Colorectal cancer

Summary

Colorectal cancer (MONDO:0005575) is a cancer (an umbrella term covering 5 Mondo subtypes) with 48 cohort genes (2,226 GWAS associations across 198 studies; 38 CIViC-evidence somatic drivers; 1,641 ClinVar predisposition records) and 4,699 clinical trials. The dominant Reactome pathway is Impaired BRCA2 binding to PALB2 (8 cohort genes). Molecularly, MSI High confers sensitivity to Ipilimumab/Nivolumab Regimen in Colorectal Cancer (CIViC Level A); 411 further subtype–drug associations are mapped below. Top therapeutic interventions include bevacizumab, leucovorin, and irinotecan.

At a glance

• Classification: Cancer
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 48
• GWAS associations: 2,226
• ClinVar variants: 1,641
• Clinical trials: 4,699
• Precision-medicine evidence (CIViC): 412 subtype–drug associations

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	colorectal cancer
Mondo ID	MONDO:0005575
OMIM	114500
Orphanet	466667
DOID	DOID:5672, DOID:9256
NCIT	C4978
SNOMED CT	363510005
UMLS	C0346629
MedGen	83428
Anatomy (UBERON)	UBERON:0012652
Is cancer (heuristic)	yes

Also known as: cancer of colorectum · cancer of large bowel · cancer of large intestine · cancer of the large bowel · colon cancer, advanced, somatic · colon cancer, somatic · colorectal cancer · colorectal cancer with chromosomal instability, somatic · colorectal cancer, autosomal dominant, somatic mutation · colorectal cancer, somatic · colorectal cancer, susceptibility to, autosomal dominant, somatic mutation · colorectum cancer · CRC · malignant colorectal neoplasm · malignant colorectal tumor · malignant colorectal tumour · malignant colorectum neoplasm · malignant large bowel neoplasm · malignant large bowel tumor · malignant large bowel tumour (+16 more)

Data availability: 1,641 ClinVar variants · 2,226 GWAS associations (198 studies) · 15 GenCC gene-disease records.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › digestive system disorder › intestinal disorder › intestinal neoplasm › colorectal neoplasm › colorectal cancer

Related subtypes (8): rectal neoplasm, colorectal leiomyoma, colonic neoplasm, colorectal adenoma, colorectal gastrointestinal stromal tumor, colorectal hamartoma, colorectal neuroendocrine tumor G1, small intestinal intraepithelial neoplasia

Subtypes (5): rectal cancer, malignant colon neoplasm, familial colorectal cancer, colorectal carcinoma, colorectal lymphoma

Genetics & variants

GWAS landscape

2,226 GWAS associations across 198 studies. Top hits map to 25 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs2337113	3e-150	SMAD7	G	0.17
rs11874392	4e-74	SMAD7	A	1.17
rs7226855	6e-71	SMAD7	A	1.21
rs6983267	3e-64	PCAT1, CASC8, POU5F1B, CCAT2	G	1.16
rs7013278	2e-56	POU5F1B, PCAT1, CASC8	T	1.15
rs28840750	4e-41	RHPN2	G	0.19
rs2293581	9e-40	GREM1-AS1, GREM1	A	1.15
rs966816	2e-38	FGFR3P3 - CASC20	A	0.09
rs58658771	6e-37	SCG5 - GREM1	A	1.15
rs2735940	6e-36	TERT - MIR4457	G	0.08
rs16892766	1e-35	LINC00536 - EIF3H	C	1.26
rs73376930	7e-35	GREM1	G	1.18
rs1445012	7e-35	RNU1-150P - TTC33	C	0.1
rs11200014	8e-35	FGFR2	A
rs3087967	6e-33	POU2AF2	T	1.15
rs6066825	2e-32	PREX1	G	0.08
rs35107139	7e-31	BMP4	C	0.08
rs4939827	3e-30	SMAD7	T	1.14
rs4813802	8e-30	CASC20 - LINC01713	G	0.08
rs12682374	7e-29	PCAT1, CASC8, POU5F1B	C	1.2
rs1741640	2e-28	LAMA5	C	1.16
rs7894531	3e-28	RNA5SP299 - LINC02676	?	1.16
rs12601991	7e-28	HNF1B	T
rs8179460	1e-27	LAMC1	C	0.07
rs7229639	2e-27	SMAD7	A	1.21
rs16969681	3e-27	SCG5 - GREM1	T	1.22
rs7014346	9e-26	CASC8, PCAT1, POU5F1B	A	1.19
rs4871022	1e-24	CASC8, POU5F1B, PCAT1	T	0.83
rs2423279	2e-24	RN7SL547P - SRSF10P2	C	0.07
rs653178	3e-24	ATXN2	T	0.08

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST003017	Schumacher FR	2015	18,299	19,656	Genome-wide association study of colorectal cancer identifies six new susceptibility loci.
GCST001787	Peters U	2012	12,696	15,113	Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis.
GCST003874	Gong J	2016	11,219	11,382	Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer.
GCST002415	Figueiredo JC	2014	9,287	9,117	Genome-wide diet-gene interaction analyses for risk of colorectal cancer.
GCST002596	Du M	2014	9,006	9,503	No evidence of gene-calcium interactions from genome-wide analysis of colorectal cancer risk.
GCST002816	Nan H	2015	8,634	8,553	Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants.
GCST001794	Jiao S	2012	8,380	10,558	Genome-wide search for gene-gene interactions in colorectal cancer.
GCST001544	Dunlop MG	2012	8,323	9,457	Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk.
GCST002919	Al-Tassan NA	2015	7,577	9,979	A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer.
GCST003208	Cheng TH	2015	5,725	13,396	Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	4
Tier 3: regulatory	4
Tier 4: intronic/intergenic	42

MAF distribution

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

Functional consequences

Consequence	Count
intron_variant	26
intergenic_variant	12
non_coding_transcript_exon_variant	4
regulatory_region_variant	4
5_prime_UTR_variant	3
3_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs2337113	18	48925957	A>G,T	0.05	intron_variant	SMAD7	3e-150	Tier 4: intronic/intergenic
rs11874392	18	48926786	A>G,T	0.455	intron_variant	SMAD7	4e-74	Tier 4: intronic/intergenic
rs7226855	18	48927678	A>G,T	0.05	intron_variant	SMAD7	6e-71	Tier 4: intronic/intergenic
rs6983267	8	127401060	G>T	0.477	non_coding_transcript_exon_variant	PCAT1, CASC8, POU5F1B, CCAT2	3e-64	Tier 4: intronic/intergenic
rs7013278	8	127402647	T>C,G	0.376	intron_variant	POU5F1B, PCAT1, CASC8	2e-56	Tier 4: intronic/intergenic
rs28840750	19	33029021	T>G	0.05	intron_variant	RHPN2	4e-41	Tier 4: intronic/intergenic
rs2293581	15	32718535	G>A,C,T	0.212	non_coding_transcript_exon_variant	GREM1-AS1, GREM1	9e-40	Tier 4: intronic/intergenic
rs966816	20	6395834	G>A	0.05	regulatory_region_variant	FGFR3P3 - CASC20	2e-38	Tier 3: regulatory
rs58658771	15	32709533	T>A,C,G	0.194	intergenic_variant	SCG5 - GREM1	6e-37	Tier 4: intronic/intergenic
rs2735940	5	1296371	A>G,T	0.05	non_coding_transcript_exon_variant	TERT - MIR4457	6e-36	Tier 4: intronic/intergenic
rs16892766	8	116618444	A>C	0.05	regulatory_region_variant	LINC00536 - EIF3H	1e-35	Tier 3: regulatory
rs73376930	15	32720301	A>C,G	0.05	intron_variant	GREM1	7e-35	Tier 4: intronic/intergenic
rs1445012	5	40282004	G>C	0.05	intergenic_variant	RNU1-150P - TTC33	7e-35	Tier 4: intronic/intergenic
rs11200014	10	121575416	G>A,T	0.05	intron_variant	FGFR2	8e-35	Tier 4: intronic/intergenic
rs3087967	11	111286111	T>A,C,G	0.05	3_prime_UTR_variant	POU2AF2	6e-33	Tier 2: splice/UTR
rs6066825	20	48723580	A>G,T	0.05	intron_variant	PREX1	2e-32	Tier 4: intronic/intergenic
rs35107139	14	53952388	A>C,G,T	0.05	5_prime_UTR_variant	BMP4	7e-31	Tier 2: splice/UTR
rs4939827	18	48927093	T>A,C	0.468	intron_variant	SMAD7	3e-30	Tier 4: intronic/intergenic
rs4813802	20	6718948	T>A,G	0.05	regulatory_region_variant	CASC20 - LINC01713	8e-30	Tier 3: regulatory
rs12682374	8	127398703	C>A,G,T	0.05	intron_variant	PCAT1, CASC8, POU5F1B	7e-29	Tier 4: intronic/intergenic
rs1741640	20	62357358	T>A,C,G	0.05	intron_variant	LAMA5	2e-28	Tier 4: intronic/intergenic
rs7894531	10	8692798	G>A,T	0.36	intergenic_variant	RNA5SP299 - LINC02676	3e-28	Tier 4: intronic/intergenic
rs12601991	17	37741642	T>A,G	0.05	intron_variant	HNF1B	7e-28	Tier 4: intronic/intergenic
rs8179460	1	183087087	T>A,C	0.05	intron_variant	LAMC1	1e-27	Tier 4: intronic/intergenic
rs7229639	18	48924606	A>C,G	0.17	intron_variant	SMAD7	2e-27	Tier 4: intronic/intergenic
rs16969681	15	32700910	C>T	0.09	regulatory_region_variant	SCG5 - GREM1	3e-27	Tier 3: regulatory
rs7014346	8	127412547	A>C,G	0.18	intron_variant	CASC8, PCAT1, POU5F1B	9e-26	Tier 4: intronic/intergenic
rs4871022	8	127415475	C>G,T	0.318	5_prime_UTR_variant	CASC8, POU5F1B, PCAT1	1e-24	Tier 2: splice/UTR
rs2423279	20	7831703	T>C	0.05	intergenic_variant	RN7SL547P - SRSF10P2	2e-24	Tier 4: intronic/intergenic
rs653178	12	111569952	C>A,G,T	0.05	intron_variant	ATXN2	3e-24	Tier 4: intronic/intergenic

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

276 uncertain significance, 124 conflicting classifications of pathogenicity, 57 benign/likely benign, 52 pathogenic, 35 pathogenic/likely pathogenic, 21 likely benign, 20 benign, 10 likely pathogenic, 3 risk factor, 1 pathogenic/likely pathogenic/pathogenic, low penetrance, 1 protective

ClinVar	Variant (HGVS)	Gene	Classification	Review
1120225	NM_000038.6(APC):c.2798_2804del (p.Asn933fs)	APC	Pathogenic	criteria provided, single submitter
1174016	NM_000038.6(APC):c.1383_1390delinsATGAATGA (p.His462_His464delinsTer)	APC	Pathogenic	no assertion criteria provided
127312	NM_000038.6(APC):c.646C>T (p.Arg216Ter)	APC	Pathogenic	criteria provided, multiple submitters, no conflicts
1685521	NM_000038.6(APC):c.412G>T (p.Glu138Ter)	APC	Pathogenic	criteria provided, multiple submitters, no conflicts
1685522	NM_000038.6(APC):c.833_834insT (p.Gln278fs)	APC	Pathogenic	criteria provided, single submitter
1685523	NM_000038.6(APC):c.1798del (p.Thr600fs)	APC	Pathogenic	criteria provided, single submitter
1685524	NM_000038.6(APC):c.4434_4437del (p.Arg1478fs)	APC	Pathogenic	criteria provided, single submitter
181835	NM_000038.6(APC):c.5490_5493del (p.Asn1830fs)	APC	Pathogenic	criteria provided, multiple submitters, no conflicts
183078	NM_000038.6(APC):c.3149del (p.Ala1050fs)	APC	Pathogenic	criteria provided, multiple submitters, no conflicts
184937	NM_000038.6(APC):c.994C>T (p.Arg332Ter)	APC	Pathogenic	criteria provided, multiple submitters, no conflicts
184999	NM_000038.6(APC):c.847C>T (p.Arg283Ter)	APC	Pathogenic	reviewed by expert panel
2583948	NM_000038.6(APC):c.423-12A>G	APC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2584112	NM_000038.6(APC):c.6634dup (p.Gln2212fs)	APC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1174014	NM_000051.4(ATM):c.7736_7737insC (p.Arg2579fs)	ATM	Pathogenic	no assertion criteria provided
1369686	NM_004655.4(AXIN2):c.973dup (p.Tyr325fs)	AXIN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2059267	NM_004655.4(AXIN2):c.1186C>T (p.Gln396Ter)	AXIN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2583406	NM_004655.4(AXIN2):c.74del (p.Pro25fs)	AXIN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2583537	NM_004655.4(AXIN2):c.94del (p.Glu32fs)	AXIN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127478	NM_000057.4(BLM):c.1642C>T (p.Gln548Ter)	BLM	Pathogenic	criteria provided, multiple submitters, no conflicts
1500163	NM_000057.4(BLM):c.99-8_112del	BLM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2499621	NM_000057.4(BLM):c.3254dup (p.Arg1086fs)	BLM	Pathogenic	criteria provided, single submitter
13973	NM_004333.6(BRAF):c.770A>G (p.Gln257Arg)	BRAF	Pathogenic	reviewed by expert panel
13976	NM_004333.6(BRAF):c.1495A>G (p.Lys499Glu)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162795	NM_004333.6(BRAF):c.2135C>A (p.Ala712Asp)	BRAF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685577	NM_004333.6(BRAF):c.1591T>C (p.Trp531Arg)	BRAF	Pathogenic	criteria provided, multiple submitters, no conflicts
1703205	NM_007294.4(BRCA1):c.1378del (p.Ile460fs)	BRCA1	Pathogenic	no assertion criteria provided
1703206	NM_007294.4(BRCA1):c.1439del (p.Asn480fs)	BRCA1	Pathogenic	no assertion criteria provided
1703207	NM_000059.4(BRCA2):c.2312del (p.Ile770_Leu771insTer)	BRCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
127447	NM_000051.4(ATM):c.7630-2A>C	C11orf65	Pathogenic	criteria provided, multiple submitters, no conflicts
1066705	NM_007194.4(CHEK2):c.684-2A>G	CHEK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 72 · Orphanet: 163 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 6

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

Gene	HGNC	Evidence routes
DCC	DCC	GWAS, GenCC, Orphanet
APC	APC	GWAS, Orphanet
BRCA2	BRCA2	GWAS, Orphanet
CDH1	CDH1	GWAS, Orphanet
CTNNB1	CTNNB1	GWAS, Orphanet
FGFR2	FGFR2	GWAS, Orphanet

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
DCC	LoF	COADREAD,ESCA,HCC,PAAD,PRAD	CIViC #1396
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
APC	LoF	AML,ANSC,CHOL,COAD,COADREAD,CSCC,EGC,ESCA,ESCC,HCC,LUAD,MEL,MT,NETNOS,NSCLC,PRAD,PROSTATE,READ,STAD,STOMACH,UM,VULVA	CIViC #66
BRAF	Act	BLCA,BRCA,CHOL,CLLSLL,COAD,COADREAD,CSCC,DLBCLNOS,GBM,GIST,HGGNOS,LGGNOS,LUAD,MEL,MLYM,NSCLC,OVT,PAST,PCM,PRAD,PRCC,PROSTATE,READ,SACA,SKCM,STAD,UCEC,WDTC	CIViC #5
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
FBXW7	LoF	ANSC,BLCA,BRCA,CEAD,CESC,CHOL,CLLSLL,COAD,COADREAD,ESCA,HNSC,LUAD,LUSC,MBL,NETNOS,NPC,PAAD,PAST,READ,STAD,UCEC,UCS	CIViC #12903
CDH1	LoF	BLCA,BRCA,CSCC,DLBCLNOS,ESCA,STAD	CIViC #888
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
FLCN	LoF	LUAD	CIViC #19959
SH2B3	Act	MDS	CIViC #7954
ERBB2	Act	BLCA,BRCA,CESC,CHOL,COADREAD,EGC,ESCA,ESCC,LMS,LUAD,NSCLC,OVT,PRCC,READ,STAD,UCEC	CIViC #20
EZH2	Act	ALL,AML,DLBCLNOS,ES,MLYM,NHL	CIViC #63
FGFR2	Act	BRCA,CHOL,LUSC,SACA,UCEC	CIViC #22
AKT1	Act	ALL,BRCA,CESC,COADREAD,PRAD,PROSTATE,SARCNOS,UCEC,WDTC	CIViC #2
GNAS	Act	BRCA,COADREAD,ESCA,HCC,LUAD,MBL,PAAD,PANCREAS	CIViC #2319
HLA-C	LoF	DLBCLNOS	CIViC #2608
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
SMAD4	LoF	BRCA,CESC,CHOL,COAD,COADREAD,ESCA,ESCC,GBC,HNSC,LUAD,NSCLC,PAAD,PANCREAS,PRAD,PROSTATE,READ,STAD,STOMACH	CIViC #77
MLH1			CIViC #3532
MSH2			CIViC #3628
MSH6			CIViC #2478
NRAS	Act	ALL,AML,ANGS,CHOL,CLLSLL,COAD,COADREAD,GBM,HCC,LGGNOS,LUAD,LUSC,MEL,MGCT,NPC,OVT,PCM,PROSTATE,SKCM,THYM,UCEC,WDTC	CIViC #36
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
PIK3R1	LoF	ACYC,BRCA,CHOL,COAD,COADREAD,GB,GBM,HNSC,LGGNOS,LUSC,OVT,PRAD,STAD,UCEC,UCS	CIViC #4289
POLE	Act	ACC,BLCA	CIViC #4386
THBS2			CIViC #5761
TOP1	Act	BCC,HCC	CIViC #5845
TYMS			CIViC #5971
UGT1A			CIViC #6023

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TP53	Moderate	Autosomal dominant	colorectal cancer	12
BLM	Limited	Autosomal dominant	colorectal cancer	12
BUB1	Limited	Autosomal dominant	familial colorectal cancer	7
FLCN	Limited	Autosomal dominant	colorectal cancer	12
MCM8	Limited	Autosomal dominant	colorectal cancer	6
SETD6	Limited	Unknown	colorectal cancer
DCC	No Known Disease Relationship	Unknown	colorectal cancer	12
DLC1	No Known Disease Relationship	Unknown	colorectal cancer	3
PTPRJ	No Known Disease Relationship	Unknown	colorectal cancer	3
SRC	No Known Disease Relationship	Unknown	colorectal cancer	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DCC	Orphanet:238722	Familial congenital mirror movements
DCC	Orphanet:2744	Horizontal gaze palsy with progressive scoliosis
DCC	Orphanet:478	Kallmann 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
APC	Orphanet:220460	Attenuated familial adenomatous polyposis
APC	Orphanet:261584	5q22 microdeletion syndrome
APC	Orphanet:314022	Gastric adenocarcinoma and proximal polyposis of the stomach
APC	Orphanet:3258	Cenani-Lenz syndrome
APC	Orphanet:873	Desmoid tumor
BLM	Orphanet:125	Bloom syndrome
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease
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

Cohort genes → proteins

48 cohort genes, 47 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	3
gwas_and_clinvar	4
civic_only	12
multi_evidence	29

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DCC	HGNC:2701	ENSG00000187323	P43146	Netrin receptor DCC	gwas,gencc,clinvar,civic_evidence
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	gencc,clinvar,civic_evidence
APC	HGNC:583	ENSG00000134982	P25054	Adenomatous polyposis coli protein	gwas,clinvar,civic_evidence
BLM	HGNC:1058	ENSG00000197299	P54132	RecQ-like DNA helicase BLM	gencc,clinvar
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	clinvar,civic_evidence
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	gwas,clinvar
ARID1A	HGNC:11110	ENSG00000117713	O14497	AT-rich interactive domain-containing protein 1A	clinvar,civic_evidence
BUB1	HGNC:1148	ENSG00000169679	O43683	Mitotic checkpoint serine/threonine-protein kinase BUB1	gencc,clinvar
FBXW7	HGNC:16712	ENSG00000109670	Q969H0	F-box/WD repeat-containing protein 7	clinvar,civic_evidence
CDH1	HGNC:1748	ENSG00000039068	P12830	Cadherin-1	gwas,clinvar
CTNNB1	HGNC:2514	ENSG00000168036	P35222	Catenin beta-1	gwas,clinvar
FLCN	HGNC:27310	ENSG00000154803	Q8NFG4	Folliculin	gencc,clinvar
DLC1	HGNC:2897	ENSG00000164741	Q96QB1	Rho GTPase-activating protein 7	gencc,clinvar
SH2B3	HGNC:29605	ENSG00000111252	Q9UQQ2	SH2B adapter protein 3	gwas,civic_evidence
ERBB2	HGNC:3430	ENSG00000141736	P04626	Receptor tyrosine-protein kinase erbB-2	clinvar,civic_evidence
EZH2	HGNC:3527	ENSG00000106462	Q15910	Histone-lysine N-methyltransferase EZH2	gwas,civic_evidence
FGFR2	HGNC:3689	ENSG00000066468	P21802	Fibroblast growth factor receptor 2	gwas,clinvar
AKT1	HGNC:391	ENSG00000142208	P31749	RAC-alpha serine/threonine-protein kinase	clinvar,civic_evidence
GNAS	HGNC:4392	ENSG00000087460	O95467	Neuroendocrine secretory protein 55	gwas,civic_evidence
HLA-C	HGNC:4933	ENSG00000204525	P10321	HLA class I histocompatibility antigen, C alpha chain	gwas,civic_evidence
KRAS	HGNC:6407	ENSG00000133703	P01116	GTPase KRas	clinvar,civic_evidence
SMAD4	HGNC:6770	ENSG00000141646	Q13485	SMAD family member 4	clinvar,civic_evidence
MLH1	HGNC:7127	ENSG00000076242	P40692	DNA mismatch repair protein Mlh1	gwas,civic_evidence
MSH2	HGNC:7325	ENSG00000095002	P43246	DNA mismatch repair protein Msh2	clinvar,civic_evidence
MSH6	HGNC:7329	ENSG00000116062	P52701	DNA mismatch repair protein Msh6	clinvar,civic_evidence
NRAS	HGNC:7989	ENSG00000213281	P01111	GTPase NRas	clinvar,civic_evidence
PIK3CA	HGNC:8975	ENSG00000121879	P42336	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	clinvar,civic_evidence
PIK3R1	HGNC:8979	ENSG00000145675	P27986	Phosphatidylinositol 3-kinase regulatory subunit alpha	clinvar,civic_evidence
POLE	HGNC:9177	ENSG00000177084	Q07864	DNA polymerase epsilon catalytic subunit A	clinvar,civic_evidence
PTPRJ	HGNC:9673	ENSG00000149177	Q12913	Receptor-type tyrosine-protein phosphatase eta	gencc,clinvar
SRC	HGNC:11283	ENSG00000197122	P12931	Proto-oncogene tyrosine-protein kinase Src	gencc
THBS2	HGNC:11786	ENSG00000186340	P35442	Thrombospondin-2	civic_evidence
TOP1	HGNC:11986	ENSG00000198900	P11387	DNA topoisomerase 1	civic_evidence
TYMS	HGNC:12441	ENSG00000176890	P04818	Thymidylate synthase	civic_evidence
UGT1A	HGNC:12529			UDP glucuronosyltransferase family 1 member A complex locus	civic_evidence
VEGFA	HGNC:12680	ENSG00000112715	P15692	Vascular endothelial growth factor A, long form	civic_evidence
PPP1R15A	HGNC:14375	ENSG00000087074	O75807	Protein phosphatase 1 regulatory subunit 15A	civic_evidence
MCM8	HGNC:16147	ENSG00000125885	Q9UJA3	DNA helicase MCM8	gencc
HSPH1	HGNC:16969	ENSG00000120694	Q92598	Heat shock protein 105 kDa	civic_evidence
CDKN1A	HGNC:1784	ENSG00000124762	P38936	Cyclin-dependent kinase inhibitor 1	civic_evidence
CDX2	HGNC:1806	ENSG00000165556	Q99626	Homeobox protein CDX-2	civic_evidence
SLTM	HGNC:20709	ENSG00000137776	Q9NWH9	SAFB-like transcription modulator	civic_evidence
SETD6	HGNC:26116	ENSG00000103037	Q8TBK2	N-lysine methyltransferase SETD6	gencc
SLFN11	HGNC:26633	ENSG00000172716	Q7Z7L1	Schlafen family member 11	civic_evidence
DKK1	HGNC:2891	ENSG00000107984	O94907	Dickkopf-related protein 1	civic_evidence
RNF4	HGNC:10067	ENSG00000063978	P78317	E3 ubiquitin-protein ligase RNF4	gwas
RNGTT	HGNC:10073	ENSG00000111880	O60942	mRNA-capping enzyme	gwas
CNNM1	HGNC:102	ENSG00000119946	Q9NRU3	Metal transporter CNNM1	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DCC	Netrin receptor DCC	Receptor for netrin required for axon guidance.
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
APC	Adenomatous polyposis coli protein	Tumor suppressor.
BLM	RecQ-like DNA helicase BLM	ATP-dependent DNA helicase that unwinds double-stranded (ds)DNA in a 3’-5’ direction.
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
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).
BUB1	Mitotic checkpoint serine/threonine-protein kinase BUB1	Serine/threonine-protein kinase that performs 2 crucial functions during mitosis: it is essential for spindle-assembly checkpoint signaling and for correct chromosome alignment.
FBXW7	F-box/WD repeat-containing protein 7	Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
CDH1	Cadherin-1	Cadherins are calcium-dependent cell adhesion proteins.
CTNNB1	Catenin beta-1	Key downstream component of the canonical Wnt signaling pathway.
FLCN	Folliculin	Multi-functional protein, involved in both the cellular response to amino acid availability and in the regulation of glycolysis.
DLC1	Rho GTPase-activating protein 7	Functions as a GTPase-activating protein for the small GTPases RHOA, RHOB, RHOC and CDC42, terminating their downstream signaling.
SH2B3	SH2B adapter protein 3	Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.
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.
EZH2	Histone-lysine N-methyltransferase EZH2	Catalytic subunit of the PRC2/EED-EZH2 complex, a Polycomb group (PcG) complex that methylates ‘Lys-9’ (H3K9me) and ‘Lys-27’ (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene.
FGFR2	Fibroblast growth factor receptor 2	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation, migration and apoptosis, and in the regulation of embryonic de…
AKT1	RAC-alpha serine/threonine-protein kinase	AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis.
HLA-C	HLA class I histocompatibility antigen, C alpha chain	Antigen-presenting major histocompatibility complex class I (MHCI) molecule with an important role in reproduction and antiviral immunity.
KRAS	GTPase KRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
SMAD4	SMAD family member 4	In muscle physiology, plays a central role in the balance between atrophy and hypertrophy.
MLH1	DNA mismatch repair protein Mlh1	Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR).
MSH2	DNA mismatch repair protein Msh2	Component of the post-replicative DNA mismatch repair system (MMR).
MSH6	DNA mismatch repair protein Msh6	Component of the post-replicative DNA mismatch repair system (MMR).
NRAS	GTPase NRas	Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
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.
PIK3R1	Phosphatidylinositol 3-kinase regulatory subunit alpha	Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane.
POLE	DNA polymerase epsilon catalytic subunit A	Catalytic component of the DNA polymerase epsilon complex.
PTPRJ	Receptor-type tyrosine-protein phosphatase eta	Tyrosine phosphatase which dephosphorylates or contributes to the dephosphorylation of CTNND1, FLT3, PDGFRB, MET, KDR, LYN, SRC, MAPK1, MAPK3, EGFR, TJP1, OCLN, PIK3R1 and PIK3R2.
SRC	Proto-oncogene tyrosine-protein kinase Src	Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G…
THBS2	Thrombospondin-2	Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions.
TOP1	DNA topoisomerase 1	Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex.
TYMS	Thymidylate synthase	Catalyzes the reductive methylation of 2’-deoxyuridine 5’-monophosphate (dUMP) to thymidine 5’-monophosphate (dTMP), using the cosubstrate, 5,10- methylenetetrahydrofolate (CH2H4folate) as a 1-carbon donor and reductant and contributes to…
VEGFA	Vascular endothelial growth factor A, long form	Participates in the induction of key genes involved in the response to hypoxia and in the induction of angiogenesis such as HIF1A.
PPP1R15A	Protein phosphatase 1 regulatory subunit 15A	Recruits the serine/threonine-protein phosphatase PPP1CA to prevents excessive phosphorylation of the translation initiation factor eIF-2A/EIF2S1, thereby reversing the shut-off of protein synthesis initiated by stress-inducible kinases an…
MCM8	DNA helicase MCM8	Component of the MCM8-MCM9 complex, which is involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR).
HSPH1	Heat shock protein 105 kDa	Acts as a nucleotide-exchange factor (NEF) for chaperone proteins HSPA1A and HSPA1B, promoting the release of ADP from HSPA1A/B thereby triggering client/substrate protein release.
CDKN1A	Cyclin-dependent kinase inhibitor 1	Plays an important role in controlling cell cycle progression and DNA damage-induced G2 arrest.
CDX2	Homeobox protein CDX-2	Transcription factor which regulates the transcription of multiple genes expressed in the intestinal epithelium.
SLTM	SAFB-like transcription modulator	When overexpressed, acts as a general inhibitor of transcription that eventually leads to apoptosis.
SETD6	N-lysine methyltransferase SETD6	Protein-lysine N-methyltransferase.
SLFN11	Schlafen family member 11	Inhibitor of DNA replication that promotes cell death in response to DNA damage.
DKK1	Dickkopf-related protein 1	Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6.
RNF4	E3 ubiquitin-protein ligase RNF4	E3 ubiquitin-protein ligase which binds polysumoylated chains covalently attached to proteins and mediates ‘Lys-6’-, ‘Lys-11’-, ‘Lys-48’- and ‘Lys-63’-linked polyubiquitination of those substrates and their subsequent targeting to the prot…
RNGTT	mRNA-capping enzyme	Bifunctional mRNA-capping enzyme exhibiting RNA 5’-triphosphate monophosphatase activity in the N-terminal part and mRNA guanylyltransferase activity in the C-terminal part.
CNNM1	Metal transporter CNNM1	Probable metal transporter.

Protein-family classification

Druggable: 17 · Difficult: 6 · Unknown: 25 · Druggable fraction: 0.35

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	8	4.6×	0.002
Phosphatase	2	3.5×	0.391
Enzyme (other)	5	1.2×	0.849
Antibody/Immunoglobulin	2	1.2×	0.849
Other/Unknown	25	0.9×	0.849
Scaffold/PPI	2	0.7×	0.849
Transcription factor	4	0.7×	0.849

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DCC	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
APC	Other/Unknown	no		Armadillo, APC_rpt, SAMP
BLM	Enzyme (other)	yes	3.6.4.12	Helicase_C-like, HRDC_dom, DNA/RNA_helicase_DEAH_CS
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
ARID1A	Other/Unknown	no		ARID_dom, ARM-like, ARM-type_fold
BUB1	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
FBXW7	Scaffold/PPI	no		WD40_rpt, F-box_dom, WD40/YVTN_repeat-like_dom_sf
CDH1	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin_pro_dom
CTNNB1	Other/Unknown	no		Armadillo, ARM-like, Beta-catenin
FLCN	Other/Unknown	no		Folliculin, Folliculin_DENN, Folliculin/SMCR8_longin
DLC1	Other/Unknown	no		RhoGAP_dom, SAM, START_lipid-bd_dom
SH2B3	Scaffold/PPI	no		SH2, PH_domain, PH-like_dom_sf
ERBB2	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
EZH2	Enzyme (other)	yes	2.1.1.356	SANT/Myb, SET_dom, EZH1/EZH2_N
FGFR2	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
AKT1	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, PH_domain
GNAS	Other/Unknown	no		NESP55, Gprotein_alpha_S, Gprotein_alpha_su
HLA-C	Antibody/Immunoglobulin	yes		MHC_I_a_a1/a2, Ig_C1-set, Ig-like_dom
KRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
SMAD4	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
MLH1	Other/Unknown	no		MutL/Mlh/PMS, DNA_mismatch_S5_2-like, Ribsml_uS5_D2-typ_fold_subgr
MSH2	Other/Unknown	no		DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS-lik_N, DNA_mismatch_repair_MutS_core
MSH6	Other/Unknown	no		PWWP_dom, DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS-lik_N
NRAS	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
PIK3CA	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom
PIK3R1	Kinase	yes	2.7.1.153	RhoGAP_dom, SH2, SH3_domain
POLE	Transcription factor	no	2.7.7.7	DNA-dir_DNA_pol_B_exonuc, DNA-dir_DNA_pol_B, RNaseH-like_sf
PTPRJ	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat
SRC	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
THBS2	Other/Unknown	no		EGF, TSP1_rpt, VWF_dom
TOP1	Enzyme (other)	yes	5.6.2.1	TopoI, TopoI_DNA-bd_euk, DNA_brk_join_enz
TYMS	Enzyme (other)	yes	2.1.1.45	Thymidylate_synthase, Thymidylate_synthase_AS, Thymidate_synth/dCMP_Mease_dom
UGT1A	Other/Unknown	no
VEGFA	Other/Unknown	no		PDGF/VEGF_dom, PD_growth_factor_CS, VEGF_C
PPP1R15A	Other/Unknown	no		Prot_Pase1_reg-su15A/B_C, PPP1R15
MCM8	Other/Unknown	no		MCM_dom, AAA+_ATPase, NA-bd_OB-fold
HSPH1	Other/Unknown	no		Hsp_70_fam, Heat_shock_70_CS, HSP70_peptide-bd_sf
CDKN1A	Other/Unknown	no		CDI_dom, CDKN1A, CDI_dom_sf
CDX2	Transcription factor	no		HTH_motif, HD, Caudal_activation_dom
SLTM	Other/Unknown	no		RRM_dom, SAP_dom, Nucleotide-bd_a/b_plait_sf
SETD6	Other/Unknown	no		SET_dom, N-lys_methylase_SETD6, Rubisco_LSMT_subst-bd
SLFN11	Other/Unknown	no		Schlafen_AlbA_2_dom, SLFN_3-like_DNA/RNA_helicase, P-loop_NTPase
DKK1	Other/Unknown	no		Dickkopf_N, DKK1-4, Dkk1_Cys2
RNF4	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS
RNGTT	Phosphatase	yes	2.7.7.50	Dual-sp_phosphatase_cat-dom, Tyr_Pase_dom, mRNA_cap_enzyme_adenylation
CNNM1	Other/Unknown	no		CBS_dom, CNNM, Ion_transp-like_CBS

Expression context

Cohort genes with no expression data: 1.

47 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)	47
unknown	1

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	11
calcaneal tendon	7
ganglionic eminence	6
secondary oocyte	6
primordial germ cell in gonad	4
embryo	4
stromal cell of endometrium	4
oocyte	4
buccal mucosa cell	3
adrenal tissue	3
right hemisphere of cerebellum	3
sural nerve	3
leukocyte	3
monocyte	3
right testis	2
colonic epithelium	2
gingival epithelium	2
cerebellar hemisphere	2
lower esophagus mucosa	2
endometrium epithelium	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DCC	154	broad	marker	cortical plate, right testis, left testis
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
APC	297	ubiquitous	marker	substantia nigra pars compacta, substantia nigra pars reticulata, medial globus pallidus
BLM	199	ubiquitous	marker	parotid gland, primordial germ cell in gonad, secondary oocyte
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
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
BUB1	185	ubiquitous	marker	ventricular zone, primordial germ cell in gonad, ganglionic eminence
FBXW7	290	ubiquitous	marker	Brodmann (1909) area 23, calcaneal tendon, colonic epithelium
CDH1	245	broad	marker	jejunal mucosa, esophagus squamous epithelium, gingival epithelium
CTNNB1	295	ubiquitous	marker	adrenal tissue, ventricular zone, periodontal ligament
FLCN	261	ubiquitous	marker	buccal mucosa cell, right hemisphere of cerebellum, cerebellar hemisphere
DLC1	268	ubiquitous	marker	adrenal tissue, lower lobe of lung, sural nerve
SH2B3	260	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
ERBB2	276	ubiquitous	marker	lower esophagus mucosa, right uterine tube, sural nerve
EZH2	216	ubiquitous	marker	ganglionic eminence, ventricular zone, embryo
FGFR2	272	broad	marker	C1 segment of cervical spinal cord, spinal cord, corpus callosum
AKT1	273	ubiquitous	marker	stromal cell of endometrium, ganglionic eminence, endometrium epithelium
GNAS	312	ubiquitous	marker	type B pancreatic cell, postcentral gyrus, Brodmann (1909) area 46
HLA-C	134	ubiquitous	marker	blood, right lung, spleen
KRAS	298	ubiquitous	marker	trigeminal ganglion, pylorus, nipple
SMAD4	288	ubiquitous	marker	ventricular zone, ganglionic eminence, calcaneal tendon
MLH1	296	ubiquitous	marker	tibialis anterior, skeletal muscle tissue of rectus abdominis, deltoid
MSH2	278	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
MSH6	293	ubiquitous	marker	ventricular zone, embryo, ganglionic eminence
NRAS	278	ubiquitous	marker	gingival epithelium, epithelium of nasopharynx, secondary oocyte
PIK3CA	284	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon
PIK3R1	294	ubiquitous	marker	calcaneal tendon, caput epididymis, corpus epididymis
POLE	221	ubiquitous	marker	right hemisphere of cerebellum, right testis, cerebellar hemisphere
PTPRJ	242	ubiquitous	marker	ileal mucosa, leukocyte, monocyte

Protein interactions among cohort

Intra-cohort edges: 63.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
AKT1	16,601
CTNNB1	15,668
KRAS	14,509
SRC	11,608
ERBB2	9,659
EZH2	9,646
CDH1	8,738
FBXW7	7,956
NRAS	7,598

Intra-cohort edges

A	B	Sources
AKT1	DLC1	string_interaction
AKT1	PIK3CA	biogrid_interaction, string_interaction
AKT1	PIK3R1	string_interaction
APC	CTNNB1	intact, string_interaction
APC	SLFN11	biogrid_interaction
ARID1A	MSH2	string_interaction
BLM	MLH1	string_interaction
BLM	MSH6	string_interaction
BRAF	BRCA2	biogrid_interaction
BRAF	FBXW7	biogrid_interaction
BRAF	FGFR2	biogrid_interaction
BRAF	KRAS	biogrid_interaction, intact, string_interaction
BRAF	MLH1	string_interaction
BRAF	NRAS	biogrid_interaction, intact, string_interaction
BRAF	PIK3CA	biogrid_interaction, string_interaction
BRAF	POLE	intact
BRAF	TP53	string_interaction
BRCA2	MLH1	string_interaction
BRCA2	MSH2	string_interaction
BRCA2	MSH6	string_interaction
BRCA2	TP53	string_interaction
CDH1	CTNNB1	biogrid_interaction, intact, string_interaction
CDH1	ERBB2	string_interaction
CDKN1A	TP53	string_interaction
CDX2	FBXW7	biogrid_interaction
CNNM1	HLA-C	biogrid_interaction
CTNNB1	DKK1	biogrid_interaction, string_interaction
CTNNB1	FBXW7	string_interaction
CTNNB1	PTPRJ	intact, string_interaction
CTNNB1	SMAD4	string_interaction
DLC1	SRC	string_interaction
ERBB2	KRAS	string_interaction
ERBB2	PIK3CA	string_interaction
ERBB2	PIK3R1	intact
ERBB2	SH2B3	intact
ERBB2	SRC	string_interaction
EZH2	SH2B3	string_interaction
FBXW7	PIK3CA	string_interaction
FBXW7	TP53	string_interaction
GNAS	KRAS	intact
KRAS	NRAS	intact
KRAS	PIK3CA	string_interaction
KRAS	TP53	string_interaction
MCM8	MLH1	intact
MCM8	MSH2	intact
MCM8	MSH6	intact
MLH1	MSH2	string_interaction
MLH1	MSH6	string_interaction
MLH1	POLE	string_interaction
MSH2	MSH6	biogrid_interaction, intact, string_interaction

Structural data

PDB: 44 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
GNAS	O95467	490
TP53	P04637	313
PIK3CA	P42336	135
BRAF	P15056	131
PIK3R1	P27986	105
SRC	P12931	79
ERBB2	P04626	63
FGFR2	P21802	63
TYMS	P04818	61
VEGFA	P15692	56
CTNNB1	P35222	50
AKT1	P31749	43
EZH2	Q15910	38
NRAS	P01111	35
APC	P25054	31
MSH2	P43246	30
CDH1	P12830	22
POLE	Q07864	18
BLM	P54132	15
TOP1	P11387	15
BRCA2	P51587	14
HLA-C	P10321	13
CDKN1A	P38936	13
SMAD4	Q13485	12
DCC	P43146	9
BUB1	O43683	9
RNGTT	O60942	9
MSH6	P52701	8
SLFN11	Q7Z7L1	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CNNM1	Q9NRU3	67.07
SH2B3	Q9UQQ2	63.45
SLTM	Q9NWH9	52.38

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1,023. Enrichment computed across 250 evidence-associated genes (177 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 177 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Impaired BRCA2 binding to PALB2	8	20.6×	1e-06	BLM, BRCA2, BRCA1, XRCC2, RAD51AP1, BRIP1, RMI1, PALB2
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	8	19.1×	1e-06	BLM, BRCA2, BRCA1, XRCC2, RAD51AP1, BRIP1, RMI1, PALB2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	8	19.1×	1e-06	BLM, BRCA2, BRCA1, XRCC2, RAD51AP1, BRIP1, RMI1, PALB2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	8	19.1×	1e-06	BLM, BRCA2, BRCA1, XRCC2, RAD51AP1, BRIP1, RMI1, PALB2
RNA Polymerase II Transcription	28	3.6×	1e-06	BLM, ARID1A, AKT1, SMAD4, MLH1, MSH2, RNGTT, BMP2 (+20 more)
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	8	17.8×	2e-06	BLM, BRCA2, BRCA1, XRCC2, RAD51AP1, BRIP1, RMI1, PALB2
Diseases of DNA repair	7	22.6×	2e-06	BLM, BRCA2, MLH1, MSH2, MSH6, BRCA1, RMI1
Homologous DNA Pairing and Strand Exchange	8	17.2×	2e-06	BLM, BRCA2, BRCA1, XRCC2, RAD51AP1, BRIP1, RMI1, PALB2
HDR through Homologous Recombination (HRR)	10	10.8×	3e-06	BLM, BRCA2, POLE, BRCA1, XRCC2, RAD51AP1, BRIP1, POLD3 (+2 more)
Gene expression (Transcription)	30	3.0×	5e-06	BLM, ARID1A, AKT1, SMAD4, MLH1, MSH2, RNGTT, BMP2 (+22 more)
Resolution of D-loop Structures through Holliday Junction Intermediates	8	13.6×	9e-06	BLM, BRCA2, BRCA1, XRCC2, RAD51AP1, BRIP1, RMI1, PALB2
Transcriptional regulation by RUNX2	8	11.5×	3e-05	AKT1, SMAD4, BMP2, SOX9, SRC, CCND1, CDKN1A, SATB2
Cell Cycle	19	3.9×	4e-05	BLM, BRCA2, BUB1, AKT1, MLH1, BRCA1, AURKA, BUB1B (+11 more)
FLT3 Signaling	7	13.7×	4e-05	SH2B3, AKT1, KRAS, NRAS, PIK3CA, PIK3R1, CDKN1B
RUNX3 regulates CDKN1A transcription	4	36.9×	1e-04	TP53, SMAD4, TGFB1, CDKN1A
Signaling by FLT3 ITD and TKD mutants	5	21.5×	1e-04	KRAS, NRAS, PIK3CA, PIK3R1, CDKN1A
TCF dependent signaling in response to WNT	10	6.7×	1e-04	APC, CTNNB1, AKT1, SOX9, TCF7L2, TERT, WNT4, WNT8B (+2 more)
Formation of definitive endoderm	5	20.2×	2e-04	CDH1, CTNNB1, SMAD4, TCF7L2, CXCR4
Transcriptional regulation by RUNX3	7	10.8×	2e-04	SMAD4, SRC, TCF7L2, TEAD3, TGFB1, CCND1, CDKN1A
MITF-M-regulated melanocyte development	10	6.5×	2e-04	ARID1A, CDH1, BRCA1, SOX9, TBX3, TCF7L2, TERT, TFEB (+2 more)
Signaling by ERBB2 ECD mutants	5	19.0×	2e-04	ERBB2, KRAS, NRAS, PIK3CA, PIK3R1
Signaling by FLT3 fusion proteins	5	16.1×	5e-04	KRAS, NRAS, PIK3CA, PIK3R1, CDKN1A
Disease	31	2.3×	5e-04	APC, BLM, BRAF, BRCA2, CDH1, AKT1, SMAD4, MLH1 (+23 more)
Mismatch Repair	3	48.4×	6e-04	MLH1, MSH2, MSH6
Diseases of Mismatch Repair (MMR)	3	48.4×	6e-04	MLH1, MSH2, MSH6
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	14.7×	7e-04	KRAS, NRAS, PIK3CA, PIK3R1, SRC
Homology Directed Repair	6	10.5×	7e-04	BLM, BRCA2, RNF4, BRCA1, BABAM1, RMI1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	6	10.5×	7e-04	BLM, BRCA2, RNF4, BRCA1, BABAM1, RMI1
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	5	14.0×	8e-04	CDH1, CTNNB1, SRC, CDC42, CTNNA1
Signaling by FGFR4 in disease	4	21.5×	8e-04	KRAS, NRAS, PIK3CA, PIK3R1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 229 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of transcription by RNA polymerase II	41	2.7×	2e-05	TP53, CTNNB1, FGFR2, AKT1, SMAD4, PIK3R1, RNF4, BMP2 (+33 more)
epithelial to mesenchymal transition	9	12.3×	5e-05	CTNNB1, FGFR2, SMAD4, BMP2, BMP7, SOX9, TGFB1, WNT4 (+1 more)
cellular response to indole-3-methanol	4	58.9×	7e-05	CDH1, CTNNB1, BRCA1, CTNNA1
response to X-ray	6	23.2×	7e-05	TP53, BLM, BRCA2, MSH2, XRCC2, CCND1
tissue homeostasis	7	17.2×	7e-05	SOX9, STK11, TP53INP2, YAP1, PRICKLE1, NANOS1, CUBN
positive regulation of epithelial cell proliferation	9	9.6×	1e-04	ERBB2, FGFR2, BMP4, BMP5, SOX9, TCF7L2, TGFB1, VEGFA (+1 more)
positive regulation of epithelial to mesenchymal transition	8	11.1×	1e-04	CTNNB1, EZH2, SMAD4, BMP2, BMP4, BMP7, TCF7L2, TGFB1
negative regulation of canonical Wnt signaling pathway	12	6.2×	1e-04	APC, CTNNB1, SMAD4, BMP2, SOX9, STK11, TCF7L2, PRICKLE1 (+4 more)
positive regulation of gene expression	21	3.5×	1e-04	TP53, BRAF, CTNNB1, AKT1, KRAS, SMAD4, BMP2, BMP4 (+13 more)
negative regulation of epithelial cell differentiation	5	26.3×	2e-04	KRAS, SOX9, TBX3, CCND1, YAP1
in utero embryonic development	15	4.7×	2e-04	TP53, CTNNB1, FLCN, FGFR2, SMAD4, MSH2, BMP2, TBX3 (+7 more)
cellular response to ionizing radiation	7	12.6×	2e-04	TP53, BLM, BRCA2, BRCA1, TGFB1, RAD51AP1, CDKN1A
positive regulation of protein localization to nucleus	7	12.0×	3e-04	AKT1, BMP4, SRC, STK11, TCF7L2, TGFB1, YAP1
response to gamma radiation	6	15.2×	3e-04	TP53, BRCA2, TGFB1, TIGAR, TOP1, XRCC2
double-strand break repair via homologous recombination	10	6.8×	3e-04	BLM, BRCA2, BRCA1, XRCC2, MCM8, RAD51AP1, RAD54B, RMI1 (+2 more)
cellular response to BMP stimulus	6	14.7×	4e-04	SMAD4, BMP2, BMP4, BMP7, BMPR1B, SOX9
positive regulation of DNA-templated transcription	24	2.9×	4e-04	TP53, BLM, BRCA2, ARID1A, CDH1, CTNNB1, SMAD4, RNF4 (+16 more)
osteoblast differentiation	11	5.8×	4e-04	CTNNB1, AKT1, SMAD4, BMP2, BMP4, BMP7, BMPR1B, WWOX (+3 more)
epidermal growth factor receptor signaling pathway	8	8.7×	4e-04	BRAF, CTNNB1, ERBB2, AKT1, PIK3CA, SOX9, SRC, PRICKLE1
DNA damage response	16	3.7×	8e-04	TP53, APC, BLM, FBXW7, BRCA1, STK11, TIGAR, PPP1R15A (+8 more)
positive regulation of osteoblast differentiation	8	7.8×	8e-04	CTNNB1, BMP2, BMP4, BMP7, BMPR1B, VEGFA, WNT4, YAP1
odontogenesis of dentin-containing tooth	7	9.2×	0.001	CTNNB1, BMP2, BMP4, BMP7, TGFB1, BCL11B, CTNNA1
cellular senescence	7	9.0×	0.001	TP53, BRCA2, TBX3, ZMIZ1, CDKN1A, CDKN1B, CDKN2B
anterior/posterior axis specification	5	16.0×	0.001	CTNNB1, BMP4, AURKA, CDX1, CDX2
endocardial cushion formation	4	24.5×	0.001	BMP2, BMP5, BMP7, TBX3
double-strand break repair	8	7.1×	0.001	TP53, BRCA2, MSH2, BRCA1, CHEK2, TDP2, BRIP1, BABAM1
negative regulation of steroid biosynthetic process	3	44.1×	0.002	BMP2, BMP5, WNT4
positive regulation of Wnt signaling pathway	6	10.0×	0.002	FGFR2, BMP2, TERT, TLR2, MACF1, DACT1
positive regulation of SMAD protein signal transduction	6	10.0×	0.002	SMAD4, BMP2, BMP4, BMP5, BMP7, TGFB1
negative regulation of gene expression	13	3.9×	0.002	FBXW7, CTNNB1, PIK3CA, BMP2, BMP4, SLC24A3, SOX9, AURKA (+5 more)

Therapeutics

Drug target analysis

Approved (phase 4): 17 · Phase ≥3: 17 · Phased (≥1): 20 · Undrugged: 28

Druggability breadth: 108 of 250 evidence-associated genes (43%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

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

Symbol	Example approved molecule
TP53	NITROFURANTOIN
BLM	AMIFOSTINE
BRAF	VEMURAFENIB
BUB1	GILTERITINIB
CTNNB1	DITHIAZANINE IODIDE
ERBB2	CLOTRIMAZOLE
EZH2	TAZEMETOSTAT
FGFR2	PONATINIB
AKT1	CAPIVASERTIB
KRAS	VEMURAFENIB
PIK3CA	IDELALISIB
PIK3R1	IDELALISIB
SRC	PONATINIB
TOP1	TOPOTECAN HYDROCHLORIDE
TYMS	FOLIC ACID
VEGFA	VADADUSTAT
SLTM	CABOZANTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BLM	284	4
TP53	196	4
SRC	103	4
ERBB2	83	4
PIK3CA	67	4
FGFR2	59	4
BRAF	48	4
AKT1	30	4
PIK3R1	26	4
TOP1	12	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	BLM, ERBB2, TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	BLM, TP53
AMIODARONE HYDROCHLORIDE	4	BLM, TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	BLM, TP53
NICARDIPINE HYDROCHLORIDE	4	BLM, TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53
MECHLORETHAMINE HYDROCHLORIDE	4	TP53
ECONAZOLE NITRATE	4	TP53
TRIFLUPROMAZINE HYDROCHLORIDE	4	BLM, TP53
PROCHLORPERAZINE EDISYLATE	4	TP53
DEQUALINIUM CHLORIDE	4	BLM, TP53

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 16.

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

Symbol	Assays	Type breakdown
PIK3CA	2,034	Binding:2009, ADMET:19, Toxicity:4, Functional:2
AKT1	1,942	Binding:1900, Functional:34, ADMET:7, Toxicity:1
SRC	1,917	Binding:1858, Functional:43, ADMET:16
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
ERBB2	1,221	Binding:1136, Functional:79, ADMET:6
TOP1	1,200	Binding:1161, Functional:38, ADMET:1
FGFR2	966	Binding:940, Functional:22, ADMET:4
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
KRAS	861	Binding:829, Functional:32
EZH2	839	Binding:833, Functional:6
PIK3R1	493	Binding:470, ADMET:23
TYMS	376	Binding:373, ADMET:2, Functional:1
CTNNB1	361	Binding:358, Functional:3
BUB1	86	Binding:84, Functional:2
BLM	82	Binding:78, Functional:4
VEGFA	64	Binding:64
APC	24	Binding:24
CDH1	18	Binding:18
NRAS	18	Binding:18
HSPH1	18	Binding:14, Functional:4
CDKN1A	16	Binding:8, Functional:8
SLTM	14	Binding:14
MSH6	10	Binding:10
MSH2	9	Binding:9
ARID1A	6	Binding:6
SMAD4	6	Binding:6
SLFN11	6	Binding:6
RNGTT	6	Binding:6
PTPRJ	5	Binding:4, ADMET:1
DKK1	5	Binding:5
RNF4	3	Binding:3
HLA-C	1	Binding:1
PPP1R15A	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BLM	3.6.4.12	DNA helicase
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
BUB1	2.7.11.1	non-specific serine/threonine protein kinase
ERBB2	2.7.10.1	receptor protein-tyrosine kinase
EZH2	2.1.1.356	[histone H3]-lysine27 N-trimethyltransferase
FGFR2	2.7.10.1	receptor protein-tyrosine kinase
AKT1	2.7.11.1	non-specific serine/threonine protein kinase
KRAS	3.6.5.2	small monomeric GTPase
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
PIK3R1	2.7.1.153	phosphatidylinositol-4,5-bisphosphate 3-kinase
POLE	2.7.7.7	DNA-directed DNA polymerase
PTPRJ	3.1.3.48	protein-tyrosine-phosphatase
SRC	2.7.10.2	non-specific protein-tyrosine kinase
TOP1	5.6.2.1, 5.99.1.2	DNA topoisomerase, DNA topoisomerase
TYMS	2.1.1.45	thymidylate synthase
RNGTT	2.7.7.50, 3.6.1.74	mRNA guanylyltransferase, mRNA 5’-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TP53	869
BRAF	1,442
CTNNB1	361
ERBB2	1,221
EZH2	839
FGFR2	966
AKT1	1,942
KRAS	861
PIK3CA	2,034
PIK3R1	493
SRC	1,917
TOP1	1,200
TYMS	376

Pharmacogenomics

Cohort genes with a PharmGKB record: 48; 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)
NITROFURANTOIN	4	TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	BLM, ERBB2, TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	BLM, TP53
AMIODARONE HYDROCHLORIDE	4	BLM, TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	BLM, TP53
NICARDIPINE HYDROCHLORIDE	4	BLM, TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53
MECHLORETHAMINE HYDROCHLORIDE	4	TP53
ECONAZOLE NITRATE	4	TP53
TRIFLUPROMAZINE HYDROCHLORIDE	4	BLM, TP53
PROCHLORPERAZINE EDISYLATE	4	TP53
DEQUALINIUM CHLORIDE	4	BLM, TP53

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	17	TP53, BLM, BRAF, BUB1, CTNNB1, ERBB2, EZH2, FGFR2, AKT1, KRAS (+7 more)
B	Phased (≥1) drug, not yet approved	3	MSH6, NRAS, RNGTT
C	Druggable family + PDB, no drug	3	DCC, HLA-C, PTPRJ
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	25	APC, BRCA2, ARID1A, FBXW7, CDH1, FLCN, DLC1, SH2B3, GNAS, SMAD4 (+15 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
APC	24	CTNNB1
CDH1	18	CTNNB1
SMAD4	6	CTNNB1
MLH1	0	MSH6
POLE	0	MSH6
DCC	0	—
BRCA2	0	—
ARID1A	6	—
FBXW7	0	—
FLCN	0	—
DLC1	0	—
SH2B3	0	—
GNAS	0	—
HLA-C	1	—
MSH2	9	—
PTPRJ	5	—
THBS2	0	—
UGT1A	0	—
PPP1R15A	1	—
MCM8	0	—
HSPH1	18	—
CDKN1A	16	—
CDX2	0	—
SETD6	0	—
SLFN11	6	—
DKK1	5	—
RNF4	3	—
CNNM1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4,699.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	500
PHASE3	361
PHASE1/PHASE2	113
PHASE4	72
PHASE2/PHASE3	54

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04281667	PHASE4	ACTIVE_NOT_RECRUITING	Mechanical Bowel Preparation and Oral Antibiotics Versus Mechanical Bowel Preparation Only Prior Rectal Surgery
NCT05726136	PHASE4	RECRUITING	Fluid Challenge and Plasma Volume, During Surgery
NCT06090994	PHASE4	RECRUITING	Prevention of Recurrence and Metastasis of Colorectal Cancer by Comparing Huaier With Capecitabine Monotherapy
NCT06118762	PHASE4	RECRUITING	Clinical Study of Fruquintinib Combined With Raltitrexed in the Treatment of Metastatic Colorectal Cancer
NCT06550453	PHASE4	RECRUITING	Safety and Efficacy of Pembrolizumab in Combination with Bevacizumab + CapeOX in the Neoadjuvant Treatment of RAS-mutated, BRAF Wild-type, Microsatellite-stabilized, Locally Advanced Colorectal Cancer
NCT06562543	PHASE4	RECRUITING	A Trial to Evaluate the Safety and Activity of Fruquintinib in Minority Populations With Advanced, Previously Treated Colorectal Cancer
NCT06665334	PHASE4	NOT_YET_RECRUITING	To Explore the Effect of Huaier Granule on the Negative Conversion Rate After the CEA Level Increases Again After Colorectal Cancer Surgery
NCT06881563	PHASE4	NOT_YET_RECRUITING	Intrathecal Morphine Versus Epidural Analgesia for Laparoscopic Colon Surgery
NCT07020468	PHASE4	ACTIVE_NOT_RECRUITING	Neoadjuvant Therapy （NALIRIFOX） for Locally Advanced Colon and Upper Rectal Cancer
NCT07094893	PHASE4	NOT_YET_RECRUITING	Anti-EGFR Agents in Patients With Right-sided Advanced Colorectal Cancer With Wild-type RAS and AREG/EREG High Status
NCT07152886	PHASE4	NOT_YET_RECRUITING	The Effects of Clostridium Butyricum on Adverse Events During Adjuvant Chemotherapy for Colorectal Cancer
NCT07446465	PHASE4	NOT_YET_RECRUITING	FOLFOX Chemotherapy Combined With Fruquintinib and Serplulimab as First-Line Conversion Therapy for Initially Unresectable pMMR/MSS Colorectal Cancer
NCT00114829	PHASE4	UNKNOWN	Preoperative Assessment of Colon Tumor
NCT00114842	PHASE4	COMPLETED	Magnetic Resonance (MR) Colonography With Fecal Tagging
NCT00114946	PHASE4	TERMINATED	A Study to Compare Two Avastin-Based Treatment Regimens for the Treatment of Metastatic Colorectal Cancer
NCT00122720	PHASE4	COMPLETED	The Effect of Darbepoetin Upon Rehabilitation for Colorectal Cancer Surgery
NCT00129870	PHASE4	TERMINATED	CONCEPT: Comparison of Oxaliplatin vs Conventional Methods With Calcium/Magnesium in First-Line Metastatic Colorectal Cancer
NCT00138060	PHASE4	COMPLETED	Toxicity/Benefit Ratio Optimization of Chemotherapy in Colorectal Cancer (CRC) Patients by Determination of Individual Genotypic Determinants
NCT00216424	PHASE4	TERMINATED	Capecitabine (Xeloda) and Radiation for Patients With Rectosigmoid Carcinoma
NCT00327093	PHASE4	TERMINATED	Elaboration of a Model for Predicting Efficacy of Monoclonal Antibodies (Cetuximab and Bevacizumab) in Patients With Colorectal Cancer and Liver Metastases
NCT00332943	PHASE4	COMPLETED	MR Colonography With Fecal Tagging. Barium vs. BariumFerumoxsil
NCT00441311	PHASE4	COMPLETED	Dissemination of Colorectal Cancer Screening to Primary Care Physicians
NCT00460837	PHASE4	WITHDRAWN	Comparison of Bowel Preparation in Virtual Colonoscopy (VC) - Patient Experience
NCT00473980	PHASE4	COMPLETED	Preoperative Non-steroidal Anti-inflammatory Drugs(NSAID) to Colorectal Cancer Patients
NCT00488904	PHASE4	COMPLETED	Omega-3 Fatty Acids and Postoperative Complications After Colorectal Surgery
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00502671	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) as Adjuvant Monotherapy in Patients With Colon Cancer.
NCT00559676	PHASE4	COMPLETED	Study of Biomarkers in Patients Undergoing Chemotherapy for Metastatic Colorectal Cancer
NCT00577031	PHASE4	COMPLETED	OBELIX Study: A Study of Avastin (Bevacizumab) in Combination With XELOX in Patients With Metastatic Cancer of the Colon or Rectum.
NCT00626054	PHASE4	COMPLETED	Comparison of Two Methods of Administration of a PEG Solution
NCT00812864	PHASE4	COMPLETED	Pharmacokinetic Study of Capecitabine in Elderly Cancer Patient (≥ 75 Years)
NCT00868569	PHASE4	UNKNOWN	Transhepatic Arterial Chemotherapy (TAC) Versus Transcatheter Arterial Chemoembolization (TACE) Plus Folfox4 as the Treatment of Unresectable Liver Metastasis of Colorectal Cancer
NCT00868816	PHASE4	COMPLETED	Oxaliplatine Based Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: 8 Cycles Versus 12 Cycles
NCT00874406	PHASE4	UNKNOWN	Preoperative Transhepatic Arterial Chemotherapy (TAC) in the Treatment of Liver Metastasis of Resectable Colorectal Cancer
NCT00928928	PHASE4	COMPLETED	Oxidative Stress Markers in Open and Laparoscopic Colectomy for Cancer
NCT00942461	PHASE4	COMPLETED	Inflammatory Response in Laparoscopic and Open Colectomy
NCT01023633	PHASE4	UNKNOWN	OPTIMOX1 in Chinese mCRC Patients
NCT01271582	PHASE4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01315990	PHASE4	UNKNOWN	FOLFIRI in Combination With Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer Including a Regular Dermal Prophylaxis to Prevent Acneiforme Follicular Exanthema
NCT01493713	PHASE4	COMPLETED	Correlation Between RECIST, Morphologic Response by CT- Histopathologic Response in Hepatic Metastasis Secondary to Colorectal Cancer

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BEVACIZUMAB	4	176
LEUCOVORIN	4	153
IRINOTECAN	4	146
OXALIPLATIN	4	53
PANITUMUMAB	4	47
CETUXIMAB	4	36
CAPECITABINE	4	34
FLUOROURACIL	4	27
FLOXURIDINE	4	15
REGORAFENIB	4	13
FRUQUINTINIB	4	11
MITOMYCIN	4	8
PYRIDOXINE	4	8
ERLOTINIB	4	5
GEFITINIB	4	5
OCTREOTIDE ACETATE	4	5
LEVAMISOLE HYDROCHLORIDE	4	4
MELPHALAN	4	4
RALTITREXED	4	4
TEGAFUR	4	4
CALCIUM CARBONATE	4	2
CALCIUM GLUCONATE	4	2
CELECOXIB	4	2
CHLOROTRIANISENE	4	2
DALTEPARIN SODIUM	4	2
FOLIC ACID	4	2
LEVOLEUCOVORIN CALCIUM	4	2
MAGNESIUM SULFATE	4	2
ALBUMIN HUMAN	4	1
CALCIUM	4	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 412 predictive associations from 548 curated evidence items; also 58 prognostic, 42 oncogenic, 4 diagnostic, 2 predisposing.

Molecular subtype	Therapy	Effect	Level	CIViC
MSI High	Ipilimumab/Nivolumab Regimen	Sensitivity/Response	CIViC A	EID12561 +1
BRAF V600E	Cetuximab + Encorafenib	Sensitivity/Response	CIViC A	EID9851
ERBB2 Overexpression	Trastuzumab + Tucatinib	Sensitivity/Response	CIViC A	EID11444
KRAS G12C	Cetuximab + Adagrasib	Sensitivity/Response	CIViC A	EID12063
KRAS G12C	Sotorasib + Panitumumab	Sensitivity/Response	CIViC A	EID12264
KRAS Wildtype	Cetuximab + Chemotherapy	Sensitivity/Response	CIViC A	EID11262
KRAS Wildtype	Chemotherapy + Panitumumab	Sensitivity/Response	CIViC A	EID11264
NRAS Wildtype	Chemotherapy + Panitumumab	Sensitivity/Response	CIViC A	EID11270
KRAS Exon 2 Mutation	Cetuximab	Resistance	CIViC A	EID993 +1
KRAS Mutation	Cetuximab + Panitumumab	Resistance	CIViC A	EID5345
NRAS Mutation	Panitumumab + Cetuximab	Resistance	CIViC A	EID5344
BRAF V600E	Vemurafenib	Sensitivity/Response	CIViC B	EID1405 +4
ERBB2 Amplification	Pertuzumab + Trastuzumab	Sensitivity/Response	CIViC B	EID11668 +2
BRAF V600E	Panitumumab + Vemurafenib	Sensitivity/Response	CIViC B	EID1413 +1
BRAF V600E	Vemurafenib + Irinotecan + Cetuximab	Sensitivity/Response	CIViC B	EID1902 +1
EGFR Expression	Cetuximab	Sensitivity/Response	CIViC B	EID1572 +1
KRAS G13D	Cetuximab	Sensitivity/Response	CIViC B	EID306 +1
NRAS Q61K	Dactolisib	Sensitivity/Response	CIViC B	EID2194 +1
AREG Expression	Panitumumab	Sensitivity/Response	CIViC B	EID1020
AREG Expression	Cetuximab	Sensitivity/Response	CIViC B	EID788
BRAF Class 2 Mutations	Cetuximab + Panitumumab	Sensitivity/Response	CIViC B	EID7574
BRAF Class 3 Mutations	Cetuximab + Panitumumab	Sensitivity/Response	CIViC B	EID7575
BRAF Mutation	Panitumumab + Cetuximab	Sensitivity/Response	CIViC B	EID1404
BRAF V600	Trametinib + Dabrafenib	Sensitivity/Response	CIViC B	EID1415
BRAF V600	Vemurafenib + Cetuximab	Sensitivity/Response	CIViC B	EID1598
BRAF V600	Encorafenib + Cetuximab	Sensitivity/Response	CIViC B	EID6046
BRAF V600	Cetuximab + Encorafenib + Alpelisib	Sensitivity/Response	CIViC B	EID6047
BRAF V600	Cetuximab + Vemurafenib + Irinotecan	Sensitivity/Response	CIViC B	EID7355
BRAF V600E	Erlotinib + Vemurafenib	Sensitivity/Response	CIViC B	EID11427
BRAF V600E	Cetuximab/Encorafenib Regimen	Sensitivity/Response	CIViC B	EID11436

+382 more predictive associations (showing top 30 by evidence level).