
rs2242652	2e-21	TERT	G	0.19
rs35246381	3e-21	NAT2 - PSD3	C	0.16
rs5750711	2e-20	CBX6 - APOBEC3A	T	0.13
rs36209093	6e-20	GSTM2	C	0.17
rs17863783	9e-20	UGT1A8, UGT1A10, UGT1A7, UGT1A9, UGT1A6	G	1.75
rs1495743	1e-19	NAT2 - PSD3	G	0.15
rs56285422	2e-19	CCNE1 - PPIAP58	C	0.11
rs62104477	3e-18	C19orf12 - CCNE1	G	0.1
chr4:1762287	4e-18		A	0.15
rs811316	2e-16	FAM53A - SLBP	T	0.13
rs17868304	4e-16	UGT1A11P - UGT1A8	C	0.41
rs10853535	8e-16	SLC14A1	C	1.14
rs2294008	1e-15	JRK, PSCA	T	1.14
rs2993291	2e-15	MCF2L	A	0.13
rs1530586	2e-15	TACC3 - FGFR3	C	0.13
rs9811908	2e-15	BRK1	G	0.33
rs142003747	3e-15	CASC15	T	0.11
rs9577407	4e-15	MCF2L	G	0.12
rs2896518	5e-15	TACC3 - FGFR3	A	1.17
rs837775	5e-15	TP63 - P3H2	C	0.12
chr3:189637587	1e-14		C	0.12
rs10069690	2e-14	TERT	C	1.16
rs4446484	2e-14	LINC01411	C	0.11
chr4:1737262	3e-14		T	0.1

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475593	Verma A	2024	17,444	429,350	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90296729	Koutros S	2023	13,447	342,580	Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights.
GCST90475598	Verma A	2024	11,744	436,406	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90475599	Verma A	2024	10,664	438,177	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90296734	Koutros S	2023	7,440	9,110	Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights.
GCST90296731	Koutros S	2023	5,105	4,970	Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights.
GCST90435615	Zhou W	2018	4,165	404,796	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90296732	Koutros S	2023	3,286	2,802	Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights.
GCST90475592	Verma A	2024	3,021	117,718	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479811	Verma A	2024	3,021	117,718	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	2
Tier 3: regulatory	1
Tier 4: intronic/intergenic	47

MAF distribution

Bucket	Variants
common (>=0.05)	45
low_freq (0.01-0.05)	5
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intergenic_variant	17
intron_variant	16
unknown	11
synonymous_variant	2
non_coding_transcript_exon_variant	1
5_prime_UTR_variant	1
3_prime_UTR_variant	1
regulatory_region_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs2920295	8	142683519	A>C,G,T	0.446	intergenic_variant	PSCA - LY6K	1e-45	Tier 4: intronic/intergenic
rs2978982	8	142682072	T>C,G	0.443	synonymous_variant	PSCA	1e-44	Tier 4: intronic/intergenic
rs2585181	8	142690296	C>A	0.436	intergenic_variant	PSCA - LY6K	1e-41	Tier 4: intronic/intergenic
rs10094872	8	127707639	A>T	0.31	intron_variant	CASC11	4e-38	Tier 4: intronic/intergenic
rs9642880	8	127705823	G>A,T	0.47	intron_variant	CASC11	7e-29	Tier 4: intronic/intergenic
chr1:110229772				0.34			9e-23	Tier 4: intronic/intergenic
rs2242652	5	1279913	G>A	0.19	intron_variant	TERT	2e-21	Tier 4: intronic/intergenic
rs35246381	8	18415025	C>A,G,T	0.234	intergenic_variant	NAT2 - PSD3	3e-21	Tier 4: intronic/intergenic
rs5750711	22	38945952	T>C	0.345	intergenic_variant	CBX6 - APOBEC3A	2e-20	Tier 4: intronic/intergenic
rs36209093	1	109687165	C>T	0.402	intergenic_variant	GSTM2	6e-20	Tier 4: intronic/intergenic
rs17863783	2	233693631	G>A,T	0.02	synonymous_variant	UGT1A8, UGT1A10, UGT1A7, UGT1A9, UGT1A6	9e-20	Tier 4: intronic/intergenic
rs1495743	8	18415790	G>A,C,T	0.233	intergenic_variant	NAT2 - PSD3	1e-19	Tier 4: intronic/intergenic
rs56285422	19	29828985	C>G,T	0.317	intergenic_variant	CCNE1 - PPIAP58	2e-19	Tier 4: intronic/intergenic
rs62104477	19	29804084	G>T	0.29	intergenic_variant	C19orf12 - CCNE1	3e-18	Tier 4: intronic/intergenic
chr4:1762287				0.216			4e-18	Tier 4: intronic/intergenic
rs811316	4	1687650	T>A,C,G	0.246	intergenic_variant	FAM53A - SLBP	2e-16	Tier 4: intronic/intergenic
rs17868304	2	233608749	C>T	0.034	intergenic_variant	UGT1A11P - UGT1A8	4e-16	Tier 4: intronic/intergenic
rs10853535	18	45737582	C>A,G,T	0.44	non_coding_transcript_exon_variant	SLC14A1	8e-16	Tier 4: intronic/intergenic
rs2294008	8	142680513	C>T	0.45	5_prime_UTR_variant	JRK, PSCA	1e-15	Tier 2: splice/UTR
rs2993291	13	112999532	A>C,G,T	0.273	intron_variant	MCF2L	2e-15	Tier 4: intronic/intergenic
rs1530586	4	1759200	C>A,T	0.254	intergenic_variant	TACC3 - FGFR3	2e-15	Tier 4: intronic/intergenic
rs9811908	3	10119721	G>A,T	0.018	intron_variant	BRK1	2e-15	Tier 4: intronic/intergenic
rs142003747	6	21821984	T>A	0.328	intron_variant	CASC15	3e-15	Tier 4: intronic/intergenic
rs9577407	13	112985357	G>A,T	0.264	intron_variant	MCF2L	4e-15	Tier 4: intronic/intergenic
rs2896518	4	1755832	A>C,G,T	0.21	intergenic_variant	TACC3 - FGFR3	5e-15	Tier 4: intronic/intergenic
rs837775	3	189925884	C>T	0.239	intergenic_variant	TP63 - P3H2	5e-15	Tier 4: intronic/intergenic
chr3:189637587				0.274			1e-14	Tier 4: intronic/intergenic
rs10069690	5	1279675	C>T	0.26	intron_variant	TERT	2e-14	Tier 4: intronic/intergenic
rs4446484	5	174426678	C>A,T	0.407	intron_variant	LINC01411	2e-14	Tier 4: intronic/intergenic
chr4:1737262				0.203			3e-14	Tier 4: intronic/intergenic

ClinVar germline variants

421 retrieved; paginated sample, class counts are floors:

148 pathogenic, 112 uncertain significance, 66 conflicting classifications of pathogenicity, 27 pathogenic/likely pathogenic, 21 other, 16 benign/likely benign, 13 not provided, 6 likely pathogenic, 6 benign, 5 likely benign, 1 pathogenic; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
2582238	NM_006015.6(ARID1A):c.511C>T (p.Gln171Ter)	ARID1A	Pathogenic	no assertion criteria provided
2582239	NM_006015.6(ARID1A):c.1813C>T (p.Gln605Ter)	ARID1A	Pathogenic	no assertion criteria provided
2582240	NM_006015.6(ARID1A):c.2434C>T (p.Gln812Ter)	ARID1A	Pathogenic	no assertion criteria provided
2582241	NM_006015.6(ARID1A):c.3988C>T (p.Gln1330Ter)	ARID1A	Pathogenic	no assertion criteria provided
2582242	NM_006015.6(ARID1A):c.4372C>T (p.Gln1458Ter)	ARID1A	Pathogenic	no assertion criteria provided
2582250	NM_006015.6(ARID1A):c.2632C>T (p.Gln878Ter)	ARID1A	Pathogenic	no assertion criteria provided
2582256	NM_006015.6(ARID1A):c.5566C>T (p.Gln1856Ter)	ARID1A	Pathogenic	criteria provided, single submitter
2582260	NM_006015.6(ARID1A):c.6144G>A (p.Trp2048Ter)	ARID1A	Pathogenic	no assertion criteria provided
2582261	NM_006015.6(ARID1A):c.1210C>T (p.Gln404Ter)	ARID1A	Pathogenic	no assertion criteria provided
2582262	NM_006015.6(ARID1A):c.1585C>T (p.Gln529Ter)	ARID1A	Pathogenic	no assertion criteria provided
2582263	NM_006015.6(ARID1A):c.2008C>T (p.Gln670Ter)	ARID1A	Pathogenic	no assertion criteria provided
2582264	NM_006015.6(ARID1A):c.2272C>T (p.Gln758Ter)	ARID1A	Pathogenic	no assertion criteria provided
2582265	NM_006015.6(ARID1A):c.2323C>T (p.Gln775Ter)	ARID1A	Pathogenic	criteria provided, single submitter
2582266	NM_006015.6(ARID1A):c.2683C>T (p.Gln895Ter)	ARID1A	Pathogenic	no assertion criteria provided
2582268	NM_006015.6(ARID1A):c.4072C>T (p.Gln1358Ter)	ARID1A	Pathogenic	no assertion criteria provided
2582269	NM_006015.6(ARID1A):c.4258C>T (p.Gln1420Ter)	ARID1A	Pathogenic	no assertion criteria provided
2582270	NM_006015.6(ARID1A):c.4435C>T (p.Gln1479Ter)	ARID1A	Pathogenic	no assertion criteria provided
2582271	NM_006015.6(ARID1A):c.4891C>T (p.Gln1631Ter)	ARID1A	Pathogenic	no assertion criteria provided
2582272	NM_006015.6(ARID1A):c.5058G>A (p.Trp1686Ter)	ARID1A	Pathogenic	no assertion criteria provided
2582273	NM_006015.6(ARID1A):c.5919G>A (p.Trp1973Ter)	ARID1A	Pathogenic	no assertion criteria provided
1352830	NM_000051.4(ATM):c.5716C>T (p.Gln1906Ter)	ATM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1427072	NM_000051.4(ATM):c.7195C>T (p.Gln2399Ter)	ATM	Pathogenic	criteria provided, multiple submitters, no conflicts
2039938	NM_000051.4(ATM):c.3173G>A (p.Trp1058Ter)	ATM	Pathogenic	criteria provided, multiple submitters, no conflicts
216021	NM_000051.4(ATM):c.2413C>T (p.Arg805Ter)	ATM	Pathogenic	reviewed by expert panel
231933	NM_000051.4(ATM):c.2023C>T (p.Gln675Ter)	ATM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
233930	NM_000051.4(ATM):c.8218C>T (p.Gln2740Ter)	ATM	Pathogenic	criteria provided, multiple submitters, no conflicts
2582243	NM_000051.4(ATM):c.5129G>A (p.Trp1710Ter)	ATM	Pathogenic	criteria provided, multiple submitters, no conflicts
2582244	NM_000051.4(ATM):c.6899G>A (p.Trp2300Ter)	ATM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2582245	NM_000051.4(ATM):c.8306G>A (p.Trp2769Ter)	ATM	Pathogenic	criteria provided, single submitter
2582284	NM_000051.4(ATM):c.1681C>T (p.Gln561Ter)	ATM	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 166 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
FGFR3	Act	BLADDER,BLCA,HNSC,LUSC,PCM,PLMESO,UTUC	CIViC #23
BRCA1	LoF	BLCA,BRCA,MEL,OVT	CIViC #6
BRCA2	LoF	BLCA,BRCA,CESC,CHOL,HCC,HNSC,LUSC,MBL,OVT,PAAD,PRAD,PROSTATE,RCC,VULVA	CIViC #7
ARID1A	LoF	BL,BLCA,BRCA,CCRCC,CESC,CHOL,CLLSLL,COAD,COADREAD,DLBCLNOS,EGC,ESCA,ESCC,GBC,GBM,HCC,LGGNOS,LUAD,LUNG,LUSC,MBL,MLYM,MT,NHL,NSCLC,OS,OVT,PAAD,PANCREAS,PAST,PRAD,RCC,SCLC,SKIN,STAD,UCEC,UCS,UTUC	CIViC #6559
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
TSC1	LoF	BLCA,BRCA,COADREAD,HCC,LUAD,RCC,SKCM,STAD,UTUC	CIViC #46
KDM6A	LoF	ALL,BLADDER,BLCA,BRCA,ESCA,ESCC,GBC,HCC,HNSC,LUSC,MBL,PAAD,PAST,PRAD,PRCC,PROSTATE,SCLC,STAD	CIViC #6054
CDKN1A	LoF	BLCA,CHRCC,HCC	CIViC #913
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
CTNNB1	Act	ACC,COAD,COADREAD,ESCA,HCC,LIHB,LUAD,MBL,MEL,NSCLC,OVT,PAST,PRAD,PROSTATE,RMS,SKIN,SOFT_TISSUE,STAD,UCEC,WT	CIViC #1290
EGFR	Act	BRCA,COADREAD,GB,GBM,HGGNOS,LGGNOS,LUAD,LUSC,NSCLC,PAST,PCM,READ,SIC	CIViC #19
ERBB2	Act	BLCA,BRCA,CESC,CHOL,COADREAD,EGC,ESCA,ESCC,LMS,LUAD,NSCLC,OVT,PRCC,READ,STAD,UCEC	CIViC #20
ERBB3	Act	BLCA,BRCA,CESC,CHOL,COADREAD,NBL,PRAD,STAD,UCEC,UCS,UTUC	CIViC #1733
ERCC2	Act	BLCA	CIViC #1736
HRAS	Act	ANGS,BLCA,BRCA,COADREAD,CSCC,HNSC,LUSC,NPC,PGNG,PRAD,PROSTATE,THYM,UTUC,WDTC	CIViC #2747
KRAS	Act	ALL,AML,ANSC,BLADDER,BLCA,BRCA,CEAD,CESC,CHOL,CLLSLL,COAD,COADREAD,DLBCLNOS,EGC,ESCA,ESCC,HCC,LUAD,LUSC,MEL,MGCT,MT,NSCLC,OVT,PAAD,PANCREAS,PAST,PCM,PRAD,PRCC,READ,STAD,STOMACH,UCEC,UCS,WDTC	CIViC #30
MRE11			CIViC #3586
NF1	LoF	ACC,ALL,AML,ANGS,BLCA,BRCA,CCRCC,CHOL,CLLSLL,COADREAD,GB,GBM,GIST,HCC,HNSC,LGGNOS,LMS,LUAD,LUNG,LUSC,MEL,NBL,NSCLC,OVT,PAST,PGNG,PLMESO,RMS,SKCM,SOFT_TISSUE,STAD,THYM,UCS	CIViC #3867
ATM	LoF	BLCA,BRCA,CCRCC,CHOL,CLLSLL,COAD,COADREAD,ESCA,HCC,LUAD,LUSC,MEL,NSCLC,PAAD,PANCREAS,PANET,PCM,PLMESO,PRAD,PROSTATE,STAD,UCEC,UTUC,WDTC	CIViC #69
PIK3CA	Act	ACYC,ANGS,ANSC,BCC,BLADDER,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,COAD,COADREAD,EPM,ESCA,ESCC,GB,GBM,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LMS,LUAD,LUSC,MBL,MGCT,NPC,NSCLC,OVT,PAAD,PAST,PLMESO,PRAD,PRCC,PROSTATE,RCC,SACA,SKCM,SOFT_TISSUE,STAD,UCEC,UCS,UTUC,VULVA,WDTC	CIViC #37
PTEN	LoF	ANGS,BLCA,BRCA,CCRCC,CEAD,CESC,CHOL,CHRCC,COADREAD,CSCC,ESCA,GB,GBM,HCC,HGGNOS,HNSC,LGGNOS,LIPO,LUAD,LUSC,MBL,MEL,MT,NSCLC,OVT,PANET,PAST,PRAD,PRCC,PROSTATE,RCC,SCLC,SKCM,SOFT_TISSUE,STAD,UCEC,UCS,WDTC	CIViC #41
RB1	LoF	ACC,BLADDER,BLCA,BRCA,CESC,ESCA,GB,GBM,GIST,HCC,HNSC,LGGNOS,LIPO,LMS,LUAD,LUSC,MEL,MT,NSCLC,OS,OVT,PANCREAS,PCM,PRAD,PROSTATE,RBL,SCLC,SKCM,SOFT_TISSUE,STAD,STOMACH,UCEC,UCS	CIViC #4795

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FGFR3	Orphanet:15	Achondroplasia
FGFR3	Orphanet:1860	Thanatophoric dysplasia type 1
FGFR3	Orphanet:2363	Lacrimoauriculodentodigital syndrome
FGFR3	Orphanet:251576	Gliosarcoma
FGFR3	Orphanet:251579	Giant cell glioblastoma
FGFR3	Orphanet:35099	Non-syndromic bicoronal craniosynostosis
FGFR3	Orphanet:429	Hypochondroplasia
FGFR3	Orphanet:53271	Muenke syndrome
FGFR3	Orphanet:794	Saethre-Chotzen syndrome
FGFR3	Orphanet:85164	Camptodactyly-tall stature-scoliosis-hearing loss syndrome
FGFR3	Orphanet:85165	Severe achondroplasia-developmental delay-acanthosis nigricans syndrome
FGFR3	Orphanet:93262	Crouzon syndrome-acanthosis nigricans syndrome
FGFR3	Orphanet:93274	Thanatophoric dysplasia type 2
BRCA1	Orphanet:1331	Familial prostate cancer
BRCA1	Orphanet:1333	Familial pancreatic carcinoma
BRCA1	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRCA1	Orphanet:168829	Primary peritoneal carcinoma
BRCA1	Orphanet:227535	Hereditary breast cancer
BRCA1	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
BRCA1	Orphanet:694963	Inflammatory breast cancer
BRCA1	Orphanet:70567	Cholangiocarcinoma
BRCA1	Orphanet:84	Fanconi anemia
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
ARID1A	Orphanet:1465	Coffin-Siris 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

Cohort genes → proteins

27 cohort genes, 26 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	27

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FGFR3	HGNC:3690	ENSG00000068078	P22607	Fibroblast growth factor receptor 3	clinvar,civic_evidence
BRCA1	HGNC:1100	ENSG00000012048	P38398	Breast cancer type 1 susceptibility protein	clinvar
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	clinvar
ARID1A	HGNC:11110	ENSG00000117713	O14497	AT-rich interactive domain-containing protein 1A	clinvar
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	clinvar
TSC1	HGNC:12362	ENSG00000165699	Q92574	Hamartin	clinvar
KDM6A	HGNC:12637	ENSG00000147050	O15550	Lysine-specific demethylase 6A	clinvar
CDKN1A	HGNC:1784	ENSG00000124762	P38936	Cyclin-dependent kinase inhibitor 1	clinvar
CDKN2A	HGNC:1787	ENSG00000147889	P42771	Cyclin-dependent kinase inhibitor 2A	clinvar
CTNNA3	HGNC:2511	ENSG00000183230	Q9UI47	Catenin alpha-3	clinvar
CTNNB1	HGNC:2514	ENSG00000168036	P35222	Catenin beta-1	clinvar
LRRC56	HGNC:25430	ENSG00000161328	Q8IYG6	Leucine-rich repeat-containing protein 56	clinvar
C11orf65	HGNC:28519	ENSG00000166323	Q8NCR3	Protein MFI	clinvar
EGFR	HGNC:3236	ENSG00000146648	P00533	Epidermal growth factor receptor	clinvar
CDPF1	HGNC:33710	ENSG00000205643	Q6NVV7	Cysteine-rich DPF motif domain-containing protein 1	clinvar
ERBB2	HGNC:3430	ENSG00000141736	P04626	Receptor tyrosine-protein kinase erbB-2	clinvar
ERBB3	HGNC:3431	ENSG00000065361	P21860	Receptor tyrosine-protein kinase erbB-3	clinvar
ERCC2	HGNC:3434	ENSG00000104884	P18074	General transcription and DNA repair factor IIH helicase subunit XPD	clinvar
EGFR-AS1	HGNC:40207	ENSG00000224057		EGFR antisense RNA 1	clinvar
HRAS	HGNC:5173	ENSG00000174775	P01112	GTPase HRas	clinvar
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	clinvar
MRE11	HGNC:7230	ENSG00000020922	P49959	Double-strand break repair protein MRE11	clinvar
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	clinvar
ATM	HGNC:795	ENSG00000149311	Q13315	Serine-protein kinase ATM	clinvar
PIK3CA	HGNC:8975	ENSG00000121879	P42336	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	clinvar
PTEN	HGNC:9588	ENSG00000171862	P60484	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	clinvar
RB1	HGNC:9884	ENSG00000139687	P06400	Retinoblastoma-associated protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FGFR3	Fibroblast growth factor receptor 3	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 and apoptosis.
BRCA1	Breast cancer type 1 susceptibility protein	E3 ubiquitin-protein ligase that specifically mediates the formation of ‘Lys-6’-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage.
BRCA2	Breast cancer type 2 susceptibility protein	Involved in double-strand break repair and/or homologous recombination.
ARID1A	AT-rich interactive domain-containing protein 1A	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
TSC1	Hamartin	Non-catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolec…
KDM6A	Lysine-specific demethylase 6A	Histone demethylase that specifically demethylates ‘Lys-27’ of histone H3, thereby playing a central role in histone code.
CDKN1A	Cyclin-dependent kinase inhibitor 1	Plays an important role in controlling cell cycle progression and DNA damage-induced G2 arrest.
CDKN2A	Cyclin-dependent kinase inhibitor 2A	Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6.
CTNNA3	Catenin alpha-3	May be involved in formation of stretch-resistant cell-cell adhesion complexes.
CTNNB1	Catenin beta-1	Key downstream component of the canonical Wnt signaling pathway.
LRRC56	Leucine-rich repeat-containing protein 56	Required for the assembly of dynein arms.
C11orf65	Protein MFI	Acts as an inhibitor of mitochondrial fission.
EGFR	Epidermal growth factor receptor	Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses.
ERBB2	Receptor tyrosine-protein kinase erbB-2	Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding.
ERBB3	Receptor tyrosine-protein kinase erbB-3	Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins.
ERCC2	General transcription and DNA repair factor IIH helicase subunit XPD	ATP-dependent 5’-3’ DNA helicase.
HRAS	GTPase HRas	Involved in the activation of Ras protein signal transduction.
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
MRE11	Double-strand break repair protein MRE11	Core component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.
ATM	Serine-protein kinase ATM	Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor.
PIK3CA	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides.
PTEN	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	Dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins.
RB1	Retinoblastoma-associated protein	Tumor suppressor that is a key regulator of the G1/S transition of the cell cycle.

Protein-family classification

Druggable: 11 · Difficult: 3 · Unknown: 13 · Druggable fraction: 0.41

Family distribution

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

Family	Genes	Fold	FDR
Kinase	6	6.2×	0.002
Enzyme (other)	4	1.8×	0.552
Phosphatase	1	3.1×	0.553
Other/Unknown	13	0.9×	0.856
Scaffold/PPI	1	0.6×	0.856
Transcription factor	2	0.6×	0.856

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FGFR3	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
BRCA1	Transcription factor	no	2.3.2.27	BRCT_dom, Znf_RING, BRCA1
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
ARID1A	Other/Unknown	no		ARID_dom, ARM-like, ARM-type_fold
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
TSC1	Other/Unknown	no		Hamartin
KDM6A	Enzyme (other)	yes	1.14.11.68	JmjC_dom, TPR-like_helical_dom_sf, TPR_rpt
CDKN1A	Other/Unknown	no		CDI_dom, CDKN1A, CDI_dom_sf
CDKN2A	Scaffold/PPI	no		Ankyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor, Tumor_suppres_ARF
CTNNA3	Other/Unknown	no		Alpha_catenin, Vinculin/catenin, Alpha-catenin/vinculin-like_sf
CTNNB1	Other/Unknown	no		Armadillo, ARM-like, Beta-catenin
LRRC56	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_4, LRR_dom_sf
C11orf65	Other/Unknown	no
EGFR	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
CDPF1	Other/Unknown	no		CDPF1_dom, CDPF1
ERBB2	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
ERBB3	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
ERCC2	Enzyme (other)	yes	3.6.4.12	RAD3/XPD, DNA/RNA_helicase_DEAH_CS, Helicase-like_DEXD_c2
EGFR-AS1	Other/Unknown	no
HRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
MRE11	Other/Unknown	no		Mre11, Calcineurin-like_PHP, Mre11_DNA-bd
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot
ATM	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
PIK3CA	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom
PTEN	Phosphatase	yes	3.1.3.16	Tyr_Pase_dom, Tyr_Pase_cat, Tensin_C2-dom
RB1	Other/Unknown	no		RB_B, RB_A, Cyclin-like_dom

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	27
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	5
calcaneal tendon	5
secondary oocyte	3
adrenal tissue	3
male germ line stem cell (sensu Vertebrata) in testis	2
primordial germ cell in gonad	2
bone marrow cell	2
oocyte	2
stromal cell of endometrium	2
corpus callosum	2
left testis	2
right testis	2
right uterine tube	2
sperm	2
nipple	2
trigeminal ganglion	2
colonic epithelium	2
skin of hip	1
upper arm skin	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FGFR3	262	broad	marker	upper leg skin, skin of hip, upper arm skin
BRCA1	208	ubiquitous	marker	ventricular zone, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
BRCA2	184	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
ARID1A	286	ubiquitous	marker	bone marrow cell, ventricular zone, embryo
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
TSC1	297	ubiquitous	marker	substantia nigra pars compacta, gluteal muscle, lateral globus pallidus
KDM6A	286	ubiquitous	yes	secondary oocyte, oocyte, bone marrow cell
CDKN1A	297	ubiquitous	marker	stromal cell of endometrium, mucosa of stomach, vena cava
CDKN2A	220	ubiquitous	marker	parotid gland, cervix squamous epithelium, pituitary gland
CTNNA3	211	broad	marker	corpus callosum, heart right ventricle, medial globus pallidus
CTNNB1	295	ubiquitous	marker	adrenal tissue, ventricular zone, periodontal ligament
LRRC56	129	broad	marker	right uterine tube, right testis, left testis
C11orf65	163	ubiquitous	marker	sperm, left testis, right testis
EGFR	285	ubiquitous	marker	nipple, gingiva, gingival epithelium
CDPF1	174	ubiquitous	yes	pancreatic ductal cell, tibialis anterior, apex of heart
ERBB2	276	ubiquitous	marker	lower esophagus mucosa, right uterine tube, sural nerve
ERBB3	274	broad	marker	trigeminal ganglion, jejunal mucosa, dorsal root ganglion
ERCC2	184	ubiquitous	marker	stromal cell of endometrium, right adrenal gland, left adrenal gland
EGFR-AS1	112	tissue_specific	yes	primordial germ cell in gonad, bone marrow, thymus
HRAS	139	ubiquitous	marker	skin of abdomen, skin of leg, zone of skin
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
MRE11	254	ubiquitous	marker	calcaneal tendon, oocyte, secondary oocyte
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue
ATM	286	ubiquitous	marker	calcaneal tendon, colonic epithelium, corpus callosum
PIK3CA	284	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon
PTEN	256	ubiquitous	marker	sperm, endothelial cell, calcaneal tendon
RB1	287	ubiquitous	marker	epithelium of nasopharynx, choroid plexus epithelium, visceral pleura

Protein interactions among cohort

Intra-cohort edges: 42.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
EGFR	18,421
CTNNB1	15,668
KRAS	14,509
PTEN	11,626
ERBB2	9,659
CDKN2A	9,311
BRCA1	9,064
KDM6A	8,825
HRAS	8,064

Intra-cohort edges

A	B	Sources
ATM	BRCA1	string_interaction
ATM	BRCA2	string_interaction
ATM	MRE11	string_interaction
ATM	TP53	biogrid_interaction, string_interaction
BRCA1	BRCA2	string_interaction
BRCA1	MRE11	string_interaction
BRCA1	NF1	string_interaction
BRCA1	TP53	string_interaction
BRCA2	MRE11	string_interaction
BRCA2	TP53	string_interaction
CDKN1A	CDKN2A	string_interaction
CDKN1A	FGFR3	intact
CDKN1A	TP53	string_interaction
CDKN2A	HRAS	string_interaction
CDKN2A	KRAS	string_interaction
CDKN2A	RB1	string_interaction
CDKN2A	TP53	string_interaction
CTNNA3	CTNNB1	biogrid_interaction, intact, string_interaction
CTNNB1	PTEN	biogrid_interaction
EGFR	ERBB2	intact, string_interaction
EGFR	ERBB3	biogrid_interaction, intact, string_interaction
EGFR	HRAS	string_interaction
EGFR	PIK3CA	string_interaction
EGFR	PTEN	string_interaction
ERBB2	ERBB3	biogrid_interaction, intact, string_interaction
ERBB2	KRAS	string_interaction
ERBB2	PIK3CA	string_interaction
ERBB3	PTEN	intact
FGFR3	PIK3CA	string_interaction
HRAS	NF1	intact
HRAS	TP53	string_interaction
KDM6A	PTEN	biogrid_interaction
KRAS	NF1	string_interaction
KRAS	PIK3CA	string_interaction
KRAS	PTEN	string_interaction
KRAS	TP53	string_interaction
NF1	PTEN	biogrid_interaction, string_interaction
NF1	TP53	string_interaction
PIK3CA	PTEN	string_interaction
PTEN	TP53	string_interaction
PTEN	TSC1	string_interaction
RB1	TP53	string_interaction

Structural data

PDB: 22 · AlphaFold-only: 4 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
EGFR	P00533	388
TP53	P04637	313
HRAS	P01112	246
PIK3CA	P42336	135
ERBB2	P04626	63
ERCC2	P18074	51
CTNNB1	P35222	50
BRCA1	P38398	33
NF1	P21359	26
ERBB3	P21860	23
RB1	P06400	19
FGFR3	P22607	15
BRCA2	P51587	14
ATM	Q13315	14
CDKN1A	P38936	13
PTEN	P60484	12
MRE11	P49959	10
ARID1A	O14497	7
TSC1	Q92574	5
KDM6A	O15550	5
CDKN2A	P42771	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CDPF1	Q6NVV7	87.30
CTNNA3	Q9UI47	81.65
C11orf65	Q8NCR3	74.69
LRRC56	Q8IYG6	56.07

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 446. Enrichment computed across 27 evidence-associated genes (22 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 22 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by ERBB2 KD Mutants	6	115.3×	3e-09	EGFR, ERBB2, ERBB3, HRAS, KRAS, PIK3CA
Signaling by ERBB2 ECD mutants	5	152.7×	2e-08	EGFR, ERBB2, HRAS, KRAS, PIK3CA
SHC1 events in ERBB2 signaling	5	108.1×	8e-08	EGFR, ERBB2, ERBB3, HRAS, KRAS
Signaling by ERBB2 TMD/JMD mutants	5	108.1×	8e-08	EGFR, ERBB2, ERBB3, HRAS, KRAS
RAF/MAP kinase cascade	8	22.2×	1e-07	FGFR3, EGFR, ERBB2, ERBB3, HRAS, KRAS, NF1, PIK3CA
Defective homologous recombination repair (HRR) due to PALB2 loss of function	4	173.0×	4e-07	BRCA1, BRCA2, MRE11, ATM
Diseases of DNA Double-Strand Break Repair	4	148.3×	6e-07	BRCA1, BRCA2, MRE11, ATM
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	4	148.3×	6e-07	BRCA1, BRCA2, MRE11, ATM
Signaling by FLT3 ITD and TKD mutants	4	138.4×	7e-07	CDKN1A, HRAS, KRAS, PIK3CA
Constitutive Signaling by EGFRvIII	4	129.8×	8e-07	EGFR, HRAS, KRAS, PIK3CA
PI3K events in ERBB2 signaling	4	122.1×	1e-06	EGFR, ERBB2, ERBB3, PIK3CA
GRB2 events in ERBB2 signaling	4	115.3×	1e-06	EGFR, ERBB2, HRAS, KRAS
Resolution of D-Loop Structures	4	115.3×	1e-06	BRCA1, BRCA2, MRE11, ATM
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	4	103.8×	1e-06	EGFR, HRAS, KRAS, PIK3CA
Diseases of DNA repair	4	103.8×	1e-06	BRCA1, BRCA2, MRE11, ATM
Signaling by FLT3 fusion proteins	4	103.8×	1e-06	CDKN1A, HRAS, KRAS, PIK3CA
Signaling by FGFR3 in disease	4	90.3×	2e-06	FGFR3, HRAS, KRAS, PIK3CA
Impaired BRCA2 binding to PALB2	4	83.0×	3e-06	BRCA1, BRCA2, MRE11, ATM
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	4	76.9×	4e-06	BRCA1, BRCA2, MRE11, ATM
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	4	76.9×	4e-06	BRCA1, BRCA2, MRE11, ATM
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	4	76.9×	4e-06	BRCA1, BRCA2, MRE11, ATM
RAS signaling downstream of NF1 loss-of-function variants	3	222.5×	4e-06	HRAS, KRAS, NF1
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	4	71.6×	5e-06	BRCA1, BRCA2, MRE11, ATM
Homologous DNA Pairing and Strand Exchange	4	69.2×	5e-06	BRCA1, BRCA2, MRE11, ATM
Homology Directed Repair	4	56.1×	1e-05	BRCA1, BRCA2, MRE11, ATM
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	4	56.1×	1e-05	BRCA1, BRCA2, MRE11, ATM
Impaired BRCA2 binding to RAD51	4	56.1×	1e-05	BRCA1, BRCA2, MRE11, ATM
Constitutive Signaling by Aberrant PI3K in Cancer	5	28.8×	1e-05	FGFR3, EGFR, ERBB2, ERBB3, PIK3CA
PIP3 activates AKT signaling	6	18.2×	1e-05	FGFR3, CDKN1A, EGFR, ERBB2, ERBB3, PIK3CA
EGFR Transactivation by Gastrin	3	155.7×	1e-05	EGFR, HRAS, KRAS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 25 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Ras protein signal transduction	7	57.5×	2e-08	TP53, CDKN1A, CDKN2A, HRAS, KRAS, NF1, RB1
neuron apoptotic process	7	51.9×	2e-08	TP53, ERBB3, HRAS, KRAS, NF1, ATM, RB1
cellular senescence	6	71.0×	5e-08	BRCA2, TP53, CDKN1A, CDKN2A, HRAS, ATM
regulation of cell cycle	8	23.9×	2e-07	BRCA1, TP53, TSC1, CDKN1A, CDKN2A, HRAS, ATM, RB1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	6	50.6×	2e-07	EGFR, ERBB2, ERBB3, NF1, PIK3CA, PTEN
Schwann cell development	4	168.5×	9e-07	ERBB2, ERBB3, HRAS, NF1
replicative senescence	4	158.6×	1e-06	TP53, CDKN1A, CDKN2A, ATM
heart development	7	22.1×	2e-06	KDM6A, CDKN1A, ERBB2, ERBB3, NF1, ATM, PTEN
epidermal growth factor receptor signaling pathway	5	49.6×	4e-06	CTNNB1, EGFR, ERBB2, ERBB3, PIK3CA
cellular response to gamma radiation	4	96.3×	6e-06	TP53, CDKN1A, HRAS, ATM
oncogene-induced cell senescence	3	288.9×	7e-06	CDKN1A, CDKN2A, HRAS
double-strand break repair	5	40.6×	8e-06	BRCA1, BRCA2, TP53, MRE11, ATM
mitotic G2 DNA damage checkpoint signaling	4	71.0×	2e-05	BRCA1, CDKN1A, MRE11, ATM
cellular response to ionizing radiation	4	65.8×	2e-05	BRCA1, BRCA2, TP53, CDKN1A
fibroblast proliferation	4	62.7×	2e-05	TP53, CDKN1A, HRAS, NF1
MAPK cascade	5	30.6×	2e-05	FGFR3, CTNNB1, HRAS, KRAS, NF1
positive regulation of MAPK cascade	6	19.4×	2e-05	FGFR3, CTNNB1, EGFR, ERBB2, ERBB3, HRAS
DNA damage response, signal transduction by p53 class mediator	4	57.4×	3e-05	BRCA2, TP53, CDKN1A, ATM
negative regulation of cell growth	5	28.8×	3e-05	BRCA1, TP53, CDKN1A, CDKN2A, RB1
negative regulation of cell population proliferation	7	11.8×	5e-05	TP53, TSC1, CDKN1A, CDKN2A, CTNNB1, HRAS, PTEN
regulation of long-term neuronal synaptic plasticity	3	119.0×	7e-05	HRAS, KRAS, NF1
positive regulation of neuron apoptotic process	4	43.5×	7e-05	TP53, CTNNB1, NF1, ATM
glial cell proliferation	3	106.4×	9e-05	TP53, KRAS, RB1
myelination	4	40.2×	9e-05	TSC1, ERBB2, ERBB3, HRAS
positive regulation of epithelial cell proliferation	4	39.1×	9e-05	EGFR, ERBB2, ERBB3, HRAS
wound healing	4	36.4×	1e-04	CDKN1A, ERBB2, ERBB3, NF1
forebrain astrocyte development	2	449.4×	2e-04	KRAS, NF1
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	3	59.5×	5e-04	BRCA2, TP53, CDKN1A
double-strand break repair via homologous recombination	4	25.0×	5e-04	BRCA1, BRCA2, MRE11, ATM
negative regulation of mammary gland epithelial cell proliferation	2	269.6×	5e-04	BRCA2, CDKN2A

Therapeutics

Drug target analysis

Approved (phase 4): 13 · Phase ≥3: 13 · Phased (≥1): 14 · Undrugged: 13

Druggability breadth: 19 of 27 evidence-associated genes (70%) 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
FGFR3	PONATINIB
BRCA1	RIBOFLAVIN
TP53	NITROFURANTOIN
KDM6A	DEFERIPRONE
CTNNB1	DITHIAZANINE IODIDE
EGFR	LEVODOPA
ERBB2	CLOTRIMAZOLE
ERBB3	MOBOCERTINIB
ERCC2	SUNITINIB
HRAS	LONAFARNIB
KRAS	VEMURAFENIB
ATM	AMIODARONE HYDROCHLORIDE
PIK3CA	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
EGFR	175	4
ERBB2	83	4
PIK3CA	67	4
FGFR3	64	4
ATM	35	4
ERBB3	23	4
ERCC2	16	4
BRCA1	12	4
KRAS	11	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	EGFR, ERBB2, FGFR3
PEMIGATINIB	4	FGFR3
NINTEDANIB	4	FGFR3
FEDRATINIB	4	EGFR, FGFR3, PIK3CA
LENVATINIB	4	FGFR3
AXITINIB	4	EGFR, FGFR3
SORAFENIB	4	EGFR, ERBB2, FGFR3
INFIGRATINIB PHOSPHATE	4	FGFR3
INFIGRATINIB	4	FGFR3
ENTRECTINIB	4	FGFR3
CERITINIB	4	EGFR, FGFR3
VANDETANIB	4	EGFR, ERBB2, ERBB3, FGFR3
NINTEDANIB ESYLATE	4	FGFR3
BRIGATINIB	4	EGFR, ERBB2, FGFR3
ERDAFITINIB	4	FGFR3
FUTIBATINIB	4	FGFR3
PAZOPANIB	4	FGFR3
SUNITINIB	4	EGFR, ERCC2, FGFR3, PIK3CA
DASATINIB	4	EGFR, ERBB2, ERBB3, FGFR3, PIK3CA
CRIZOTINIB	4	EGFR, FGFR3, PIK3CA
MIDOSTAURIN	4	EGFR, FGFR3, PIK3CA
RIBOFLAVIN	4	BRCA1
DAUNORUBICIN HYDROCHLORIDE	4	BRCA1
TOPOTECAN HYDROCHLORIDE	4	BRCA1
DAUNORUBICIN	4	BRCA1, TP53
DOXORUBICIN HYDROCHLORIDE	4	BRCA1
MESALAMINE	4	BRCA1
DIPYRIDAMOLE	4	ATM, BRCA1
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 12.

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

Symbol	Assays	Type breakdown
EGFR	6,531	Binding:6211, Functional:173, ADMET:138, Toxicity:9
PIK3CA	2,034	Binding:2009, ADMET:19, Toxicity:4, Functional:2
ERBB2	1,221	Binding:1136, Functional:79, ADMET:6
FGFR3	975	Binding:948, Functional:18, ADMET:9
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
KRAS	861	Binding:829, Functional:32
CTNNB1	361	Binding:358, Functional:3
ATM	240	Binding:233, Functional:5, ADMET:2
ERBB3	169	Binding:169
RB1	59	Binding:59
HRAS	48	Binding:45, Functional:3
KDM6A	40	Binding:36, Functional:4
MRE11	36	Binding:36
CDKN1A	16	Binding:8, Functional:8
BRCA1	13	Binding:9, Functional:4
PTEN	8	Binding:8
ARID1A	6	Binding:6
ERCC2	3	Binding:3
CDKN2A	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FGFR3	2.7.10.1	receptor protein-tyrosine kinase
BRCA1	2.3.2.27	RING-type E3 ubiquitin transferase
KDM6A	1.14.11.68	[histone H3]-trimethyl-L-lysine27 demethylase
EGFR	2.7.10.1	receptor protein-tyrosine kinase
ERBB2	2.7.10.1	receptor protein-tyrosine kinase
ERBB3	2.7.10.1	receptor protein-tyrosine kinase
ERCC2	3.6.4.12	DNA helicase
HRAS	3.6.5.2	small monomeric GTPase
KRAS	3.6.5.2	small monomeric GTPase
ATM	2.7.11.1	non-specific serine/threonine protein kinase
PIK3CA	2.7.1.137, 2.7.1.153, 2.7.11.1	phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase
PTEN	3.1.3.16, 3.1.3.67	protein-serine/threonine phosphatase, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
FGFR3	975
TP53	869
CTNNB1	361
EGFR	6,531
ERBB2	1,221
ERBB3	169
KRAS	861
ATM	240
PIK3CA	2,034

Pharmacogenomics

Cohort genes with a PharmGKB record: 26; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

30 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	EGFR, ERBB2, FGFR3
PEMIGATINIB	4	FGFR3
NINTEDANIB	4	FGFR3
FEDRATINIB	4	EGFR, FGFR3, PIK3CA
LENVATINIB	4	FGFR3
AXITINIB	4	EGFR, FGFR3
SORAFENIB	4	EGFR, ERBB2, FGFR3
INFIGRATINIB PHOSPHATE	4	FGFR3
INFIGRATINIB	4	FGFR3
ENTRECTINIB	4	FGFR3
CERITINIB	4	EGFR, FGFR3
VANDETANIB	4	EGFR, ERBB2, ERBB3, FGFR3
NINTEDANIB ESYLATE	4	FGFR3
BRIGATINIB	4	EGFR, ERBB2, FGFR3
ERDAFITINIB	4	FGFR3
FUTIBATINIB	4	FGFR3
PAZOPANIB	4	FGFR3
SUNITINIB	4	EGFR, ERCC2, FGFR3, PIK3CA
DASATINIB	4	EGFR, ERBB2, ERBB3, FGFR3, PIK3CA
CRIZOTINIB	4	EGFR, FGFR3, PIK3CA
MIDOSTAURIN	4	EGFR, FGFR3, PIK3CA
RIBOFLAVIN	4	BRCA1
DAUNORUBICIN HYDROCHLORIDE	4	BRCA1
TOPOTECAN HYDROCHLORIDE	4	BRCA1
DAUNORUBICIN	4	BRCA1, TP53
DOXORUBICIN HYDROCHLORIDE	4	BRCA1
MESALAMINE	4	BRCA1
DIPYRIDAMOLE	4	ATM, BRCA1
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	13	FGFR3, BRCA1, TP53, KDM6A, CTNNB1, EGFR, ERBB2, ERBB3, ERCC2, HRAS (+3 more)
B	Phased (≥1) drug, not yet approved	1	RB1
C	Druggable family + PDB, no drug	1	PTEN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	12	BRCA2, ARID1A, TSC1, CDKN1A, CDKN2A, CTNNA3, LRRC56, C11orf65, CDPF1, EGFR-AS1 (+2 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BRCA2	0	BRCA1
CTNNA3	0	CTNNB1
MRE11	36	BRCA1, ATM
NF1	0	KRAS
PTEN	8	TP53
ARID1A	6	—
TSC1	0	—
CDKN1A	16	—
CDKN2A	2	—
LRRC56	0	—
C11orf65	0	—
CDPF1	0	—
EGFR-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 42.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	20
PHASE2	10
PHASE1	5
PHASE3	4
PHASE1/PHASE2	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05822934	PHASE3	ACTIVE_NOT_RECRUITING	Carboplatin-gemcitabine Versus Cisplatin- Gemcitabine as Neoadjuvant Chemotherapy for Treatment of Muscle Invasive Urinary Bladder Cancer
NCT00384891	PHASE3	TERMINATED	Hyperthermia Treatment in Conjunction With Mitomycin C Versus Bacillus Calmette-Guérin Immunotherapy (BCG) for Superficial Bladder Cancer
NCT03335059	PHASE3	TERMINATED	Mitomycin C Intravesical Chemotherapy in Conjunction With Synergo® Radiofrequency-Induced Hyperthermia for Treatment of Carcinoma in Situ Non-Muscle Invasive Bladder Cancer Patients Unresponsive to Bacillus Calmette-Guérin, With or Without Papillary Tumors.
NCT04534075	PHASE3	COMPLETED	Dietary Fiber During Radiotherapy - a Placebo-controlled Randomized Trial
NCT03844256	PHASE1/PHASE2	RECRUITING	A Study of Mitomycin-c/ Capecitabine ChemoRadiotherapy Combined With Nivolumab Monotherapy or Ipilumimab and Nivolumab, as Bladder Sparing Curative Treatment for Muscle Invasive Bladder Cancer: the CRIMI Study
NCT04861584	PHASE2	RECRUITING	Neoadjuvant Toripalimab in Combination with Gemcitabine and Cisplatin Therapy in Local Advanced Bladder Cancer Subjects
NCT05072600	PHASE2	RECRUITING	Pembrolizumab Monotherapy Following Tri-modality Treatment for Selected Patients With Muscle-invasive Bladder Cancer
NCT05644041	PHASE2	RECRUITING	Intravesical Gem/Doce in Patients With NMIBC
NCT06290687	PHASE2	RECRUITING	Partial Cystectomy & Extended Pelvic Lymph Node Dissection With SOC Perioperative Systemic Therapy
NCT06822010	PHASE2	RECRUITING	SeqUential GeMcitabine and MITomycin Treatment for Favorable High-Risk Upper Urinary Tract Urothelial Carcinoma
NCT07184021	PHASE2	NOT_YET_RECRUITING	Neoadjuvent Dose-dense Gemcitabine and Cisplatin In Muscle Invasive Bladder Cancer
NCT00462488	PHASE2	COMPLETED	Study of Vicinium for Treating Patients With Non-Invasive Urothelial Carcinoma In Situ
NCT01374789	PHASE2	TERMINATED	PURO Panitumumab in Combination With Gemcitabine/Cisplatin in Advanced Urothelial Cancer
NCT03529890	PHASE2	UNKNOWN	Radio-Immunotherapy Before Cystectomy in Locally Advanced Urothelial Carcinoma of the Bladder
NCT03636256	PHASE1/PHASE2	COMPLETED	Evaluation of NanoDoce® in Participants With Urothelial Carcinoma
NCT04066894	PHASE2	TERMINATED	Sacral Nerve Stimulation in Treating Low Anterior Resection Syndrome or Fecal Incontinence in Patients With Locally Advanced Rectal Cancer or Other Pelvic Cancer, the RESTORE Study
NCT03132922	PHASE1	ACTIVE_NOT_RECRUITING	MAGE-A4ᶜ¹º³²T for Multi-Tumor
NCT02437539	PHASE1	COMPLETED	Evaluation of a New Radiotracer (68Ga-NOTA-AE105) for Diagnosing Aggressive Cancer With Positron Emission Tomography
NCT02720367	PHASE1	COMPLETED	Safety and Tolerability of TAR-200 mg in Subjects With Non-Muscle-Invasive Bladder Cancer
NCT02722538	PHASE1	COMPLETED	Safety and Tolerability of GemRIS 225 mg in Subjects With Muscle-Invasive Bladder Cancer
NCT02897765	PHASE1	COMPLETED	A Personal Cancer Vaccine (NEO-PV-01) w/ Nivolumab for Patients With Melanoma, Lung Cancer or Bladder Cancer
NCT02139371	EARLY_PHASE1	COMPLETED	Evaluation of a New Radiotracer (64Cu-DOTA-AE105) for Diagnosing Aggressive Cancer With Positron Emission Tomography
NCT00872495	Not specified	RECRUITING	Evaluation of Non-Invasive Assays for the Detection of Urothelial Cancer
NCT05621837	Not specified	RECRUITING	Quantifying Systemic Immunosuppression to Personalize Cancer Therapy
NCT06307704	Not specified	ACTIVE_NOT_RECRUITING	Lung US for PEEP Optimization in Robotic Radical Prostatectomy or Cystectomy Patients
NCT06675656	Not specified	NOT_YET_RECRUITING	Predictive Role of Microbiome in Patients With Urothelial Carcinoma
NCT07165236	Not specified	RECRUITING	Association of POCD With Circulating Biomarkers in Patients Undergoing TUR of Bladder Tumor
NCT01836978	Not specified	COMPLETED	Prehabilitation to Enhance Postoperative Functional Capacity Following Radical Cystectomy
NCT02228330	Not specified	UNKNOWN	Prospective Clinical Trial - Obturator Reflex Predictors and Blockage
NCT03433924	Not specified	COMPLETED	An Epidemiologic Study on PD-L1 Expression Combined With Clinical Observation in the Chinese MIUBC Patients.
NCT03998579	Not specified	COMPLETED	Physical Rehabilitation Among Patients Undergoing Radical Cystectomy Due to Urinary Bladder Cancer
NCT04525781	Not specified	UNKNOWN	Clinicoepidimiological Study and Clinical Outcome in Patients With Urinary Bladder Cancer
NCT04635566	Not specified	COMPLETED	Pharmacological Enhancement for Nocturnal Incontinence in Orthotopic Bladder Substitute
NCT04718948	Not specified	UNKNOWN	Multimodal Spectroscopy to Detect Urothelial Cancer in Urine
NCT04812145	Not specified	UNKNOWN	Role of Hypofractionated Radiotherapy With Concurrent Gemcitabine in Treatment of Urinary Bladder Carcinoma
NCT05335707	Not specified	WITHDRAWN	Longitudinal Geriatric Assessment to Optimize Outcomes of Older Patients With Muscle-Invasive Bladder Cancer After Radical Cystectomy
NCT05787938	Not specified	UNKNOWN	Role of MRI in Assessment of the Urinary Bladder Wall Post Transurethral Tumor Resection
NCT05946369	Not specified	COMPLETED	Neutrophils to Lymphocytes Ratio in Predicting the Response to BCG in Non-muscle Invasive Bladder Cancer
NCT06115434	Not specified	UNKNOWN	Comparing Operative, Postoperative and Quality of Life of Patients After Salvage and Radical Cystectomy
NCT06156787	Not specified	COMPLETED	Patterns of Urinary Bladder Cancer in Darfur, Suda

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MITOMYCIN	4	2
OPORTUZUMAB MONATOX	3	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 4 predictive associations from 4 curated evidence items; also 5 oncogenic, 2 prognostic.

Molecular subtype	Therapy	Effect	Level	CIViC
ERBB2 G292R	Neratinib	Sensitivity/Response	CIViC B	EID12119
FGFR3 Mutation	Cisplatin + Gemcitabine	Sensitivity/Response	CIViC B	EID7566
FGFR3 S249C	Erdafitinib	Sensitivity/Response	CIViC D	EID8811
KDM6A Loss	EZH2 Inhibitor	Sensitivity/Response	CIViC D	EID11749