Renal cell adenocarcinoma

Summary

Renal cell adenocarcinoma (MONDO:0005549) is a disease (an umbrella term covering 9 Mondo subtypes) with 15 cohort genes and 1,179 clinical trials. The dominant Reactome pathway is G1 Phase (3 cohort genes). Molecularly, TSC1 Loss-of-function confers sensitivity to MTOR Inhibitor in Renal Cell Carcinoma (CIViC Level B); 25 further subtype–drug associations are mapped below. Top therapeutic interventions include sunitinib, cabozantinib, and sorafenib.

At a glance

• Umbrella term: 9 Mondo subtypes
• Cohort genes: 15
• Clinical trials: 1,179
• Precision-medicine evidence (CIViC): 26 subtype–drug associations

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	renal cell adenocarcinoma
Mondo ID	MONDO:0005549
EFO	EFO:0005708
NCIT	C9385
GARD	0024205
Is cancer (heuristic)	no

Also known as: adenocarcinoma of kidney · adenocarcinoma of the kidney · carcinoma, renal cell, malignant · kidney adenocarcinoma · RCC · renal cell adenocarcinoma · renal cell cancer · renal cell carcinoma · renal cell carcinoma, stage unspecified

Data availability: 294 cell lines · 23 intOGen driver records.

Disease family

An umbrella term covering 9 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › cancer › carcinoma › adenocarcinoma › renal cell carcinoma › renal cell adenocarcinoma

Related subtypes (10): mucinous tubular and spindle renal cell carcinoma, renal pelvis adenocarcinoma, Wolffian duct adenocarcinoma, collecting duct carcinoma, cystic renal cell carcinoma, kidney medullary carcinoma, adrenal cortex carcinoma, nonpapillary renal cell carcinoma, MIT family translocation renal cell carcinoma, acquired cystic disease-associated renal cell carcinoma

Subtypes (9): childhood kidney cell carcinoma, hereditary renal cell carcinoma, sarcomatoid renal cell carcinoma, clear cell renal carcinoma, renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusions, papillary renal cell carcinoma, chromophobe renal cell carcinoma, renal cell carcinoma associated with neuroblastoma, tubulocystic renal cell carcinoma

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 45 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RNF2	Orphanet:528084	Non-specific syndromic intellectual disability
TSC1	Orphanet:210159	Adult hepatocellular carcinoma
TSC1	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC1	Orphanet:538	Lymphangioleiomyomatosis
TSC1	Orphanet:805	Tuberous sclerosis complex
VHL	Orphanet:238557	Chuvash erythrocytosis
VHL	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
VHL	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
VHL	Orphanet:892	Von Hippel-Lindau disease
CCND1	Orphanet:29073	Multiple myeloma
CCND1	Orphanet:52416	Mantle cell lymphoma
CCND1	Orphanet:67038	B-cell chronic lymphocytic leukemia
CCND1	Orphanet:892	Von Hippel-Lindau disease
FBXW7	Orphanet:528084	Non-specific syndromic intellectual disability
CDKN2A	Orphanet:1333	Familial pancreatic carcinoma
CDKN2A	Orphanet:1501	Adrenocortical carcinoma
CDKN2A	Orphanet:252206	Melanoma and neural system tumor syndrome
CDKN2A	Orphanet:404560	Familial atypical multiple mole melanoma syndrome
CDKN2A	Orphanet:524	Li-Fraumeni syndrome
CDKN2A	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
CDKN2A	Orphanet:618	Familial melanoma
CDKN2A	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia
CDKN2B	Orphanet:618	Familial melanoma
CDKN2B	Orphanet:652	Multiple endocrine neoplasia type 1
FLCN	Orphanet:122	Birt-Hogg-Dubé syndrome
FLCN	Orphanet:2903	Familial spontaneous pneumothorax
FLCN	Orphanet:422526	Hereditary clear cell renal cell carcinoma
PBRM1	Orphanet:404511	Clear cell papillary renal cell carcinoma
EPAS1	Orphanet:247511	Autosomal dominant secondary polycythemia
EPAS1	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
EPAS1	Orphanet:324299	Multiple paragangliomas associated with polycythemia
KLLN	Orphanet:201	Cowden syndrome
KLLN	Orphanet:227535	Hereditary breast cancer
FLT3	Orphanet:102724	Acute myeloid leukemia with t(8;21)(q22;q22) translocation
FLT3	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
FLT3	Orphanet:589534	Mixed phenotype acute leukemia with t(9;22)(q34.1;q11.2)
FLT3	Orphanet:589595	Mixed phenotype acute leukemia with t(v;11q23.3)
FLT3	Orphanet:98829	Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22)
FLT3	Orphanet:98832	Acute myeloid leukemia with minimal differentiation
FLT3	Orphanet:98833	Acute myeloblastic leukemia without maturation
FLT3	Orphanet:98834	Acute myeloblastic leukemia with maturation
FLT3	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia
HMOX1	Orphanet:562509	Heme oxygenase-1 deficiency
HMOX1	Orphanet:586	Cystic fibrosis
B4GALT1	Orphanet:79332	B4GALT1-CDG

Cohort genes → proteins

15 cohort genes, 15 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	15

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNF2	HGNC:10061	ENSG00000121481	Q99496	E3 ubiquitin-protein ligase RING2	civic_evidence
TSC1	HGNC:12362	ENSG00000165699	Q92574	Hamartin	civic_evidence
VHL	HGNC:12687	ENSG00000134086	P40337	von Hippel-Lindau disease tumor suppressor	civic_evidence
CCND1	HGNC:1582	ENSG00000110092	P24385	G1/S-specific cyclin-D1	civic_evidence
FBXW7	HGNC:16712	ENSG00000109670	Q969H0	F-box/WD repeat-containing protein 7	civic_evidence
CDKN2A	HGNC:1787	ENSG00000147889	P42771	Cyclin-dependent kinase inhibitor 2A	civic_evidence
CDKN2B	HGNC:1788	ENSG00000147883	P42772	Cyclin-dependent kinase 4 inhibitor B	civic_evidence
FLCN	HGNC:27310	ENSG00000154803	Q8NFG4	Folliculin	civic_evidence
PBRM1	HGNC:30064	ENSG00000163939	Q86U86	Protein polybromo-1	civic_evidence
EPAS1	HGNC:3374	ENSG00000116016	Q99814	Endothelial PAS domain-containing protein 1	civic_evidence
KLLN	HGNC:37212	ENSG00000227268	B2CW77	Killin	civic_evidence
FLT3	HGNC:3765	ENSG00000122025	P36888	Receptor-type tyrosine-protein kinase FLT3	civic_evidence
HIF1A	HGNC:4910	ENSG00000100644	Q16665	Hypoxia-inducible factor 1-alpha	civic_evidence
HMOX1	HGNC:5013	ENSG00000100292	P09601	Heme oxygenase 1	civic_evidence
B4GALT1	HGNC:924	ENSG00000086062	P15291	Beta-1,4-galactosyltransferase 1	civic_evidence

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RNF2	E3 ubiquitin-protein ligase RING2	E3 ubiquitin-protein ligase that mediates monoubiquitination of ‘Lys-119’ of histone H2A (H2AK119Ub), thereby playing a central role in histone code and gene regulation.
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…
VHL	von Hippel-Lindau disease tumor suppressor	Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex.
CCND1	G1/S-specific cyclin-D1	Regulatory component of the cyclin D1-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S transition.
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.
CDKN2A	Cyclin-dependent kinase inhibitor 2A	Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6.
CDKN2B	Cyclin-dependent kinase 4 inhibitor B	Interacts strongly with CDK4 and CDK6.
FLCN	Folliculin	Multi-functional protein, involved in both the cellular response to amino acid availability and in the regulation of glycolysis.
PBRM1	Protein polybromo-1	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
EPAS1	Endothelial PAS domain-containing protein 1	Transcription factor involved in the induction of oxygen regulated genes.
KLLN	Killin	DNA-binding protein involved in S phase checkpoint control-coupled apoptosis by mediating p53/TP53-induced apoptosis.
FLT3	Receptor-type tyrosine-protein kinase FLT3	Tyrosine-protein kinase that acts as a cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells.
HIF1A	Hypoxia-inducible factor 1-alpha	Functions as a master transcriptional regulator of the adaptive response to hypoxia.
HMOX1	Heme oxygenase 1	Catalyzes the oxidative cleavage of heme at the alpha-methene bridge carbon, released as carbon monoxide (CO), to generate biliverdin IXalpha, while releasing the central heme iron chelate as ferrous iron.
B4GALT1	Beta-1,4-galactosyltransferase 1	Galactosyltransferase acting in the Golgi stacks.

Protein-family classification

Druggable: 4 · Difficult: 6 · Unknown: 5 · Druggable fraction: 0.27

Family distribution

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

Family	Genes	Fold	FDR
Scaffold/PPI	3	3.5×	0.261
Enzyme (other)	3	2.4×	0.310
Transcription factor	3	1.6×	0.450
Kinase	1	1.9×	0.530
Other/Unknown	5	0.6×	0.978

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNF2	Transcription factor	no	2.3.2.27	Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS
TSC1	Other/Unknown	no		Hamartin
VHL	Enzyme (other)	yes	2.3.2.B13	VHL_tumour_suppress_b/a_dom, VHL_alpha_dom, VHL_beta_dom
CCND1	Other/Unknown	no		Cyclin_C-dom, Cyclin_N, Cyclin-like_dom
FBXW7	Scaffold/PPI	no		WD40_rpt, F-box_dom, WD40/YVTN_repeat-like_dom_sf
CDKN2A	Scaffold/PPI	no		Ankyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor, Tumor_suppres_ARF
CDKN2B	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor
FLCN	Other/Unknown	no		Folliculin, Folliculin_DENN, Folliculin/SMCR8_longin
PBRM1	Other/Unknown	no		BAH_dom, Bromodomain, HMG_box_dom
EPAS1	Transcription factor	no		PAS, Nuc_translocat, PAC
KLLN	Other/Unknown	no
FLT3	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS
HIF1A	Transcription factor	no		PAS, HIF-1_alpha, PAC
HMOX1	Enzyme (other)	yes	1.14.14.18	Haem_Oase, Haem_Oase-like, Haem_Oase-like_multi-hlx
B4GALT1	Enzyme (other)	yes	2.4.1.133	Galactosyl_T, Galactosyl_T_C, Galactosyl_T_N

Expression context

Cohort genes with no expression data: 0.

15 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)	15
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	3
ganglionic eminence	2
monocyte	2
stromal cell of endometrium	2
buccal mucosa cell	2
cerebellar hemisphere	2
male germ line stem cell (sensu Vertebrata) in testis	2
pancreatic ductal cell	2
primordial germ cell in gonad	1
gluteal muscle	1
lateral globus pallidus	1
substantia nigra pars compacta	1
mononuclear cell	1
endometrium epithelium	1
upper arm skin	1
Brodmann (1909) area 23	1
calcaneal tendon	1
colonic epithelium	1
cervix squamous epithelium	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNF2	178	ubiquitous	marker	primordial germ cell in gonad, cortical plate, ganglionic eminence
TSC1	297	ubiquitous	marker	substantia nigra pars compacta, gluteal muscle, lateral globus pallidus
VHL	186	ubiquitous	marker	cortical plate, monocyte, mononuclear cell
CCND1	280	ubiquitous	marker	endometrium epithelium, stromal cell of endometrium, upper arm skin
FBXW7	290	ubiquitous	marker	Brodmann (1909) area 23, calcaneal tendon, colonic epithelium
CDKN2A	220	ubiquitous	marker	parotid gland, cervix squamous epithelium, pituitary gland
CDKN2B	219	ubiquitous	marker	jejunal mucosa, colonic mucosa, lower esophagus mucosa
FLCN	261	ubiquitous	marker	buccal mucosa cell, right hemisphere of cerebellum, cerebellar hemisphere
PBRM1	289	ubiquitous	marker	cortical plate, ganglionic eminence, amniotic fluid
EPAS1	298	ubiquitous	marker	right lung, lower lobe of lung, adult organism
KLLN	149		marker	tibialis anterior, male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell
FLT3	166	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, cerebellar hemisphere, cerebellar cortex
HIF1A	295	ubiquitous	marker	pancreatic ductal cell, epithelial cell of pancreas, corpus epididymis
HMOX1	230	ubiquitous	marker	cartilage tissue, spleen, monocyte
B4GALT1	276	ubiquitous	marker	buccal mucosa cell, stromal cell of endometrium, left uterine tube

Protein interactions among cohort

Intra-cohort edges: 12.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HIF1A	9,734
CDKN2A	9,311
CCND1	8,328
FBXW7	7,956
TSC1	5,445
EPAS1	4,652
HMOX1	4,054
RNF2	3,814
FLT3	3,570
PBRM1	3,540

Intra-cohort edges

A	B	Sources
B4GALT1	TSC1	biogrid_interaction
CCND1	CDKN2A	biogrid_interaction, string_interaction
CCND1	CDKN2B	string_interaction
CDKN2A	CDKN2B	biogrid_interaction
CDKN2A	HIF1A	string_interaction
EPAS1	HIF1A	string_interaction
EPAS1	VHL	biogrid_interaction, intact, string_interaction
FLCN	KLLN	string_interaction
FLT3	VHL	biogrid_interaction
HIF1A	VHL	biogrid_interaction, intact, string_interaction
PBRM1	VHL	biogrid_interaction
TSC1	VHL	biogrid_interaction

Structural data

PDB: 13 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VHL	P40337	142
EPAS1	Q99814	43
PBRM1	Q86U86	30
HMOX1	P09601	26
HIF1A	Q16665	25
B4GALT1	P15291	19
RNF2	Q99496	15
CCND1	P24385	11
FLT3	P36888	11
FBXW7	Q969H0	7
TSC1	Q92574	5
CDKN2A	P42771	5
FLCN	Q8NFG4	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CDKN2B	P42772	90.12
KLLN	B2CW77	51.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 192. Enrichment computed across 15 evidence-associated genes (14 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 14 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
G1 Phase	3	84.4×	0.001	CCND1, CDKN2A, CDKN2B
PTK6 Expression	2	271.9×	0.002	EPAS1, HIF1A
Cyclin D associated events in G1	3	49.9×	0.002	CCND1, CDKN2A, CDKN2B
RUNX3 regulates p14-ARF	2	163.1×	0.002	CCND1, CDKN2A
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	3	42.2×	0.002	VHL, EPAS1, HIF1A
Mitotic G1 phase and G1/S transition	3	39.5×	0.002	CCND1, CDKN2A, CDKN2B
Regulation of gene expression by Hypoxia-inducible Factor	2	135.9×	0.003	EPAS1, HIF1A
Cellular response to hypoxia	2	125.5×	0.003	EPAS1, HIF1A
Neddylation	4	13.5×	0.003	VHL, FBXW7, EPAS1, HIF1A
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	2	81.6×	0.005	CCND1, CDKN2A
Interleukin-4 and Interleukin-13 signaling	3	22.1×	0.005	CCND1, HIF1A, HMOX1
Defective B4GALT1 causes CDG-2d	1	815.7×	0.007	B4GALT1
Evasion of Oncogene Induced Senescence Due to p14ARF Defects	1	815.7×	0.007	CDKN2A
Evasion of Oxidative Stress Induced Senescence Due to p14ARF Defects	1	815.7×	0.007	CDKN2A
FLT3 mutants bind TKIs	1	815.7×	0.007	FLT3
KW2449-resistant FLT3 mutants	1	815.7×	0.007	FLT3
semaxanib-resistant FLT3 mutants	1	815.7×	0.007	FLT3
crenolanib-resistant FLT3 mutants	1	815.7×	0.007	FLT3
gilteritinib-resistant FLT3 mutants	1	815.7×	0.007	FLT3
lestaurtinib-resistant FLT3 mutants	1	815.7×	0.007	FLT3
midostaurin-resistant FLT3 mutants	1	815.7×	0.007	FLT3
pexidartinib-resistant FLT3 mutants	1	815.7×	0.007	FLT3
ponatinib-resistant FLT3 mutants	1	815.7×	0.007	FLT3
quizartinib-resistant FLT3 mutants	1	815.7×	0.007	FLT3
sorafenib-resistant FLT3 mutants	1	815.7×	0.007	FLT3
sunitinib-resistant FLT3 mutants	1	815.7×	0.007	FLT3
tandutinib-resistant FLT3 mutants	1	815.7×	0.007	FLT3
linifanib-resistant FLT3 mutants	1	815.7×	0.007	FLT3
tamatinib-resistant FLT3 mutants	1	815.7×	0.007	FLT3
Pre-NOTCH Expression and Processing	2	52.6×	0.007	CCND1, B4GALT1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of TOR signaling	3	112.3×	8e-04	TSC1, FLCN, HIF1A
cellular response to hypoxia	4	32.3×	1e-03	VHL, CCND1, EPAS1, HIF1A
regulation of G1/S transition of mitotic cell cycle	3	61.3×	0.001	CDKN2A, CDKN2B, PBRM1
negative regulation of epithelial cell proliferation	3	58.1×	0.001	CDKN2B, FLCN, B4GALT1
negative regulation of cell population proliferation	5	14.0×	0.001	TSC1, VHL, CDKN2A, CDKN2B, PBRM1
intracellular oxygen homeostasis	2	204.3×	0.002	EPAS1, HIF1A
mammary gland epithelial cell proliferation	2	204.3×	0.002	CCND1, CDKN2A
protein stabilization	4	17.8×	0.003	TSC1, VHL, FBXW7, CDKN2A
negative regulation of macroautophagy	2	149.8×	0.003	TSC1, HMOX1
response to iron ion	2	124.8×	0.004	CCND1, HIF1A
regulation of protein neddylation	2	124.8×	0.004	EPAS1, HIF1A
embryonic placenta development	2	102.1×	0.005	EPAS1, HIF1A
TOR signaling	2	102.1×	0.005	FLCN, HIF1A
regulation of G0 to G1 transition	2	89.9×	0.006	CDKN2B, PBRM1
amyloid fibril formation	2	80.2×	0.006	VHL, CDKN2A
multicellular organismal-level iron ion homeostasis	2	77.5×	0.007	EPAS1, HMOX1
positive regulation of macroautophagy	2	70.2×	0.007	HIF1A, HMOX1
positive regulation of transforming growth factor beta receptor signaling pathway	2	70.2×	0.007	CDKN2B, FLCN
liver regeneration	2	68.1×	0.007	CCND1, FLT3
lactation	2	56.2×	0.010	CCND1, HIF1A
positive regulation of chemokine production	2	49.9×	0.012	HIF1A, HMOX1
positive regulation of circulating fibrinogen levels	1	1123.5×	0.013	B4GALT1
negative regulation of cell proliferation involved in kidney development	1	1123.5×	0.013	FLCN
negative regulation of SREBP signaling pathway	1	1123.5×	0.013	FBXW7
negative regulation of TORC1 signaling	2	43.2×	0.013	TSC1, VHL
epithelial cell proliferation	2	41.6×	0.014	FLCN, B4GALT1
negative regulation of transcription by RNA polymerase II	5	5.9×	0.014	RNF2, VHL, CCND1, CDKN2A, FLCN
cellular senescence	2	39.4×	0.014	CDKN2A, CDKN2B
negative regulation of gene expression	3	13.8×	0.015	VHL, FBXW7, HIF1A
wound healing involved in inflammatory response	1	561.7×	0.015	HMOX1

Therapeutics

Drugs indicated for this disease

7 approved, 5 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Axitinib	Approved (phase 4)
Belzutifan	Approved (phase 4)
Everolimus	Approved (phase 4)
Ipilimumab	Approved (phase 4)
Nivolumab	Approved (phase 4)
Pembrolizumab	Approved (phase 4)
Sunitinib	Approved (phase 4)
Avelumab	Phase 3 (in late-stage trials)
Cabozantinib	Phase 3 (in late-stage trials)
Lenvatinib	Phase 3 (in late-stage trials)
Tivozanib	Phase 3 (in late-stage trials)
Zanzalintinib	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Camrelizumab, Evolocumab, Tiragolumab.

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 5 · Phased (≥1): 6 · Undrugged: 9

Druggability breadth: 10 of 15 evidence-associated genes (67%) 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
VHL	OSIMERTINIB
CCND1	PALBOCICLIB
EPAS1	BELZUTIFAN
FLT3	PONATINIB
HIF1A	EMETINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HIF1A	255	4
FLT3	143	4
CCND1	35	4
VHL	7	4
EPAS1	7	4
PBRM1	2	2
RNF2	0	0
TSC1	0	0
FBXW7	0	0
CDKN2A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OSIMERTINIB	4	VHL
BRIGATINIB	4	FLT3, VHL
CRIZOTINIB	4	FLT3, VHL
ADAGRASIB	4	VHL
PALBOCICLIB	4	CCND1, FLT3
ABEMACICLIB	4	CCND1, FLT3
RIBOCICLIB	4	CCND1
TRILACICLIB	4	CCND1
BELZUTIFAN	4	EPAS1
EMETINE	4	EPAS1, HIF1A
DOXORUBICIN	4	EPAS1, HIF1A
TOPOTECAN	4	EPAS1, HIF1A
PONATINIB	4	FLT3
AFATINIB	4	FLT3
FEDRATINIB	4	FLT3
TIVOZANIB	4	FLT3
AXITINIB	4	FLT3
SORAFENIB	4	FLT3
NERATINIB	4	FLT3
INFIGRATINIB PHOSPHATE	4	FLT3
INFIGRATINIB	4	FLT3
IBRUTINIB	4	FLT3
REGORAFENIB	4	FLT3
ENTRECTINIB	4	FLT3
PACRITINIB	4	FLT3
FOSTAMATINIB	4	FLT3
QUIZARTINIB DIHYDROCHLORIDE	4	FLT3
CABOZANTINIB	4	FLT3
CERITINIB	4	FLT3
VANDETANIB	4	FLT3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
VHL	3,575	Binding:3482, Functional:54, ADMET:39
FLT3	3,132	Binding:3096, Functional:24, ADMET:8, Toxicity:4
CCND1	576	Binding:574, Functional:1, ADMET:1
HIF1A	427	Binding:411, Functional:16
EPAS1	241	Binding:233, Functional:8
PBRM1	193	Binding:193
HMOX1	23	Binding:22, ADMET:1
RNF2	16	Binding:16
B4GALT1	9	Binding:9
CDKN2A	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RNF2	2.3.2.27	RING-type E3 ubiquitin transferase
VHL	2.3.2.B13
FLT3	2.7.10.1	receptor protein-tyrosine kinase
HMOX1	1.14.14.18	heme oxygenase (biliverdin-producing)
B4GALT1	2.4.1.133, 2.4.1.22, 2.4.1.38, 2.4.1.90	xylosylprotein 4-beta-galactosyltransferase, lactose synthase, beta-N-acetylglucosaminylglycopeptide beta-1,4-galactosyltransferase, N-acetyllactosamine synthase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
VHL	3,575
CCND1	576
PBRM1	193
EPAS1	241
FLT3	3,132
HIF1A	427

Pharmacogenomics

Cohort genes with a PharmGKB record: 15; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

25 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
OSIMERTINIB	4	VHL
BRIGATINIB	4	FLT3, VHL
CRIZOTINIB	4	FLT3, VHL
ADAGRASIB	4	VHL
PALBOCICLIB	4	CCND1, FLT3
ABEMACICLIB	4	CCND1, FLT3
RIBOCICLIB	4	CCND1
TRILACICLIB	4	CCND1
EMETINE	4	EPAS1, HIF1A
DOXORUBICIN	4	EPAS1, HIF1A
TOPOTECAN	4	EPAS1, HIF1A
PONATINIB	4	FLT3
AFATINIB	4	FLT3
FEDRATINIB	4	FLT3
NERATINIB	4	FLT3
INFIGRATINIB PHOSPHATE	4	FLT3
INFIGRATINIB	4	FLT3
IBRUTINIB	4	FLT3
REGORAFENIB	4	FLT3
ENTRECTINIB	4	FLT3
PACRITINIB	4	FLT3
FOSTAMATINIB	4	FLT3
QUIZARTINIB DIHYDROCHLORIDE	4	FLT3
CERITINIB	4	FLT3
VANDETANIB	4	FLT3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	VHL, CCND1, EPAS1, FLT3, HIF1A
B	Phased (≥1) drug, not yet approved	1	PBRM1
C	Druggable family + PDB, no drug	2	HMOX1, B4GALT1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	7	RNF2, TSC1, FBXW7, CDKN2A, CDKN2B, FLCN, KLLN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RNF2	16	—
TSC1	0	—
FBXW7	0	—
CDKN2A	2	—
CDKN2B	0	—
FLCN	0	—
KLLN	0	—
HMOX1	23	—
B4GALT1	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1,179.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	342
Not specified	276
PHASE1	242
PHASE1/PHASE2	134
PHASE3	65
EARLY_PHASE1	18
PHASE4	17
PHASE2/PHASE3	6

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06903312	PHASE4	RECRUITING	Primary Tumor Ablation and Outcome in Metastatic Renal Cell Carcinoma Treated With Immunotherapy Combinations.
NCT06934057	PHASE4	RECRUITING	Cabozantinib and Nivolumab Among Older Patients With Renal Cell Carcinoma
NCT07028125	PHASE4	RECRUITING	Digital Monitoring of Self-reported Symptoms by Patients Treated With Cabozantinib Plus Nivolumab for Advanced Clear-cell Renal Carcinoma
NCT07405086	PHASE4	RECRUITING	Morning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
NCT00172003	PHASE4	COMPLETED	Effect of Zoledronic Acid in Patients With Renal Cell Cancer and Bone Metastasis
NCT00414765	PHASE4	COMPLETED	Aldesleukin in Participants With Metastatic Renal Cell Carcinoma or Metastatic Melanoma
NCT00777504	PHASE4	UNKNOWN	Study to the Optimal Duration of Therapy With Oral Angiogenesis Inhibitors
NCT00930345	PHASE4	TERMINATED	Biological, Pathological and Imagery Markers in the First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma
NCT01206764	PHASE4	COMPLETED	A Trial of Everolimis in Patients With Advanced Renal Cell Carcinoma.
NCT01266837	PHASE4	COMPLETED	Open Label, Single Arm Trial to Characterize Patients With Metastatic RCC Treated With Everolimus After Failure of the First VEGF-targeted Therapy (MARC-2)
NCT01402089	PHASE4	COMPLETED	Cytochrom p450 3A4 and 1A2 Phenotyping for the Individualization of Treatment With Sunitinib or Erlotinib in Cancer Patients
NCT02056587	PHASE4	COMPLETED	Everolimus in Patients With Metastatic Renal Cell Carcinoma Following Progression on Prior Bevacizumab Treatment
NCT02338570	PHASE4	TERMINATED	Outcome-related Factors in Patients With Metastatic Renal Cell Carcinoma Treated With Everolimus (ORCHIDEE)
NCT02555748	PHASE4	COMPLETED	Therapeutic Drug Monitoring of Sunitinib and Pazopanib in Advanced or Metastatic Renal Cell Carcinoma
NCT02596035	PHASE4	COMPLETED	An Investigational Immuno-therapy Safety Trial of Nivolumab in Patients With Advanced or Metastatic Renal Cell Carcinoma
NCT02982954	PHASE4	COMPLETED	A Study to Evaluate the Safety of Nivolumab and Ipilimumab in Subjects With Previously Untreated Advanced or Metastatic Renal Cell Cancer
NCT05949424	PHASE4	UNKNOWN	OPTI - DOSE: Optimal Dosing of Oral Anticancer Drugs in Older Adults
NCT01224288	PHASE3	ACTIVE_NOT_RECRUITING	Dynamic Contrast Enhancement Computed Tomography for Evaluating Tumor Perfusion in Patients With Metastatic Renal Cell Carcinoma Receiving Targeted Therapies: Renal Cell Carcinoma (RCC) Scramble
NCT01575548	PHASE3	ACTIVE_NOT_RECRUITING	Pazopanib Hydrochloride in Treating Patients With Metastatic Kidney Cancer Who Have No Evidence of Disease After Surgery
NCT02811861	PHASE3	ACTIVE_NOT_RECRUITING	Lenvatinib/Everolimus or Lenvatinib/Pembrolizumab Versus Sunitinib Alone as Treatment of Advanced Renal Cell Carcinoma
NCT03055013	PHASE3	ACTIVE_NOT_RECRUITING	Nivolumab in Treating Patients With Localized Kidney Cancer Undergoing Nephrectomy
NCT03141177	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Nivolumab Combined With Cabozantinib Compared to Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma
NCT03288532	PHASE3	RECRUITING	Renal Adjuvant MultiPle Arm Randomised Trial
NCT03592472	PHASE3	RECRUITING	A Study of Pazopanib With or Without Abexinostat in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma (RENAVIV)
NCT03793166	PHASE3	ACTIVE_NOT_RECRUITING	Immunotherapy With Nivolumab and Ipilimumab Followed by Nivolumab or Nivolumab With Cabozantinib for Patients With Advanced Kidney Cancer, The PDIGREE Study
NCT03873402	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Participants With Advanced Kidney Cancer
NCT03937219	PHASE3	ACTIVE_NOT_RECRUITING	Study of Cabozantinib in Combination With Nivolumab and Ipilimumab in Patients With Previously Untreated Advanced or Metastatic Renal Cell Carcinoma
NCT04510597	PHASE3	RECRUITING	Comparing the Outcome of Immunotherapy-Based Drug Combination Therapy With or Without Surgery to Remove the Kidney in Metastatic Kidney Cancer, the PROBE Trial
NCT05078047	PHASE3	RECRUITING	Study Comparing the Standard Administration of IO Versus the Same IO Administered Each 3 Months in Patients in Response After 6 Months of Standard IO
NCT05219318	PHASE3	ACTIVE_NOT_RECRUITING	Treatment Pause Versus Treatment Continuation in IMDC Good or Intermediate Risk With Only One Adverse Prognostic Factor in mRCC Patients With an Objective Response at 12 Months of Treatment With PD1/ PDL1 ICIs + VEGFR-Tyrosine Kinase Inhibitors
NCT05522231	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Efficacy and Safety of Fruquintinib in Combination With Sintilimab in Advanced Renal Cell Carcinoma (FRUSICA-2)
NCT05738694	PHASE3	RECRUITING	Neoadjuvant of Axitinib Plus PD-1 to Improve Disease Free Survival of Patients With Renal Cell Carcinoma
NCT05770037	PHASE2/PHASE3	RECRUITING	DETERMINE Trial Treatment Arm 01: Alectinib in Adult, Paediatric and Teenage/Young Adult Patients With ALK Positive Cancers
NCT05796973	PHASE3	RECRUITING	Measuring Oncological Value of Exercise and Statin
NCT05863351	PHASE3	ACTIVE_NOT_RECRUITING	Focused Radiation Versus Systemic Therapy for Kidney Cancer Patients With Limited Metastasis, SOAR Study
NCT06500455	PHASE3	RECRUITING	Testing Longer Duration Radiation Therapy Versus the Usual Radiation Therapy in Patients With Cancer That Has Spread to the Brain
NCT06661720	PHASE3	RECRUITING	Testing the Addition of the Anti-Cancer Drug Tivozanib to Immunotherapy (Pembrolizumab) After Surgery to Remove All Known Sites of Kidney Cancer
NCT06726421	PHASE3	RECRUITING	Systemic Therapy Alone or With Stereotactic Body Radiotherapy for Oligometastatic Kidney Cancer (STROKER Study)
NCT07165418	PHASE3	NOT_YET_RECRUITING	A Comparison of Vorolanib Tablets Combined With Everolimus Versus Sunitinib in Patients With Advanced Renal Cell Carcinoma Who Have Progressed After Treatment With Immunotherapy Monotherapy or in Combination With TKI
NCT07197580	PHASE3	RECRUITING	Phase 3 Study to Assess Safety and Efficacy of 177Lu-TLX250 in Advanced Relapsed or Recurrent ccRCC

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SUNITINIB	4	40
CABOZANTINIB	4	33
SORAFENIB	4	30
PAZOPANIB	4	23
ATEZOLIZUMAB	4	22
TIVOZANIB	4	21
AXITINIB	4	20
NIVOLUMAB	4	11
TEMSIROLIMUS	4	9
BELZUTIFAN	4	8
IPILIMUMAB	4	7
EVEROLIMUS	4	5
LENVATINIB	4	5
AVELUMAB	4	4
OXALIPLATIN	4	4
PEMBROLIZUMAB	4	4
ERLOTINIB HYDROCHLORIDE	4	3
IXABEPILONE	4	3
PERFLUTREN	4	3
VORINOSTAT	4	3
ALDESLEUKIN	4	2
FLUDEOXYGLUCOSE F 18	4	2
INTERFERON ALFA-2A	4	2
INTERFERON ALFA-2B	4	2
PANITUMUMAB	4	2
PANOBINOSTAT	4	2
RAMUCIRUMAB	4	2
ZOLEDRONIC ACID	4	2
ALECTINIB	4	1
AZACITIDINE	4	1

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 26 predictive associations from 27 curated evidence items; also 40 predisposing, 4 prognostic, 3 oncogenic, 1 diagnostic.

Molecular subtype	Therapy	Effect	Level	CIViC
TSC1 Loss-of-function	MTOR Inhibitor	Sensitivity/Response	CIViC B	EID5837 +1
EPAS1 Overexpression	Pazopanib	Sensitivity/Response	CIViC B	EID1673
HDAC2 Expression	Pazopanib + Abexinostat	Sensitivity/Response	CIViC B	EID7057
HIF1A EXPRESSION	Pazopanib	Sensitivity/Response	CIViC B	EID1674
KDM5C Mutation	Sunitinib + Everolimus	Sensitivity/Response	CIViC B	EID5997
MTOR Gain-of-Function	MTOR Inhibitor	Sensitivity/Response	CIViC B	EID5839
PBRM1 Loss-of-function	Ipilimumab	Sensitivity/Response	CIViC B	EID7301
PBRM1 Loss-of-function	Nivolumab + Pembrolizumab	Sensitivity/Response	CIViC B	EID7536
PBRM1 Loss-of-function	Atezolizumab + Durvalumab	Sensitivity/Response	CIViC B	EID7537
PBRM1 Loss-of-function	Nivolumab	Sensitivity/Response	CIViC B	EID7584
PBRM1 Mutation	Sunitinib + Everolimus	Sensitivity/Response	CIViC B	EID5996
TSC2 Loss-of-function	MTOR Inhibitor	Sensitivity/Response	CIViC B	EID5838
VHL Mutation	Pazopanib	Sensitivity/Response	CIViC B	EID1672
VHL Mutation	Anti-VEGF Monoclonal Antibody	Sensitivity/Response	CIViC B	EID4832
VHL Mutation	Everolimus	Sensitivity/Response	CIViC B	EID5323
BAP1 Mutation	Everolimus + Sunitinib	Resistance	CIViC B	EID5339
HMOX1 EXPRESSION	Sorafenib + Sunitinib	Resistance	CIViC B	EID829
VHL Loss	Pazopanib	Resistance	CIViC B	EID4829
FLT3 T227M	Sunitinib	Adverse Response	CIViC B	EID1317
FLCN c.1285dupC	Everolimus	Sensitivity/Response	CIViC C	EID10137
CCND1 Amplification	Palbociclib	Sensitivity/Response	CIViC D	EID1560
CDKN2A Loss	Palbociclib	Sensitivity/Response	CIViC D	EID1373
CDKN2B Loss	Palbociclib	Sensitivity/Response	CIViC D	EID1374
VHL Loss-of-function	Temsirolimus	Sensitivity/Response	CIViC D	EID4828
EML4::ALK e2::e20		Sensitivity/Response	CIViC E	EID1266
FBXW7 Loss-of-function	Everolimus	Sensitivity/Response	CIViC E	EID1628