Chromophobe renal cell carcinoma

Summary

Chromophobe renal cell carcinoma (MONDO:0017885) is a cancer with 4 cohort genes (3 CIViC-evidence somatic drivers; 3 ClinVar predisposition records) and 14 clinical trials. Top therapeutic interventions include cabozantinib, pazopanib hydrochloride, and radium ra 223 dichloride.

At a glance

• Classification: Cancer
• Prevalence: <1 / 1 000 000 (Europe) [Orphanet-validated]
• Cohort genes: 4
• ClinVar variants: 3
• Clinical trials: 14

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.01	Europe	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	chromophobe renal cell carcinoma
Mondo ID	MONDO:0017885
EFO	EFO:0000335
Orphanet	319303
DOID	DOID:4471
NCIT	C4146
SNOMED CT	733471003
UMLS	C1266042
MedGen	266091
GARD	0006064
Is cancer (heuristic)	yes

Also known as: CHRCC · ChRCC · chromophobe adenocarcinoma · chromophobe carcinoma · chromophobe carcinoma of kidney · chromophobe carcinoma of the kidney · chromophobe cell carcinoma of kidney · chromophobe cell carcinoma of the kidney · chromophobe renal cell adenocarcinoma · chromophobe renal cell cancer · chromophobe renal cell carcinoma · CRCC · renal cell carcinoma, chromophobe type

Data availability: 3 ClinVar variants · 4 cell lines · 11 intOGen driver records.

Disease family

An umbrella term covering 2 Mondo subtypes.

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

Related subtypes (8): 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, renal cell carcinoma associated with neuroblastoma, tubulocystic renal cell carcinoma

Subtypes (2): classic variant of chromophobe renal cell carcinoma, eosinophilic variant of chromophobe 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

ClinVar germline variants

3 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3368	NM_144997.7(FLCN):c.1277_1278delinsA (p.Ile426fs)	FLCN	Pathogenic	no assertion criteria provided
12648	NM_000458.4(HNF1B):c.46del (p.Leu16fs)	HNF1B	Pathogenic	criteria provided, single submitter
14948	NM_000545.8(HNF1A):c.92G>A (p.Gly31Asp)	HNF1A	Benign	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 20 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
VHL	LoF	CCRCC,PGNG,RCC	CIViC #58
HNF1A	LoF	HCC,PRCC
FLCN	LoF	LUAD	CIViC #19959

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
HNF1A	Orphanet:319303	Chromophobe renal cell carcinoma
HNF1A	Orphanet:324575	Hyperinsulinism due to HNF1A deficiency
HNF1A	Orphanet:404511	Clear cell papillary renal cell carcinoma
HNF1A	Orphanet:552	MODY
HNF1B	Orphanet:1309	Medullary sponge kidney
HNF1B	Orphanet:1331	Familial prostate cancer
HNF1B	Orphanet:2578	Mayer-Rokitansky-Küster-Hauser syndrome type 2
HNF1B	Orphanet:261265	17q12 microdeletion syndrome
HNF1B	Orphanet:93111	HNF1B-related autosomal dominant tubulointerstitial kidney disease
HNF1B	Orphanet:93172	Renal dysplasia, unilateral
HNF1B	Orphanet:93173	Renal dysplasia, bilateral
HNF1B	Orphanet:97363	Unilateral multicystic dysplastic kidney
HNF1B	Orphanet:97364	Bilateral multicystic dysplastic kidney
FLCN	Orphanet:122	Birt-Hogg-Dubé syndrome
FLCN	Orphanet:2903	Familial spontaneous pneumothorax
FLCN	Orphanet:422526	Hereditary clear cell renal cell carcinoma

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	1
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VHL	HGNC:12687	ENSG00000134086	P40337	von Hippel-Lindau disease tumor suppressor	civic_evidence
HNF1A	HGNC:11621	ENSG00000135100	P20823	Hepatocyte nuclear factor 1-alpha	clinvar
HNF1B	HGNC:11630	ENSG00000275410	P35680	Hepatocyte nuclear factor 1-beta	clinvar
FLCN	HGNC:27310	ENSG00000154803	Q8NFG4	Folliculin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VHL	von Hippel-Lindau disease tumor suppressor	Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex.
HNF1A	Hepatocyte nuclear factor 1-alpha	Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver.
HNF1B	Hepatocyte nuclear factor 1-beta	Transcription factor that binds to the inverted palindrome 5’-GTTAATNATTAAC-3'.
FLCN	Folliculin	Multi-functional protein, involved in both the cellular response to amino acid availability and in the regulation of glycolysis.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.25

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
Transcription factor	2	4.1×	0.223
Enzyme (other)	1	3.0×	0.441
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VHL	Enzyme (other)	yes	2.3.2.B13	VHL_tumour_suppress_b/a_dom, VHL_alpha_dom, VHL_beta_dom
HNF1A	Transcription factor	no		HD, HNF1b_C, HNF1a_C
HNF1B	Transcription factor	no		HD, HNF1b_C, HNF-1_N
FLCN	Other/Unknown	no		Folliculin, Folliculin_DENN, Folliculin/SMCR8_longin

Expression context

Cohort genes with no expression data: 0.

3 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
monocyte	1
mononuclear cell	1
liver	1
mucosa of transverse colon	1
right lobe of liver	1
adult mammalian kidney	1
kidney	1
metanephros cortex	1
buccal mucosa cell	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VHL	186	ubiquitous	marker	cortical plate, monocyte, mononuclear cell
HNF1A	81	tissue_specific	yes	right lobe of liver, mucosa of transverse colon, liver
HNF1B	74	broad	marker	metanephros cortex, adult mammalian kidney, kidney
FLCN	261	ubiquitous	marker	buccal mucosa cell, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VHL	3,522
HNF1A	2,491
HNF1B	1,660
FLCN	1,317

Intra-cohort edges

A	B	Sources
HNF1A	HNF1B	biogrid_interaction, intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VHL	P40337	142
HNF1A	P20823	6
FLCN	Q8NFG4	4
HNF1B	P35680	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Replication of the SARS-CoV-1 genome	1	713.8×	0.011	VHL
Replication of the SARS-CoV-2 genome	1	713.8×	0.011	VHL
Regulation of gene expression in early pancreatic precursor cells	1	356.9×	0.013	HNF1B
RHOBTB3 ATPase cycle	1	285.5×	0.013	VHL
Nephron development	1	219.6×	0.014	HNF1B
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	178.4×	0.014	HNF1B
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	150.3×	0.014	HNF1B
Regulation of gene expression in beta cells	1	129.8×	0.014	HNF1A
Developmental Lineage of Pancreatic Acinar Cells	1	75.1×	0.020	HNF1B
SUMOylation of ubiquitinylation proteins	1	73.2×	0.020	VHL
Developmental Lineage of Pancreatic Ductal Cells	1	57.1×	0.023	HNF1B
Amino acids regulate mTORC1	1	50.1×	0.023	FLCN
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	1	49.2×	0.023	VHL
Neddylation	1	11.8×	0.088	VHL
Antigen processing: Ubiquitination & Proteasome degradation	1	9.3×	0.103	VHL

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pancreas development	2	337.0×	0.001	HNF1A, HNF1B
insulin secretion	2	216.1×	0.001	HNF1A, HNF1B
epithelial cell proliferation	2	156.0×	0.002	HNF1B, FLCN
positive regulation of transcription initiation by RNA polymerase II	2	135.9×	0.002	HNF1A, HNF1B
regulation of pronephros size	1	4213.0×	0.002	HNF1B
pronephric nephron tubule development	1	4213.0×	0.002	HNF1B
ureteric bud elongation	1	4213.0×	0.002	HNF1B
obsolete negative regulation of mesenchymal cell apoptotic process involved in mesonephric nephron morphogenesis	1	4213.0×	0.002	HNF1B
mesenchymal cell apoptotic process involved in metanephros development	1	4213.0×	0.002	HNF1B
negative regulation of cell proliferation involved in kidney development	1	4213.0×	0.002	FLCN
positive regulation of DNA-templated transcription	3	21.0×	0.002	HNF1A, HNF1B, VHL
hepatoblast differentiation	1	2106.5×	0.003	HNF1B
mesonephric duct formation	1	2106.5×	0.003	HNF1B
renal D-glucose absorption	1	1404.3×	0.004	HNF1A
regulation of branch elongation involved in ureteric bud branching	1	1404.3×	0.004	HNF1B
cell proliferation involved in kidney development	1	1404.3×	0.004	FLCN
negative regulation of mesenchymal cell apoptotic process involved in metanephros development	1	1404.3×	0.004	HNF1B
negative regulation of transcription by RNA polymerase II	3	13.3×	0.004	HNF1B, VHL, FLCN
negative regulation of post-translational protein modification	1	1053.2×	0.004	FLCN
negative regulation of lysosome organization	1	1053.2×	0.004	FLCN
regulation of pro-B cell differentiation	1	842.6×	0.005	FLCN
endodermal cell fate specification	1	702.2×	0.005	HNF1B
inner cell mass cell differentiation	1	702.2×	0.005	HNF1B
regulation of cellular response to hypoxia	1	702.2×	0.005	VHL
negative regulation of brown fat cell differentiation	1	702.2×	0.005	FLCN
pronephros development	1	601.9×	0.006	HNF1B
regulation of Ras protein signal transduction	1	468.1×	0.007	FLCN
genitalia development	1	421.3×	0.008	HNF1B
hindbrain development	1	280.9×	0.011	HNF1B
negative regulation of glycolytic process	1	263.3×	0.011	FLCN

Therapeutics

Drugs indicated for this disease

2 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Bevacizumab	Approved (phase 4)
Nivolumab	Approved (phase 4)
Cabozantinib	Phase 3 (in late-stage trials)

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VHL	7	4
HNF1A	0	0
HNF1B	0	0
FLCN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OSIMERTINIB	4	VHL
BRIGATINIB	4	VHL
CRIZOTINIB	4	VHL
ADAGRASIB	4	VHL
ZIMLOVISERTIB	2	VHL
FORETINIB	2	VHL
DT-2216	1	VHL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
VHL	3,575	Binding:3482, Functional:54, ADMET:39
HNF1A	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
VHL	2.3.2.B13

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

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

7 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)
OSIMERTINIB	4	VHL
BRIGATINIB	4	VHL
CRIZOTINIB	4	VHL
ADAGRASIB	4	VHL
ZIMLOVISERTIB	2	VHL
FORETINIB	2	VHL
DT-2216	1	VHL

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	VHL
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	HNF1A, HNF1B, FLCN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HNF1A	1	—
HNF1B	0	—
FLCN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 14.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	8
Not specified	3
PHASE1/PHASE2	1
EARLY_PHASE1	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03541902	PHASE2	ACTIVE_NOT_RECRUITING	Cabozantinib or Sunitinib Malate in Treating Participants With Metastatic Variant Histology Renal Cell Carcinoma
NCT03635892	PHASE2	ACTIVE_NOT_RECRUITING	A Study of Nivolumab In Combination With Cabozantinib in Patients With Non-Clear Cell Renal Cell Carcinoma
NCT03866382	PHASE2	RECRUITING	Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare Genitourinary Tumors
NCT04071223	PHASE2	ACTIVE_NOT_RECRUITING	Testing the Addition of a New Anti-cancer Drug, Radium-223 Dichloride, to the Usual Treatment (Cabozantinib) for Advanced Renal Cell Cancer That Has Spread to the Bone, RadiCaL Study
NCT04413123	PHASE2	ACTIVE_NOT_RECRUITING	Cabozantinib In Combo With NIVO + IPI In Advanced NCCRCC
NCT00126503	PHASE1/PHASE2	COMPLETED	Sorafenib Tosylate and Bevacizumab in Treating Patients With Advanced Kidney Cancer
NCT01767636	PHASE2	COMPLETED	Pazopanib Hydrochloride in Treating Patients With Metastatic Kidney Cancer
NCT03177239	PHASE2	UNKNOWN	Phase II Sequential Treatment Trial of Single Agent Nivolumab, Then Combination Ipilimumab + Nivolumab in Metastatic or Unresectable Non-Clear Cell Renal Cell Carcinoma (ANZUP1602)
NCT03685448	PHASE2	COMPLETED	ANZUP - Non-clear Cell Post Immunotherapy CABozantinib (UNICAB)
NCT06805825	PHASE1	RECRUITING	A Study of the c-Kit Specific Antibody-Drug Conjugate NN3201 for Advanced and/or Metastatic Solid Tumors Known to Express c-Kit
NCT06318871	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Memory-like Natural Killer (NK) Cell Therapy in Patients With Renal Cell Carcinoma or Urothelial Carcinoma
NCT04623502	Not specified	RECRUITING	An Investigation of Kidney and Urothelial Tumor Metabolism in Patients Undergoing Surgical Resection and/or Biopsy
NCT06339138	Not specified	ACTIVE_NOT_RECRUITING	Identification of Novel High Quality Methylated DNA Markers in Renal Tumors: Whole Methylome Discovery, Tissue Validation, and Feasibility Testing In Blood and Urine, The INQUIRE Study
NCT07243067	Not specified	NOT_YET_RECRUITING	Tumor-Derived Extracellular Vesicles for Noninvasive Molecular Classification of Kidney Cancer

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CABOZANTINIB	4	6
PAZOPANIB HYDROCHLORIDE	4	1
RADIUM RA 223 DICHLORIDE	4	1
SORAFENIB	4	1
CHEMBL4215501	0	3
CHEMBL4849721	0	3
EXELIXIS	0	3
CHEMBL3109278	0	1