Clear Cell Renal Cell Carcinoma

MONDO:0005005 Pathograph 13 Show in embeddings browser renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, characterized by biallelic inactivation of the VHL tumor suppressor gene in over 90% of cases. VHL loss stabilizes hypoxia-inducible factors (HIF-1α and HIF-2α), driving expression of angiogenic and growth-promoting genes including VEGF, PDGF, and TGF-α. This molecular understanding led to development of VEGF/VEGFR inhibitors and the more recent HIF-2α inhibitor belzutifan, representing a paradigm shift toward targeting the root cause of the disease.

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9
Pathophys.
4
Histopath.
6
Phenotypes
1
Gaps
13
Pathograph
3
Genes
4
Medical Actions
2
Subtypes
4
Datasets
10
References
2
Deep Research
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Classifications

ICD-O Morphology
Carcinoma
Harrison's Part
ONCOLOGY HEMATOLOGY
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Subtypes

2
VHL-associated ccRCC
Hereditary form occurring in Von Hippel-Lindau disease patients with germline VHL mutations. Tumors are typically bilateral and multifocal. Patients also develop hemangioblastomas, pheochromocytomas, and pancreatic neuroendocrine tumors.
Sporadic ccRCC
Comprises 95% of ccRCC cases. Somatic VHL inactivation occurs through mutation, deletion, or promoter hypermethylation. Additional mutations in chromatin remodeling genes (PBRM1, BAP1, SETD2) affect prognosis.
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Discussions and Knowledge Gaps

1
Should on-treatment hypertension be used to guide VEGFR TKI dosing in metastatic ccRCC — titrating dose upward until blood pressure rises — or does it only index drug exposure retrospectively?
OPEN QUESTION OPEN ccrcc_vegfr_tki_hypertension_as_efficacy_biomarker
Attached to
pathophysiology#Treatment-Emergent Vasoconstriction and Increased Peripheral Vascular Resistance phenotypes#Treatment-Emergent Hypertension treatments#VEGFR Tyrosine Kinase Inhibitors
ccRCC is where this question is decided, because the pivotal data are in sunitinib-treated mRCC rather than in the drug class at large. Two independent analyses of the pooled sunitinib trial database associate on-treatment hypertension with markedly better response, progression-free survival, and overall survival, and the association survives adjustment for baseline IMDC risk. That is a strong pharmacodynamic signal: because the toxicity is on-target, a blood-pressure rise plausibly reports how much VEGF pathway inhibition a given patient actually achieved. It is nonetheless recorded here as an open question, not as an established prognostic or dosing rule, for two reasons. First, both analyses are retrospective analyses of the same pooled database, so they are not independent replications; the time-dependent-covariate and landmark analyses address immortal-time bias but do not make the design prospective. Second, an association between a toxicity and a good outcome does not license the inverse intervention — no trial has shown that deliberately dose-escalating to a blood-pressure target improves survival, and treating the absence of hypertension as undertreatment would be a clinically consequential inference drawn from an observational correlation. Curating this as settled would license exactly that inference. This is the ccRCC-specific instance of the module-level open question recorded as vegfi_hypertension_as_efficacy_biomarker in kb/modules/vegf_inhibitor_hypertension.yaml.
Show evidence (3 references)
PMID:21527770 SUPPORT Human Clinical
"In patients with metastatic renal cell carcinoma, sunitinib-associated HTN is associated with improved clinical outcomes without clinically significant increases in HTN-associated adverse events, supporting its viability as an efficacy biomarker."
The primary source of the biomarker claim in ccRCC. Note its own wording is "supporting its viability as", i.e. a candidate biomarker, which is why this is curated as an open question rather than as established practice.
PMID:21527770 SUPPORT INDIRECT Human Clinical
"This retrospective analysis included pooled efficacy (n = 544) and safety (n = 4917) data from four studies of patients with metastatic renal cell carcinoma who were treated with sunitinib 50 mg/d"
Documents the retrospective, pooled-database design that limits how far the association can be pushed toward a dosing rule; supports the caveat rather than the claim.
PMID:26492223 SUPPORT Human Clinical
"On-treatment neutropenia and hypertension are independent biomarkers of sunitinib efficacy and may add prognostic accuracy to the IMDC model."
Shows the association holds independently of baseline IMDC risk stratification, which is the strongest version of the claim; it is drawn from the same pooled database, so it strengthens but does not independently replicate the finding.
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Pathophysiology

9
VHL Tumor Suppressor Inactivation
Biallelic VHL loss is the initiating event in ccRCC. The VHL protein normally targets HIF-α subunits for ubiquitin-mediated degradation under normoxic conditions. Without functional VHL, HIF-α accumulates and constitutively activates hypoxia response genes.
kidney epithelial cell CL:0002518 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves kidney epithelial cell (CL:0002518). CL:0002518 is a cell type from the Cell Ontology.
cellular response to hypoxia GO:0071456 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular response to hypoxia (GO:0071456). GO:0071456 is a biological process from the Gene Ontology. proteasome-mediated ubiquitin-dependent protein catabolic process GO:0043161 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161). GO:0043161 is a biological process from the Gene Ontology.
kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
HIF-2α Stabilization Loss of VHL-mediated degradation allows HIF-2α protein accumulation
Show evidence (1 reference)
PMID:37085424 SUPPORT
"These include somatic gene mutations such as VHL, PBRM1, SETD2, and BAP1"
This comprehensive review confirms VHL as the primary genomic biomarker and driver mutation in ccRCC.
HIF-2α Stabilization
Without VHL-mediated degradation, HIF-2α protein accumulates in the cytoplasm and translocates to the nucleus where it dimerizes with HIF-1β (ARNT) to form an active transcription factor. HIF-2α is the critical HIF isoform in ccRCC.
protein stabilization GO:0050821 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased protein stabilization (GO:0050821). GO:0050821 is a biological process from the Gene Ontology.
Downstream
VEGF-Driven Angiogenesis HIF-2α transcriptionally activates VEGF expression
Growth Factor Pathway Activation HIF-2α induces TGF-α and cyclin D1 expression
Metabolic Reprogramming and Aerobic Glycolysis HIF stabilization induces the glycolytic gene program (GLUT1, LDHA, PDK1) that shifts tumor metabolism toward aerobic glycolysis
VEGF-Driven Angiogenesis
HIF-2α transcriptionally activates VEGF (vascular endothelial growth factor), driving tumor neovascularization. The resulting hypervascular phenotype is characteristic of ccRCC and the basis for VEGFR-targeted therapy.
angiogenesis GO:0001525 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased angiogenesis (GO:0001525). GO:0001525 is a biological process from the Gene Ontology. vascular endothelial growth factor receptor signaling pathway GO:0048010 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased vascular endothelial growth factor receptor signaling pathway (GO:0048010). GO:0048010 is a biological process from the Gene Ontology.
Growth Factor Pathway Activation
HIF-2α activates transcription of growth-promoting genes including TGF-α (which activates EGFR signaling) and cyclin D1 (which promotes cell cycle progression). This drives tumor cell proliferation independent of angiogenesis.
cell population proliferation GO:0008283 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology.
Metabolic Reprogramming and Aerobic Glycolysis
Constitutive HIF stabilization from VHL loss reprograms tumor-cell metabolism toward aerobic glycolysis (the Warburg effect): HIF induces the glucose transporter GLUT1, glycolytic enzymes, lactate dehydrogenase A, and PDK1, while the TCA cycle is downregulated. Carbon is diverted into the pentose phosphate pathway and, together with increased fatty-acid synthesis, into biomass. The resulting glycogen and lipid accumulation produces the characteristic clear (lipid-laden) cytoplasm for which the tumor is named.
kidney epithelial cell CL:0002518 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves kidney epithelial cell (CL:0002518). CL:0002518 is a cell type from the Cell Ontology.
glycolytic process GO:0006096 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased glycolytic process (GO:0006096). GO:0006096 is a biological process from the Gene Ontology. tricarboxylic acid cycle GO:0006099 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased tricarboxylic acid cycle (GO:0006099). GO:0006099 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:23792563 SUPPORT Human Clinical
"Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein"
The TCGA molecular characterization of more than 400 ccRCC tumors documents a recurrent metabolic shift (TCA-cycle downregulation, pentose-phosphate-pathway and glutamine-transporter upregulation) that correlates with stage and severity, supporting aerobic-glycolysis-directed metabolic reprogramming.
DOI:10.1186/s12967-024-04848-x SUPPORT Computational
"Clear cell renal cell carcinoma is a prototypical tumor characterized by metabolic reprogramming"
Single-cell and spatial transcriptomic metabolic profiling identifies ccRCC as a prototypical metabolic-reprogramming tumor, with the tumor epicenter showing elevated glycolysis.
Epigenetic Dysregulation
Secondary mutations in chromatin remodeling genes (PBRM1 in 40%, BAP1 in 15%, SETD2 in 15%) contribute to ccRCC progression. BAP1 mutations are associated with higher grade tumors and worse prognosis compared to PBRM1 mutations. These mutations cooperate with VHL loss to drive tumor evolution.
chromatin remodeling GO:0006338 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chromatin remodeling (GO:0006338). GO:0006338 is a biological process from the Gene Ontology.
Downstream
Growth Factor Pathway Activation Epigenetic changes enhance proliferative gene expression programs
Show evidence (1 reference)
PMID:37085424 SUPPORT
"These include somatic gene mutations such as VHL, PBRM1, SETD2, and BAP1"
This review confirms PBRM1, SETD2, and BAP1 as recurrent genomic biomarkers in ccRCC contributing to epigenetic dysregulation.
Immune Evasion via PD-L1 and Immunosuppressive Microenvironment
ccRCC is among the most immune-infiltrated solid tumors, with abundant CD8+ T cells in the tumor microenvironment. However, chronic VHL-HIF signaling promotes an immunosuppressive milieu through VEGF-mediated inhibition of dendritic cell maturation, PD-L1 upregulation on tumor cells, and recruitment of regulatory T cells and myeloid-derived suppressor cells. This inherent immunogenicity combined with adaptive immune resistance provides the rationale for checkpoint inhibitor therapy.
CD8-positive, alpha-beta T cell CL:0000625 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD8-positive, alpha-beta T cell (CL:0000625). CL:0000625 is a cell type from the Cell Ontology.
Negative Regulation of T Cell Mediated Immunity GO:0002710 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Negative Regulation of T Cell Mediated Immunity (GO:0002710). GO:0002710 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:38762484 SUPPORT Other
"The interaction of PD-1 and PD-L1 negatively regulates adaptive immune response mainly by inhibiting the activity of effector T cells while enhancing the function of immunosuppressive regulatory T cells (Tregs), largely contributing to the maintenance of immune homeostasis that prevents..."
Review describing how tumors including ccRCC exploit PD-1/PD-L1 signaling to suppress anti-tumor immunity, relevant to the highly immune-infiltrated ccRCC microenvironment.
VSP Inhibitor Blockade of Systemic Endothelial VEGF Signaling
The therapy-emergent arm of this entry, and the mirror image of the tumor arm above. The VEGFR tyrosine kinase inhibitors used to treat ccRCC do not act only on tumor endothelium: they silence the same VEGFA-VEGFR2 signal in the systemic vasculature, where it is a tonic homeostatic input rather than a tumor-driven one. Because the ccRCC angiogenic phenotype is the reason the drug class is used here, this vascular toxicity is on-target and inseparable from the therapeutic effect, not an idiosyncratic reaction. Curated in ccRCC specifically because ccRCC is where the pivotal clinical data on this toxicity were generated.
vascular endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular endothelial cell, annotated with endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
vascular endothelial growth factor receptor signaling pathway GO:0048010 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased vascular endothelial growth factor receptor signaling pathway (GO:0048010). GO:0048010 is a biological process from the Gene Ontology.
Downstream
Treatment-Emergent Vasoconstriction and Increased Peripheral Vascular Resistance Withdrawal of endothelial VEGF signalling lowers nitric oxide, activates the endothelin system, and rarefies the microvasculature, which together raise peripheral resistance.
Show evidence (2 references)
PMID:21527770 SUPPORT Human Clinical
"Hypertension (HTN) is an on-target effect of the vascular endothelial growth factor pathway inhibitor, sunitinib."
States in the renal-cell-carcinoma setting that the blood-pressure effect of sunitinib is on-target VEGF pathway inhibition, which is exactly what this trigger node asserts for the ccRCC treatment context.
PMID:36621810 SUPPORT Other
"One of the most common side effects of these drugs is hypertension, especially in patients treated with vascular endothelial growth factor inhibitors, as well as tyrosine kinase inhibitors and proteasome inhibitors."
Establishes VEGF pathway inhibition as the leading anticancer-drug route to hypertension, generalizing the ccRCC observation to the drug class. Evidence source is OTHER because this is a scientific statement / review.
Treatment-Emergent Vasoconstriction and Increased Peripheral Vascular Resistance
The convergence step for VEGFR-TKI-induced hypertension in ccRCC: reduced endothelial nitric oxide, endothelin-1 system activation, and microvascular rarefaction shift the peripheral circulation toward constriction and raise total peripheral vascular resistance. Which of those three arms is rate-limiting is unsettled, so this entry deliberately funnels through the convergence node rather than asserting one arm — see the vegf_inhibitor_hypertension module's KNOWLEDGE_GAP discussion.
vascular smooth muscle cell CL:0000359 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular smooth muscle cell, annotated with vascular associated smooth muscle cell (CL:0000359). CL:0000359 is a cell type from the Cell Ontology. vascular endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular endothelial cell, annotated with endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
vasoconstriction GO:0042310 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased vasoconstriction (GO:0042310). GO:0042310 is a biological process from the Gene Ontology. blood vessel diameter maintenance GO:0097746 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased blood vessel diameter maintenance (GO:0097746). GO:0097746 is a biological process from the Gene Ontology.
blood vessel UBERON:0001981 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in blood vessel (UBERON:0001981). UBERON:0001981 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Treatment-Emergent Hypertension Sustained elevation of peripheral vascular resistance raises systemic arterial blood pressure during VEGFR TKI therapy.
Show evidence (1 reference)
PMID:29931399 SUPPORT Other
"The mechanism of action involves VSP inhibition, leading to decreased nitric oxide and increased endothelin production, which causes vasoconstriction, capillary rarefaction, and hypertension."
Places vasoconstriction between the mediator changes and the clinical blood-pressure rise, which is the convergence claim of this node. Evidence source is OTHER because this is a review article.
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Histopathology

4
Clear Cell Renal Cell Carcinoma VERY_FREQUENT
Clear cell RCC is the most common histologic subtype of renal cell carcinoma.
Show evidence (1 reference)
PMID:39196544 SUPPORT
"Clear cell RCC is the most common histologic subtype"
Abstract reports clear cell RCC as the most common histologic subtype.
Sarcomatoid Differentiation OCCASIONAL
Sarcomatoid (spindle-cell) dedifferentiation represents high-grade transformation of ccRCC and portends a markedly worse prognosis.
Show evidence (1 reference)
PMID:11224597 SUPPORT Human Clinical
"sarcomatoid differentiation was 8% in conventional (clear cell) renal carcinoma"
The series reports an 8% incidence of sarcomatoid differentiation in conventional (clear cell) renal carcinoma, establishing it as a recognized ccRCC morphologic feature.
Coagulative Tumor Necrosis FREQUENT
Coagulative (ischemic) tumor necrosis is an independent adverse prognostic feature in ccRCC and is routinely reported in surgical pathology.
Show evidence (1 reference)
PMID:17594714 SUPPORT Human Clinical
"Prognostic information conveyed by Ki-67 and coagulative tumor"
The study identifies coagulative tumor necrosis as carrying independent prognostic information in ccRCC, supporting it as a reported histopathologic finding.
Fuhrman Nuclear Grade VERY_FREQUENT
Fuhrman nuclear grading (based on nuclear size, nucleolar prominence, and membrane irregularity) is an established independent prognostic grading system applied to ccRCC specimens.
Show evidence (1 reference)
PMID:20804473 SUPPORT Human Clinical
"A modified, three-tiered Fuhrman grading system can be considered an"
The study applies a modified Fuhrman nuclear grading system to clear-cell RCC for prognostication, supporting Fuhrman nuclear grade as a standard ccRCC grading finding.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Clear Cell Renal Cell Carcinoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

6
Cardiovascular 1
Treatment-Emergent Hypertension VERY_FREQUENT HP:0000822 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertension (HP:0000822). HP:0000822 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26492223 SUPPORT Human Clinical
"Among the 770 patients included in the analyses, 614 (80%), 365 (47%), 172 (22%), 179 (23%), and 583 (76%) experienced on-treatment SBP-defined hypertension, neutropenia (grade ⩾2), thrombocytopenia (grade ⩾2), hand-foot syndrome (grade >0), and asthenia/fatigue (grade >0), respectively."
Quantifies on-treatment hypertension in a pooled sunitinib mRCC cohort that is >98% clear cell, supporting the VERY_FREQUENT frequency assigned here.
PMID:36621810 SUPPORT Other
"Cancer therapy-induced hypertension is often dose limiting, increases cardiovascular mortality in cancer survivors, and is usually reversible after interruption or discontinuation of treatment."
Supports the dose-limiting significance and the reversibility on drug withdrawal described for this phenotype. Evidence source is OTHER because this is a scientific statement / review.
Genitourinary 2
Renal Mass VERY_FREQUENT Renal neoplasm HP:0009726 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal neoplasm (HP:0009726). HP:0009726 is a phenotype from the Human Phenotype Ontology.
Hematuria FREQUENT HP:0000790 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hematuria (HP:0000790). HP:0000790 is a phenotype from the Human Phenotype Ontology.
Constitutional 1
Fatigue FREQUENT HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Growth 1
Weight Loss OCCASIONAL HP:0001824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Weight loss (HP:0001824). HP:0001824 is a phenotype from the Human Phenotype Ontology.
Neoplasm 1
Metastatic Disease FREQUENT Neoplasm HP:0002664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neoplasm (HP:0002664). HP:0002664 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39196544 SUPPORT Human Clinical
"Seventy percent of patients are diagnosed with stage I RCC and 11% of patients with stage IV."
A subset of RCC patients (11%) present with stage IV (metastatic) disease.
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Genetic Associations

3
VHL (Germline and Somatic Inactivating Mutations)
Gene: VHL hgnc:12687 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is VHL (hgnc:12687). hgnc:12687 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal Dominant
Show evidence (1 reference)
PMID:23792563 SUPPORT Human Clinical
"Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1)."
The TCGA molecular characterization identifies VHL (cellular oxygen sensing) as a core altered gene underlying ccRCC.
PBRM1 (Somatic Inactivating Mutations)
Gene: PBRM1 hgnc:30064 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PBRM1 (hgnc:30064). hgnc:30064 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:23792563 SUPPORT Human Clinical
"mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways"
The TCGA analysis identifies PBRM1 as part of the recurrently mutated SWI/SNF chromatin-remodelling complex in ccRCC.
BAP1 (Somatic Inactivating Mutations)
Gene: BAP1 hgnc:950 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is BAP1 (hgnc:950). hgnc:950 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:37085424 SUPPORT Human Clinical
"These include somatic gene mutations such as VHL, PBRM1, SETD2, and BAP1"
BAP1 is recognized among the recurrent somatic driver-gene mutations and candidate genomic biomarkers in ccRCC.
💊

Medical Actions

4
Nephrectomy
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Surgical resection (partial or radical nephrectomy) is the primary treatment for localized ccRCC. Cytoreductive nephrectomy may benefit selected patients with metastatic disease.
Show evidence (1 reference)
PMID:39196544 SUPPORT Human Clinical
"Treatment options for RCC confined to the kidney include surgical resection with partial or radical nephrectomy"
Partial or radical nephrectomy is a primary treatment for kidney-confined RCC.
VEGFR Tyrosine Kinase Inhibitors
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sunitinib CHEBI:38940 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sunitinib (CHEBI:38940). CHEBI:38940 is a therapeutic agent from Chemical Entities of Biological Interest. pazopanib CHEBI:71219 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pazopanib (CHEBI:71219). CHEBI:71219 is a therapeutic agent from Chemical Entities of Biological Interest. axitinib CHEBI:66910 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses axitinib (CHEBI:66910). CHEBI:66910 is a therapeutic agent from Chemical Entities of Biological Interest. cabozantinib CHEBI:72317 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cabozantinib (CHEBI:72317). CHEBI:72317 is a therapeutic agent from Chemical Entities of Biological Interest.
Sunitinib, pazopanib, axitinib, and cabozantinib target VEGFR and other kinases to block HIF-driven angiogenesis. First-line options for metastatic ccRCC, often combined with immunotherapy.
Mechanism Target:
INHIBITS VEGF-Driven Angiogenesis — VEGFR tyrosine kinase inhibitors (e.g., sunitinib, pazopanib, cabozantinib, axitinib) block VEGFR signaling on tumor endothelium, inhibiting the VEGF-driven angiogenic switch that supplies the hypervascular ccRCC.
ACTIVATES VSP Inhibitor Blockade of Systemic Endothelial VEGF Signaling — The same drugs silence VEGFA-VEGFR2 signalling in the systemic vasculature, initiating the on-target hypertension arm. This edge is ACTIVATES rather than INHIBITS because the treatment brings the node into being; it is the price of the therapeutic effect on the edge above, and it cannot be avoided by reversing it without also abolishing the antitumor action.
Show evidence (1 reference)
PMID:21527770 SUPPORT Human Clinical
"Hypertension (HTN) is an on-target effect of the vascular endothelial growth factor pathway inhibitor, sunitinib."
Attributes the hypertension arm to the sunitinib mechanism itself in renal cell carcinoma, supporting this treatment-to-toxicity edge.
Show evidence (1 reference)
PMID:39196544 SUPPORT Human Clinical
"For advanced or metastatic RCC, combinations of immune checkpoint inhibitors or the combination of immune checkpoint inhibitors with tyrosine kinase inhibitors are associated with tumor response of 42% to 71%"
Tyrosine kinase inhibitors, combined with immune checkpoint inhibitors, are a standard systemic option for advanced/metastatic RCC.
Belzutifan
Action: targeted therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is targeted therapy (NCIT:C93352). NCIT:C93352 is a clinical intervention from the NCI Thesaurus. Ontology label: Targeted Therapy NCIT:C93352
Agent: belzutifan NCIT:C135627 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses belzutifan (NCIT:C135627). NCIT:C135627 is a therapeutic agent from the NCI Thesaurus.
First-in-class HIF-2α inhibitor that directly targets the driver of ccRCC pathogenesis. Approved for VHL-associated ccRCC and showing promise in sporadic ccRCC. Represents mechanism-based targeted therapy.
Mechanism Target:
INHIBITS HIF-2α Stabilization — Belzutifan is a HIF-2alpha inhibitor that blocks the stabilized HIF-2alpha transcription factor upstream of VEGF, shutting down the pro-angiogenic transcriptional program at its source.
Immune Checkpoint Inhibitors
Action: immunotherapy procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunotherapy procedure, annotated with Immunotherapy (NCIT:C15262). NCIT:C15262 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunotherapy NCIT:C15262
Nivolumab, pembrolizumab, and ipilimumab provide durable responses in ccRCC. Often combined with VEGFR TKIs as first-line therapy for intermediate/poor risk metastatic disease.
Mechanism Target:
INHIBITS Immune Evasion via PD-L1 and Immunosuppressive Microenvironment — Anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA-4 (ipilimumab) antibodies block checkpoint-mediated immune evasion, restoring anti-tumor T cell responses in the highly immune-infiltrated ccRCC microenvironment. Combination with VEGFR TKIs additionally targets VEGF-mediated immunosuppression.
Show evidence (2 references)
PMID:39014460 SUPPORT Other
"The advent of PD1/PD-L1 inhibitors has significantly transformed the therapeutic landscape for clear cell renal cell carcinoma (ccRCC). This review provides an in-depth analysis of the biological functions and regulatory mechanisms of PD1 and PD-L1 in ccRCC, emphasizing their role in tumor..."
Review establishing PD-1/PD-L1 blockade as a transformative therapy for ccRCC, directly linking checkpoint inhibitor mechanism of action to tumor immune evasion in this cancer type.
PMID:37175653 SUPPORT Other
"ccRCC cells can express programmed death-ligand 1 (PD-L1), which interacts with the programmed cell death protein 1 (PD-1) receptor on T cells to inhibit their function."
Review confirming that ccRCC cells express PD-L1 to inhibit T cell function, supporting the rationale for checkpoint inhibitor therapy.
🔬

Biochemical Markers

1
HIF-2α Pathway Activation
📊

Related Datasets

4
an integrated molecular study of clear cell renal cell carcinoma (ccRCC) including whole-genome/exome and RNA sequencing as well as array-based gene expression/copy-number/methylation analyses ega:EGAS00001000509
an integrated molecular study of clear cell renal cell carcinoma (ccRCC) including whole-genome/exome and RNA sequencing as well as array-based gene expression/copy-number/methylation analyses
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Clear Cell Renal Cell Carcinoma"); description-level mentions were not accepted. EGA study_type: Cancer Genomics. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Transcriptome Sequencing (RNAseq) enables utilization of Formalin-Fixed, Paraffin-Embedded Biopsies with Clear Cell Renal Cell Carcinoma for Exploration of Disease Biology and Biomarker Development ega:EGAS00001001661
Formalin-fixed, paraffin-embedded (FFPE) tissues are an underused resource for molecular analyses. This proof of concept study aimed to compare RNAseq results from FFPE biopsies with the corresponding RNAlater® (Qiagen, Germany) stored samples from clear cell renal cell carcinoma (ccRCC) patients to investigate feasibility of RNAseq in archival tissue. From each of 16 patients undergoing partial or full nephrectomy, four core biopsies, such as two specimens with ccRCC and two specimens of adjacent normal tissue, were obtained with a 16g needle. One normal and one ccRCC tissue specimen per patient was stored either in FFPE or RNAlater®.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Clear Cell Renal Cell Carcinoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
ACSS2 Regulates HIF-2α Degradation through the E3-Ubiquitin Ligase MUL1 in Clear Cell Renal Cell Carcinoma metabolomics_workbench:ST002241
Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Clear Cell Renal Cell Carcinoma"). Retrieved 2026-08-02.
Proteomic analysis of clear cell renal cell carcinoma tissue versus matched normal kidney tissue massive:MSV000079972
We analyzed 84 tumor/normal pairs (177 total) using standard shotgun proteomic techniques in order to characterize the molecular landscape of clear cell renal cell carcinoma (ccRCC) and interrogated changes in protein abundance and biological pathways with ccRCC grade. These tissues were distributed across stage 1 (n = 34), 2 (n = 40), 3 (n = 42), and 4 (n = 52), with 9 pairs also including samples from metastasized tumor. These data can be (and were) combined with a previously published transcriptomic data set from the same sample cohort (NCBI GEO: GSE53757).
Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Clear Cell Renal Cell Carcinoma"). Retrieved 2026-08-02.
{ }

Source YAML

click to show 
name: Clear Cell Renal Cell Carcinoma
creation_date: '2026-01-26T02:55:13Z'
description: >-
  Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney
  cancer, characterized by biallelic inactivation of the VHL tumor suppressor
  gene in over 90% of cases. VHL loss stabilizes hypoxia-inducible factors (HIF-1α
  and HIF-2α), driving expression of angiogenic and growth-promoting genes including
  VEGF, PDGF, and TGF-α. This molecular understanding led to development of VEGF/VEGFR
  inhibitors and the more recent HIF-2α inhibitor belzutifan, representing a
  paradigm shift toward targeting the root cause of the disease.
categories:
- Genitourinary Cancer
- Hereditary Cancer Syndrome
parents:
- renal cell carcinoma
has_subtypes:
- name: VHL-associated ccRCC
  description: >-
    Hereditary form occurring in Von Hippel-Lindau disease patients with germline
    VHL mutations. Tumors are typically bilateral and multifocal. Patients also
    develop hemangioblastomas, pheochromocytomas, and pancreatic neuroendocrine tumors.
- name: Sporadic ccRCC
  description: >-
    Comprises 95% of ccRCC cases. Somatic VHL inactivation occurs through mutation,
    deletion, or promoter hypermethylation. Additional mutations in chromatin
    remodeling genes (PBRM1, BAP1, SETD2) affect prognosis.
pathophysiology:
- name: VHL Tumor Suppressor Inactivation
  description: >-
    Biallelic VHL loss is the initiating event in ccRCC. The VHL protein normally
    targets HIF-α subunits for ubiquitin-mediated degradation under normoxic
    conditions. Without functional VHL, HIF-α accumulates and constitutively
    activates hypoxia response genes.
  cell_types:
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  biological_processes:
  - preferred_term: cellular response to hypoxia
    modifier: INCREASED
    term:
      id: GO:0071456
      label: cellular response to hypoxia
  - preferred_term: proteasome-mediated ubiquitin-dependent protein catabolic process
    modifier: DECREASED
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  downstream:
  - target: HIF-2α Stabilization
    description: Loss of VHL-mediated degradation allows HIF-2α protein accumulation
  evidence:
  - reference: PMID:37085424
    reference_title: "Current Landscape of Genomic Biomarkers in Clear Cell Renal Cell Carcinoma."
    supports: SUPPORT
    snippet: "These include somatic gene mutations such as VHL, PBRM1, SETD2, and BAP1"
    explanation: This comprehensive review confirms VHL as the primary genomic biomarker and driver mutation in ccRCC.
- name: HIF-2α Stabilization
  conforms_to: "tumor_angiogenesis#Intratumoral Hypoxia and HIF Stabilization"
  description: >-
    Without VHL-mediated degradation, HIF-2α protein accumulates in the cytoplasm
    and translocates to the nucleus where it dimerizes with HIF-1β (ARNT) to form
    an active transcription factor. HIF-2α is the critical HIF isoform in ccRCC.
  biological_processes:
  - preferred_term: protein stabilization
    modifier: INCREASED
    term:
      id: GO:0050821
      label: protein stabilization
  downstream:
  - target: VEGF-Driven Angiogenesis
    description: HIF-2α transcriptionally activates VEGF expression
  - target: Growth Factor Pathway Activation
    description: HIF-2α induces TGF-α and cyclin D1 expression
  - target: Metabolic Reprogramming and Aerobic Glycolysis
    description: >-
      HIF stabilization induces the glycolytic gene program (GLUT1, LDHA, PDK1)
      that shifts tumor metabolism toward aerobic glycolysis
- name: VEGF-Driven Angiogenesis
  conforms_to: "tumor_angiogenesis#Angiogenic Switch and VEGF-Driven Neovascularization"
  description: >-
    HIF-2α transcriptionally activates VEGF (vascular endothelial growth factor),
    driving tumor neovascularization. The resulting hypervascular phenotype is
    characteristic of ccRCC and the basis for VEGFR-targeted therapy.
  biological_processes:
  - preferred_term: angiogenesis
    modifier: INCREASED
    term:
      id: GO:0001525
      label: angiogenesis
  - preferred_term: vascular endothelial growth factor receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0048010
      label: vascular endothelial growth factor receptor signaling pathway
- name: Growth Factor Pathway Activation
  description: >-
    HIF-2α activates transcription of growth-promoting genes including TGF-α
    (which activates EGFR signaling) and cyclin D1 (which promotes cell cycle
    progression). This drives tumor cell proliferation independent of angiogenesis.
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
- name: Metabolic Reprogramming and Aerobic Glycolysis
  conforms_to: "deregulated_cellular_energetics#Aerobic Glycolysis (Warburg Effect)"
  description: >-
    Constitutive HIF stabilization from VHL loss reprograms tumor-cell
    metabolism toward aerobic glycolysis (the Warburg effect): HIF induces the
    glucose transporter GLUT1, glycolytic enzymes, lactate dehydrogenase A, and
    PDK1, while the TCA cycle is downregulated. Carbon is diverted into the
    pentose phosphate pathway and, together with increased fatty-acid synthesis,
    into biomass. The resulting glycogen and lipid accumulation produces the
    characteristic clear (lipid-laden) cytoplasm for which the tumor is named.
  cell_types:
  - preferred_term: kidney epithelial cell
    term:
      id: CL:0002518
      label: kidney epithelial cell
  biological_processes:
  - preferred_term: glycolytic process
    modifier: INCREASED
    term:
      id: GO:0006096
      label: glycolytic process
  - preferred_term: tricarboxylic acid cycle
    modifier: DECREASED
    term:
      id: GO:0006099
      label: tricarboxylic acid cycle
  evidence:
  - reference: PMID:23792563
    reference_title: "Comprehensive molecular characterization of clear cell renal cell carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aggressive cancers demonstrated evidence of a metabolic shift, involving
      downregulation of genes involved in the TCA cycle, decreased AMPK and PTEN
      protein levels, upregulation of the pentose phosphate pathway and the
      glutamine transporter genes, increased acetyl-CoA carboxylase protein
    explanation: >-
      The TCGA molecular characterization of more than 400 ccRCC tumors documents
      a recurrent metabolic shift (TCA-cycle downregulation, pentose-phosphate-pathway
      and glutamine-transporter upregulation) that correlates with stage and
      severity, supporting aerobic-glycolysis-directed metabolic reprogramming.
  - reference: DOI:10.1186/s12967-024-04848-x
    reference_title: "Metabolic heterogeneity in clear cell renal cell carcinoma revealed by single-cell RNA sequencing and spatial transcriptomics"
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Clear cell renal cell carcinoma is a prototypical tumor characterized by
      metabolic reprogramming
    explanation: >-
      Single-cell and spatial transcriptomic metabolic profiling identifies ccRCC
      as a prototypical metabolic-reprogramming tumor, with the tumor epicenter
      showing elevated glycolysis.
- name: Epigenetic Dysregulation
  description: >-
    Secondary mutations in chromatin remodeling genes (PBRM1 in 40%, BAP1 in 15%,
    SETD2 in 15%) contribute to ccRCC progression. BAP1 mutations are associated
    with higher grade tumors and worse prognosis compared to PBRM1 mutations.
    These mutations cooperate with VHL loss to drive tumor evolution.
  biological_processes:
  - preferred_term: chromatin remodeling
    modifier: ABNORMAL
    term:
      id: GO:0006338
      label: chromatin remodeling
  downstream:
  - target: Growth Factor Pathway Activation
    description: Epigenetic changes enhance proliferative gene expression programs
  evidence:
  - reference: PMID:37085424
    reference_title: "Current Landscape of Genomic Biomarkers in Clear Cell Renal Cell Carcinoma."
    supports: SUPPORT
    snippet: "These include somatic gene mutations such as VHL, PBRM1, SETD2, and BAP1"
    explanation: This review confirms PBRM1, SETD2, and BAP1 as recurrent genomic biomarkers in ccRCC contributing to epigenetic dysregulation.
- name: Immune Evasion via PD-L1 and Immunosuppressive Microenvironment
  conforms_to: "immune_checkpoint_blockade#Adaptive Immune Resistance"
  description: >-
    ccRCC is among the most immune-infiltrated solid tumors, with abundant
    CD8+ T cells in the tumor microenvironment. However, chronic VHL-HIF
    signaling promotes an immunosuppressive milieu through VEGF-mediated
    inhibition of dendritic cell maturation, PD-L1 upregulation on tumor
    cells, and recruitment of regulatory T cells and myeloid-derived
    suppressor cells. This inherent immunogenicity combined with adaptive
    immune resistance provides the rationale for checkpoint inhibitor therapy.
  cell_types:
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: Negative Regulation of T Cell Mediated Immunity
    term:
      id: GO:0002710
      label: negative regulation of T cell mediated immunity
    modifier: INCREASED
  evidence:
  - reference: PMID:38762484
    reference_title: "Regulatory mechanisms of PD-1/PD-L1 in cancers."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The interaction of PD-1 and PD-L1 negatively regulates adaptive
      immune response mainly by inhibiting the activity of effector T cells
      while enhancing the function of immunosuppressive regulatory T cells
      (Tregs), largely contributing to the maintenance of immune homeostasis
      that prevents dysregulated immunity and harmful immune responses.
      However, cancer cells exploit the PD-1/PD-L1 axis to cause immune
      escape in cancer development and progression.
    explanation: >-
      Review describing how tumors including ccRCC exploit PD-1/PD-L1
      signaling to suppress anti-tumor immunity, relevant to the highly
      immune-infiltrated ccRCC microenvironment.
- name: VSP Inhibitor Blockade of Systemic Endothelial VEGF Signaling
  description: >-
    The therapy-emergent arm of this entry, and the mirror image of the tumor
    arm above. The VEGFR tyrosine kinase inhibitors used to treat ccRCC do not
    act only on tumor endothelium: they silence the same VEGFA-VEGFR2 signal in
    the systemic vasculature, where it is a tonic homeostatic input rather than
    a tumor-driven one. Because the ccRCC angiogenic phenotype is the reason the
    drug class is used here, this vascular toxicity is on-target and inseparable
    from the therapeutic effect, not an idiosyncratic reaction. Curated in ccRCC
    specifically because ccRCC is where the pivotal clinical data on this
    toxicity were generated.
  role: trigger
  biological_scale: MOLECULAR
  conforms_to: "vegf_inhibitor_hypertension#VEGF Signaling Pathway Inhibition"
  cell_types:
  - preferred_term: vascular endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: vascular endothelial growth factor receptor signaling pathway
    term:
      id: GO:0048010
      label: vascular endothelial growth factor receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:21527770
    reference_title: "Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertension (HTN) is an on-target effect of the vascular endothelial
      growth factor pathway inhibitor, sunitinib.
    explanation: >-
      States in the renal-cell-carcinoma setting that the blood-pressure effect
      of sunitinib is on-target VEGF pathway inhibition, which is exactly what
      this trigger node asserts for the ccRCC treatment context.
  - reference: PMID:36621810
    reference_title: "Cancer Therapy-Related Hypertension: A Scientific Statement From the American Heart Association."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      One of the most common side effects of these drugs is hypertension,
      especially in patients treated with vascular endothelial growth factor
      inhibitors, as well as tyrosine kinase inhibitors and proteasome
      inhibitors.
    explanation: >-
      Establishes VEGF pathway inhibition as the leading anticancer-drug route
      to hypertension, generalizing the ccRCC observation to the drug class.
      Evidence source is OTHER because this is a scientific statement / review.
  downstream:
  - target: Treatment-Emergent Vasoconstriction and Increased Peripheral Vascular Resistance
    description: >-
      Withdrawal of endothelial VEGF signalling lowers nitric oxide, activates
      the endothelin system, and rarefies the microvasculature, which together
      raise peripheral resistance.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - endothelial nitric oxide deficiency with oxidative stress
    - endothelin-1 system activation
    - microvascular rarefaction
- name: Treatment-Emergent Vasoconstriction and Increased Peripheral Vascular Resistance
  description: >-
    The convergence step for VEGFR-TKI-induced hypertension in ccRCC: reduced
    endothelial nitric oxide, endothelin-1 system activation, and microvascular
    rarefaction shift the peripheral circulation toward constriction and raise
    total peripheral vascular resistance. Which of those three arms is
    rate-limiting is unsettled, so this entry deliberately funnels through the
    convergence node rather than asserting one arm — see the
    vegf_inhibitor_hypertension module's KNOWLEDGE_GAP discussion.
  role: central_effector
  biological_scale: TISSUE
  conforms_to: "vegf_inhibitor_hypertension#Vasoconstriction and Increased Peripheral Vascular Resistance"
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  - preferred_term: vascular endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  locations:
  - preferred_term: blood vessel
    term:
      id: UBERON:0001981
      label: blood vessel
  biological_processes:
  - preferred_term: vasoconstriction
    term:
      id: GO:0042310
      label: vasoconstriction
    modifier: INCREASED
  - preferred_term: blood vessel diameter maintenance
    term:
      id: GO:0097746
      label: blood vessel diameter maintenance
    modifier: DECREASED
  evidence:
  - reference: PMID:29931399
    reference_title: "Tyrosine Kinase Inhibitor-Induced Hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mechanism of action involves VSP inhibition, leading to decreased
      nitric oxide and increased endothelin production, which causes
      vasoconstriction, capillary rarefaction, and hypertension.
    explanation: >-
      Places vasoconstriction between the mediator changes and the clinical
      blood-pressure rise, which is the convergence claim of this node.
      Evidence source is OTHER because this is a review article.
  downstream:
  - target: Treatment-Emergent Hypertension
    description: >-
      Sustained elevation of peripheral vascular resistance raises systemic
      arterial blood pressure during VEGFR TKI therapy.
histopathology:
- name: Clear Cell Renal Cell Carcinoma
  finding_term:
    preferred_term: Clear Cell Renal Cell Carcinoma
    term:
      id: NCIT:C4033
      label: Clear Cell Renal Cell Carcinoma
  frequency: VERY_FREQUENT
  description: Clear cell RCC is the most common histologic subtype of renal cell carcinoma.
  evidence:
  - reference: PMID:39196544
    reference_title: "Renal Cell Carcinoma: A Review."
    supports: SUPPORT
    snippet: "Clear cell RCC is the most common histologic subtype"
    explanation: Abstract reports clear cell RCC as the most common histologic subtype.
- name: Sarcomatoid Differentiation
  finding_term:
    preferred_term: Sarcomatoid Differentiation
    term:
      id: NCIT:C39694
      label: Sarcomatoid Features
  frequency: OCCASIONAL
  description: >-
    Sarcomatoid (spindle-cell) dedifferentiation represents high-grade
    transformation of ccRCC and portends a markedly worse prognosis.
  evidence:
  - reference: PMID:11224597
    reference_title: "Sarcomatoid differentiation in renal cell carcinoma: a study of 101 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sarcomatoid differentiation was 8% in conventional (clear cell) renal carcinoma"
    explanation: >-
      The series reports an 8% incidence of sarcomatoid differentiation in
      conventional (clear cell) renal carcinoma, establishing it as a recognized
      ccRCC morphologic feature.
- name: Coagulative Tumor Necrosis
  finding_term:
    preferred_term: Coagulative Tumor Necrosis
    term:
      id: NCIT:C39608
      label: Coagulative Necrosis
  frequency: FREQUENT
  description: >-
    Coagulative (ischemic) tumor necrosis is an independent adverse prognostic
    feature in ccRCC and is routinely reported in surgical pathology.
  evidence:
  - reference: PMID:17594714
    reference_title: "Ki-67 and coagulative tumor necrosis are independent predictors of poor outcome for patients with clear cell renal cell carcinoma and not surrogates for each other."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prognostic information conveyed by Ki-67 and coagulative tumor"
    explanation: >-
      The study identifies coagulative tumor necrosis as carrying independent
      prognostic information in ccRCC, supporting it as a reported histopathologic
      finding.
- name: Fuhrman Nuclear Grade
  finding_term:
    preferred_term: Fuhrman Nuclear Grade
    term:
      id: NCIT:C62411
      label: Fuhrman Nuclear Grade
  frequency: VERY_FREQUENT
  description: >-
    Fuhrman nuclear grading (based on nuclear size, nucleolar prominence, and
    membrane irregularity) is an established independent prognostic grading
    system applied to ccRCC specimens.
  evidence:
  - reference: PMID:20804473
    reference_title: "Application of simplified Fuhrman grading system in clear-cell renal cell carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A modified, three-tiered Fuhrman grading system can be considered an"
    explanation: >-
      The study applies a modified Fuhrman nuclear grading system to clear-cell
      RCC for prognostication, supporting Fuhrman nuclear grade as a standard
      ccRCC grading finding.

phenotypes:
- category: Genitourinary
  name: Renal Mass
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    ccRCC typically presents as a solid renal mass, often discovered incidentally
    on imaging. Classic triad of flank pain, hematuria, and palpable mass occurs
    in minority of cases.
  phenotype_term:
    preferred_term: Renal neoplasm
    term:
      id: HP:0009726
      label: Renal neoplasm
- category: Cardiovascular
  name: Treatment-Emergent Hypertension
  frequency: VERY_FREQUENT
  description: >-
    New or worsened systemic arterial hypertension emerging during VEGFR
    tyrosine kinase inhibitor therapy. This is a therapy-emergent manifestation,
    not a feature of untreated ccRCC, and it is usually reversible on
    interruption of the culprit drug. In the pooled sunitinib mRCC trial
    database (>98% clear cell histology) 614 of 770 patients (80%) met a
    systolic threshold for on-treatment hypertension, though that figure uses a
    blood-pressure cut-off rather than CTCAE grading and so runs higher than
    trial-reported adverse-event rates.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:26492223
    reference_title: "Sunitinib-associated hypertension and neutropenia as efficacy biomarkers in metastatic renal cell carcinoma patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the 770 patients included in the analyses, 614 (80%), 365 (47%),
      172 (22%), 179 (23%), and 583 (76%) experienced on-treatment SBP-defined
      hypertension, neutropenia (grade ⩾2), thrombocytopenia (grade ⩾2),
      hand-foot syndrome (grade >0), and asthenia/fatigue (grade >0),
      respectively.
    explanation: >-
      Quantifies on-treatment hypertension in a pooled sunitinib mRCC cohort
      that is >98% clear cell, supporting the VERY_FREQUENT frequency assigned
      here.
  - reference: PMID:36621810
    reference_title: "Cancer Therapy-Related Hypertension: A Scientific Statement From the American Heart Association."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cancer therapy-induced hypertension is often dose limiting, increases
      cardiovascular mortality in cancer survivors, and is usually reversible
      after interruption or discontinuation of treatment.
    explanation: >-
      Supports the dose-limiting significance and the reversibility on drug
      withdrawal described for this phenotype. Evidence source is OTHER because
      this is a scientific statement / review.
- category: Genitourinary
  name: Hematuria
  frequency: FREQUENT
  description: >-
    Gross or microscopic hematuria occurs when tumor invades the collecting system.
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
- category: Constitutional
  name: Fatigue
  frequency: FREQUENT
  description: >-
    Fatigue is common and may be related to paraneoplastic syndromes or
    advanced disease.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- category: Constitutional
  name: Weight Loss
  frequency: OCCASIONAL
  description: >-
    Unintentional weight loss may occur with metastatic disease.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
- category: Systemic
  name: Metastatic Disease
  frequency: FREQUENT
  description: >-
    ccRCC commonly metastasizes to lung, bone, liver, and brain. Metastases
    are often highly vascular and may be hypervascular on imaging.
  phenotype_term:
    preferred_term: Neoplasm
    term:
      id: HP:0002664
      label: Neoplasm
  evidence:
  - reference: PMID:39196544
    reference_title: "Renal Cell Carcinoma: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seventy percent of patients are diagnosed with stage I RCC and 11% of patients with stage IV."
    explanation: A subset of RCC patients (11%) present with stage IV (metastatic) disease.
biochemical:
- name: HIF-2α Pathway Activation
  notes: >-
    VHL loss leads to constitutive HIF-2α stabilization and activation of
    downstream targets including VEGF, PDGF, TGF-α, and cyclin D1.
genetic:
- name: VHL
  gene_term:
    preferred_term: VHL
    term:
      id: hgnc:12687
      label: VHL
  association: Germline and Somatic Inactivating Mutations
  inheritance:
  - name: Autosomal Dominant
  notes: >-
    VHL (3p25.3) is inactivated in over 90% of ccRCC through mutation, deletion,
    or promoter methylation. Germline VHL mutations cause Von Hippel-Lindau
    disease with increased ccRCC risk. Somatic VHL loss is the initiating
    event in sporadic ccRCC.
  evidence:
  - reference: PMID:23792563
    reference_title: "Comprehensive molecular characterization of clear cell renal cell carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1)."
    explanation: The TCGA molecular characterization identifies VHL (cellular oxygen sensing) as a core altered gene underlying ccRCC.
- name: PBRM1
  gene_term:
    preferred_term: PBRM1
    term:
      id: hgnc:30064
      label: PBRM1
  association: Somatic Inactivating Mutations
  notes: >-
    PBRM1 (chromatin remodeling SWI/SNF complex) mutations occur in 40% of
    ccRCC. Associated with better prognosis compared to BAP1 mutations.
  evidence:
  - reference: PMID:23792563
    reference_title: "Comprehensive molecular characterization of clear cell renal cell carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways"
    explanation: The TCGA analysis identifies PBRM1 as part of the recurrently mutated SWI/SNF chromatin-remodelling complex in ccRCC.
- name: BAP1
  gene_term:
    preferred_term: BAP1
    term:
      id: hgnc:950
      label: BAP1
  association: Somatic Inactivating Mutations
  notes: >-
    BAP1 (deubiquitinase) mutations occur in 15% of ccRCC. Associated with
    higher grade tumors and worse prognosis. Mutually exclusive with PBRM1.
  evidence:
  - reference: PMID:37085424
    reference_title: "Current Landscape of Genomic Biomarkers in Clear Cell Renal Cell Carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These include somatic gene mutations such as VHL, PBRM1, SETD2, and BAP1"
    explanation: BAP1 is recognized among the recurrent somatic driver-gene mutations and candidate genomic biomarkers in ccRCC.
treatments:
- name: Nephrectomy
  description: >-
    Surgical resection (partial or radical nephrectomy) is the primary
    treatment for localized ccRCC. Cytoreductive nephrectomy may benefit
    selected patients with metastatic disease.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:39196544
    reference_title: "Renal Cell Carcinoma: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment options for RCC confined to the kidney include surgical resection with partial or radical nephrectomy"
    explanation: Partial or radical nephrectomy is a primary treatment for kidney-confined RCC.
- name: VEGFR Tyrosine Kinase Inhibitors
  target_mechanisms:
  - target: VEGF-Driven Angiogenesis
    treatment_effect: INHIBITS
    description: VEGFR tyrosine kinase inhibitors (e.g., sunitinib, pazopanib, cabozantinib, axitinib) block VEGFR signaling on tumor endothelium, inhibiting the VEGF-driven angiogenic switch that supplies the hypervascular ccRCC.
  - target: VSP Inhibitor Blockade of Systemic Endothelial VEGF Signaling
    treatment_effect: ACTIVATES
    description: >-
      The same drugs silence VEGFA-VEGFR2 signalling in the systemic
      vasculature, initiating the on-target hypertension arm. This edge is
      ACTIVATES rather than INHIBITS because the treatment brings the node into
      being; it is the price of the therapeutic effect on the edge above, and it
      cannot be avoided by reversing it without also abolishing the antitumor
      action.
    evidence:
    - reference: PMID:21527770
      reference_title: "Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hypertension (HTN) is an on-target effect of the vascular endothelial
        growth factor pathway inhibitor, sunitinib.
      explanation: >-
        Attributes the hypertension arm to the sunitinib mechanism itself in
        renal cell carcinoma, supporting this treatment-to-toxicity edge.
  description: >-
    Sunitinib, pazopanib, axitinib, and cabozantinib target VEGFR and other
    kinases to block HIF-driven angiogenesis. First-line options for
    metastatic ccRCC, often combined with immunotherapy.
  evidence:
  - reference: PMID:39196544
    reference_title: "Renal Cell Carcinoma: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For advanced or metastatic RCC, combinations of immune checkpoint inhibitors or the combination of immune checkpoint inhibitors with tyrosine kinase inhibitors are associated with tumor response of 42% to 71%"
    explanation: Tyrosine kinase inhibitors, combined with immune checkpoint inhibitors, are a standard systemic option for advanced/metastatic RCC.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sunitinib
      term:
        id: CHEBI:38940
        label: sunitinib
    - preferred_term: pazopanib
      term:
        id: CHEBI:71219
        label: pazopanib
    - preferred_term: axitinib
      term:
        id: CHEBI:66910
        label: axitinib
    - preferred_term: cabozantinib
      term:
        id: CHEBI:72317
        label: cabozantinib
- name: Belzutifan
  target_mechanisms:
  - target: HIF-2α Stabilization
    treatment_effect: INHIBITS
    description: Belzutifan is a HIF-2alpha inhibitor that blocks the stabilized HIF-2alpha transcription factor upstream of VEGF, shutting down the pro-angiogenic transcriptional program at its source.
  description: >-
    First-in-class HIF-2α inhibitor that directly targets the driver of
    ccRCC pathogenesis. Approved for VHL-associated ccRCC and showing
    promise in sporadic ccRCC. Represents mechanism-based targeted therapy.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: belzutifan
      term:
        id: NCIT:C135627
        label: Belzutifan
- name: Immune Checkpoint Inhibitors
  description: >-
    Nivolumab, pembrolizumab, and ipilimumab provide durable responses
    in ccRCC. Often combined with VEGFR TKIs as first-line therapy for
    intermediate/poor risk metastatic disease.
  treatment_term:
    preferred_term: immunotherapy procedure
    term:
      id: NCIT:C15262
      label: Immunotherapy
  target_mechanisms:
  - target: Immune Evasion via PD-L1 and Immunosuppressive Microenvironment
    treatment_effect: INHIBITS
    description: >-
      Anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA-4 (ipilimumab) antibodies
      block checkpoint-mediated immune evasion, restoring anti-tumor T cell responses
      in the highly immune-infiltrated ccRCC microenvironment. Combination with VEGFR
      TKIs additionally targets VEGF-mediated immunosuppression.
    evidence:
    - reference: PMID:39014460
      reference_title: "PD1/PD-L1 blockade in clear cell renal cell carcinoma: mechanistic insights, clinical efficacy, and future perspectives."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The advent of PD1/PD-L1 inhibitors has significantly transformed the
        therapeutic landscape for clear cell renal cell carcinoma (ccRCC).
        This review provides an in-depth analysis of the biological functions
        and regulatory mechanisms of PD1 and PD-L1 in ccRCC, emphasizing
        their role in tumor immune evasion.
      explanation: >-
        Review establishing PD-1/PD-L1 blockade as a transformative therapy
        for ccRCC, directly linking checkpoint inhibitor mechanism of action
        to tumor immune evasion in this cancer type.
    - reference: PMID:37175653
      reference_title: "The Tumor Immune Microenvironment in Clear Cell Renal Cell Carcinoma."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        ccRCC cells can express programmed death-ligand 1 (PD-L1), which
        interacts with the programmed cell death protein 1 (PD-1) receptor
        on T cells to inhibit their function.
      explanation: >-
        Review confirming that ccRCC cells express PD-L1 to inhibit T cell
        function, supporting the rationale for checkpoint inhibitor therapy.
discussions:
- discussion_id: ccrcc_vegfr_tki_hypertension_as_efficacy_biomarker
  prompt: >-
    Should on-treatment hypertension be used to guide VEGFR TKI dosing in
    metastatic ccRCC — titrating dose upward until blood pressure rises — or
    does it only index drug exposure retrospectively?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Treatment-Emergent Vasoconstriction and Increased Peripheral Vascular Resistance
  - phenotypes#Treatment-Emergent Hypertension
  - treatments#VEGFR Tyrosine Kinase Inhibitors
  rationale: >-
    ccRCC is where this question is decided, because the pivotal data are in
    sunitinib-treated mRCC rather than in the drug class at large. Two
    independent analyses of the pooled sunitinib trial database associate
    on-treatment hypertension with markedly better response, progression-free
    survival, and overall survival, and the association survives adjustment for
    baseline IMDC risk. That is a strong pharmacodynamic signal: because the
    toxicity is on-target, a blood-pressure rise plausibly reports how much VEGF
    pathway inhibition a given patient actually achieved.
    It is nonetheless recorded here as an open question, not as an established
    prognostic or dosing rule, for two reasons. First, both analyses are
    retrospective analyses of the same pooled database, so they are not
    independent replications; the time-dependent-covariate and landmark analyses
    address immortal-time bias but do not make the design prospective. Second,
    an association between a toxicity and a good outcome does not license the
    inverse intervention — no trial has shown that deliberately dose-escalating
    to a blood-pressure target improves survival, and treating the absence of
    hypertension as undertreatment would be a clinically consequential
    inference drawn from an observational correlation. Curating this as settled
    would license exactly that inference.
    This is the ccRCC-specific instance of the module-level open question
    recorded as vegfi_hypertension_as_efficacy_biomarker in
    kb/modules/vegf_inhibitor_hypertension.yaml.
  evidence:
  - reference: PMID:21527770
    reference_title: "Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with metastatic renal cell carcinoma, sunitinib-associated HTN
      is associated with improved clinical outcomes without clinically
      significant increases in HTN-associated adverse events, supporting its
      viability as an efficacy biomarker.
    explanation: >-
      The primary source of the biomarker claim in ccRCC. Note its own wording
      is "supporting its viability as", i.e. a candidate biomarker, which is why
      this is curated as an open question rather than as established practice.
  - reference: PMID:21527770
    reference_title: "Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This retrospective analysis included pooled efficacy (n = 544) and safety
      (n = 4917) data from four studies of patients with metastatic renal cell
      carcinoma who were treated with sunitinib 50 mg/d
    explanation: >-
      Documents the retrospective, pooled-database design that limits how far
      the association can be pushed toward a dosing rule; supports the caveat
      rather than the claim.
  - reference: PMID:26492223
    reference_title: "Sunitinib-associated hypertension and neutropenia as efficacy biomarkers in metastatic renal cell carcinoma patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On-treatment neutropenia and hypertension are independent biomarkers of
      sunitinib efficacy and may add prognostic accuracy to the IMDC model.
    explanation: >-
      Shows the association holds independently of baseline IMDC risk
      stratification, which is the strongest version of the claim; it is drawn
      from the same pooled database, so it strengthens but does not
      independently replicate the finding.
disease_term:
  preferred_term: clear cell renal cell carcinoma
  term:
    id: MONDO:0005005
    label: clear cell renal carcinoma

classifications:
  icdo_morphology:
    classification_value: Carcinoma
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
references:
- reference: DOI:10.1007/s12672-024-01175-x
  title: A novel cancer-associated fibroblast signature for kidney renal clear cell carcinoma via integrated analysis of single-cell and bulk RNA-sequencing
  findings: []
- reference: DOI:10.1016/j.eururo.2023.04.003
  title: Current Landscape of Genomic Biomarkers in Clear Cell Renal Cell Carcinoma
  findings: []
- reference: DOI:10.1038/s41581-023-00800-2
  title: Metabolic alterations in hereditary and sporadic renal cell carcinoma
  findings: []
- reference: DOI:10.1038/s42003-024-06478-x
  title: Single-cell transcriptional profiling of clear cell renal cell carcinoma reveals a tumor-associated endothelial tip cell phenotype
  findings: []
- reference: DOI:10.1158/1078-0432.ccr-23-3029
  title: A First-in-Human Phase 1 Study of a Tumor-Directed RNA-Interference Drug against HIF2α in Patients with Advanced Clear Cell Renal Cell Carcinoma
  findings: []
- reference: DOI:10.1186/s12967-024-04848-x
  title: Metabolic heterogeneity in clear cell renal cell carcinoma revealed by single-cell RNA sequencing and spatial transcriptomics
  findings: []
- reference: DOI:10.3389/fgene.2023.1207233
  title: Mapping the tumor microenvironment in clear cell renal carcinoma by single-cell transcriptome analysis
  findings: []
- reference: DOI:10.3390/curroncol30100670
  title: Genomic Profiling and Molecular Characterization of Clear Cell Renal Cell Carcinoma
  findings: []
- reference: DOI:10.3390/ijms25126730
  title: The Role of the PAX Genes in Renal Cell Carcinoma
  findings: []
- reference: DOI:10.3390/ijms26010265
  title: Innovative Therapies Targeting Drug-Resistant Biomarkers in Metastatic Clear Cell Renal Cell Carcinoma (ccRCC)
  findings: []
datasets:
- accession: ega:EGAS00001000509
  title: an integrated molecular study of clear cell renal cell carcinoma (ccRCC) including whole-genome/exome and RNA sequencing as well as array-based gene expression/copy-number/methylation analyses
  description: an integrated molecular study of clear cell renal cell carcinoma (ccRCC) including whole-genome/exome and RNA sequencing as well as array-based gene expression/copy-number/methylation analyses
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Clear Cell Renal Cell Carcinoma"); description-level mentions were not accepted. EGA study_type: Cancer Genomics. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001001661
  title: Transcriptome Sequencing (RNAseq) enables utilization of Formalin-Fixed, Paraffin-Embedded Biopsies with Clear Cell Renal Cell Carcinoma for Exploration of Disease Biology and Biomarker Development
  description: Formalin-fixed, paraffin-embedded (FFPE) tissues are an underused resource for molecular analyses. This proof of concept study aimed to compare RNAseq results from FFPE biopsies with the corresponding RNAlater® (Qiagen, Germany) stored samples from clear cell renal cell carcinoma (ccRCC) patients to investigate feasibility of RNAseq in archival tissue. From each of 16 patients undergoing partial or full nephrectomy, four core biopsies, such as two specimens with ccRCC and two specimens of adjacent normal tissue, were obtained with a 16g needle. One normal and one ccRCC tissue specimen per patient was stored either in FFPE or RNAlater®.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Clear Cell Renal Cell Carcinoma"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: metabolomics_workbench:ST002241
  title: ACSS2 Regulates HIF-2α Degradation through the E3-Ubiquitin Ligase MUL1 in Clear Cell Renal Cell Carcinoma
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Clear Cell Renal Cell Carcinoma"). Retrieved 2026-08-02.
- accession: massive:MSV000079972
  title: Proteomic analysis of clear cell renal cell carcinoma tissue versus matched normal kidney tissue
  description: 'We analyzed 84 tumor/normal pairs (177 total) using standard shotgun proteomic techniques in order to characterize the molecular landscape of clear cell renal cell carcinoma (ccRCC) and interrogated changes in protein abundance and biological pathways with ccRCC grade. These tissues were distributed across stage 1 (n = 34), 2 (n = 40), 3 (n = 42), and 4 (n = 52), with 9 pairs also including samples from metastasized tumor. These data can be (and were) combined with a previously published transcriptomic data set from the same sample cohort (NCBI GEO: GSE53757).'
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Clear Cell Renal Cell Carcinoma"). Retrieved 2026-08-02.
📚

References & Deep Research

References

10
DOI:10.1007/s12672-024-01175-x
A novel cancer-associated fibroblast signature for kidney renal clear cell carcinoma via integrated analysis of single-cell and bulk RNA-sequencing
No top-level findings curated for this source.
DOI:10.1016/j.eururo.2023.04.003
Current Landscape of Genomic Biomarkers in Clear Cell Renal Cell Carcinoma
No top-level findings curated for this source.
DOI:10.1038/s41581-023-00800-2
Metabolic alterations in hereditary and sporadic renal cell carcinoma
No top-level findings curated for this source.
DOI:10.1038/s42003-024-06478-x
Single-cell transcriptional profiling of clear cell renal cell carcinoma reveals a tumor-associated endothelial tip cell phenotype
No top-level findings curated for this source.
DOI:10.1158/1078-0432.ccr-23-3029
A First-in-Human Phase 1 Study of a Tumor-Directed RNA-Interference Drug against HIF2α in Patients with Advanced Clear Cell Renal Cell Carcinoma
No top-level findings curated for this source.
DOI:10.1186/s12967-024-04848-x
Metabolic heterogeneity in clear cell renal cell carcinoma revealed by single-cell RNA sequencing and spatial transcriptomics
No top-level findings curated for this source.
DOI:10.3389/fgene.2023.1207233
Mapping the tumor microenvironment in clear cell renal carcinoma by single-cell transcriptome analysis
No top-level findings curated for this source.
DOI:10.3390/curroncol30100670
Genomic Profiling and Molecular Characterization of Clear Cell Renal Cell Carcinoma
No top-level findings curated for this source.
DOI:10.3390/ijms25126730
The Role of the PAX Genes in Renal Cell Carcinoma
No top-level findings curated for this source.
DOI:10.3390/ijms26010265
Innovative Therapies Targeting Drug-Resistant Biomarkers in Metastatic Clear Cell Renal Cell Carcinoma (ccRCC)
No top-level findings curated for this source.

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Disorder ▸

Disorder

  • Name: Clear Cell Renal Cell Carcinoma
  • Category:
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 13

Key Pathophysiology Nodes

  • VHL Tumor Suppressor Inactivation
  • HIF-2α Stabilization
  • VEGF-Driven Angiogenesis
  • Growth Factor Pathway Activation
  • Epigenetic Dysregulation
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1007/s12672-024-01175-x
  • DOI:10.1016/j.ccr-23-3029
  • DOI:10.1016/j.eururo.2023.04.003
  • DOI:10.1038/s41581-023-00800-2
  • DOI:10.1038/s42003-024-06478-x
  • DOI:10.1158/1078-0432.ccr-23-3029
  • DOI:10.1186/s12967-024-04848-x
  • DOI:10.3389/fgene.2023.1207233
  • DOI:10.3390/curroncol30100670
  • DOI:10.3390/ijms25126730
  • DOI:10.3390/ijms26010265
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 24 citations 2026-01-24T13:37:38.901613

Disease Pathophysiology Research Report

Target Disease - Disease Name: Clear Cell Renal Cell Carcinoma (ccRCC) - MONDO ID: - Category: Malignant neoplasm of kidney, epithelial; clear cell subtype

Pathophysiology description (narrative) Clear cell renal cell carcinoma is driven in the vast majority of cases by loss of the VHL tumor suppressor on chromosome 3p, which prevents pVHL-mediated ubiquitination and proteasomal degradation of HIF-1α and HIF-2α. Stabilized HIFs drive transcriptional programs for angiogenesis (VEGF/PDGF), erythropoiesis (EPO), pH regulation (CA9), glucose metabolism, and cell survival, producing a highly vascular and immunomodulatory tumor microenvironment. HIF-2α (EPAS1) is the predominant oncogenic driver in VHL-deficient ccRCC and has become a direct therapeutic target. Early truncal 3p loss co-deletes or predisposes to loss-of-function mutations in chromatin remodeling/tumor suppressor genes PBRM1, SETD2, and BAP1, which reshape chromatin, RNA processing, DNA repair, and immune–metabolic states to promote progression and metastatic competence (cotta2023currentlandscapeof pages 3-4, liu2025clinicalsignificanceof pages 18-22, liu2025clinicalsignificanceof pages 61-64).

A defining feature of ccRCC is metabolic reprogramming that supports growth in hypoxia and contributes to immune evasion. This includes a Warburg-like shift to aerobic glycolysis with suppressed mitochondrial oxidative metabolism and reduced mitochondrial biogenesis; enhanced glutamine utilization for anaplerosis and biosynthesis; and lipid/cholesterol accumulation with abundant lipid droplets. These changes are closely linked to HIF signaling and other nutrient-sensing pathways (for example, mTOR) and produce therapeutic opportunities in metabolism. RCC overall has been termed a metabolic disease, with pathogenesis tied to oxygen- and nutrient-sensing pathways and TCA-cycle enzymes; although some of these alterations are most characteristic of non-clear cell subtypes, the paradigm of metabolic rewiring is central in ccRCC (coffey2024metabolicalterationsin pages 1-3, cotta2023currentlandscapeof pages 3-4, pezzicoli2023genomicprofilingand pages 8-10).

The tumor microenvironment of ccRCC is highly vascular, hypoxic, and immune-infiltrated, with enrichment of immunosuppressive myeloid populations and exhausted T-cell states. Hypoxia-induced signaling and alternative angiogenic pathways contribute to resistance to VEGF-directed therapy, while immune checkpoints (PD-1/PD-L1, CTLA-4) are associated with poor prognosis. Single-cell and transcriptomic studies (summarized in recent reviews) link specific metastatic or resistant tumor states with distinct immune compositions, supporting personalized combinations of VEGF-TKIs and ICIs (abah2024innovativetherapiestargeting pages 2-4, pezzicoli2023genomicprofilingand pages 8-10).

Translationally, direct blockade of HIF-2α is now a validated strategy. In a first-in-human study of a tumor-targeted siRNA against HIF-2α (ARO-HIF2), objective response rate was 7.7% with disease control in 38.5%; on-target pharmacodynamic effects included variable HIF-2α downregulation in biopsies and rapid suppression of tumor-produced EPO in a patient with paraneoplastic polycythemia, although neurotoxicity limited further development (Clinical Cancer Research, 2024; doi:10.1158/1078-0432.ccr-23-3029) (liu2025clinicalsignificanceof pages 18-22). Together with evidence of HIF-2α oncogenic primacy, these data underpin the clinical development and deployment of HIF-2α–targeted agents and rational combinations in ccRCC (liu2025clinicalsignificanceof pages 18-22, cotta2023currentlandscapeof pages 3-4).

Recent developments and latest research (prioritized 2023–2024) - Genomic landscape and prognostic associations: VHL is the most frequently mutated gene (≈49–82% across cohorts), with common recurrent mutations in PBRM1 (≈29–41%), SETD2 (≈8–30%), BAP1 (≈6–19%), and KDM5C (≈4–15%). BAP1-mutant tumors have markedly worse outcomes (for example, OS ≈4.6 years for BAP1-mutant vs ≈10.6 years for PBRM1-mutant tumors), while PBRM1 alterations show signals for benefit with PD-1 blockade (e.g., enrichment among nivolumab responders and improved outcomes in CheckMate 025 exploratory analyses) (European Urology, 2023; doi:10.1016/j.eururo.2023.04.003) (cotta2023currentlandscapeof pages 3-4). - Copy-number landscape: Near-universal loss of 3p (~95%), with additional frequent events including 5q gain (~69%), 14q loss (>42%), 9p loss (~29%), 8p deletion (~32%), and 7q gains (>20%); these alterations correlate with aggressiveness and therapeutic resistance mechanisms (Int J Mol Sci, 2024; doi:10.3390/ijms26010265) (abah2024innovativetherapiestargeting pages 2-4). - Tumor mutational burden (TMB) and ICI response: ccRCC has low average TMB (~1.1 mutations/Mb) yet responds to ICIs, possibly due to frameshift indels increasing neoantigenicity; higher TMB in a subset can associate with improved survival on ICI-based therapy (Current Oncology, 2023; doi:10.3390/curroncol30100670) (pezzicoli2023genomicprofilingand pages 8-10). - Metabolic reprogramming and therapeutic implications: Authoritative synthesis in 2024 (Nature Reviews Nephrology; doi:10.1038/s41581-023-00800-2) details glycolytic shift, suppressed glucose oxidation, mitochondrial downregulation, glutamine dependency, and lipid/cholesterol remodeling in RCC, supporting trials of metabolic agents and combinations (coffey2024metabolicalterationsin pages 1-3). - HIF-2α targeting: Proof-of-concept siRNA study (ARO-HIF2) in 2024 demonstrated tumor-targeted HIF-2α downregulation with on-target effects, an ORR of 7.7%, and DCR of 38.5% in heavily pre-treated ccRCC (Clinical Cancer Research, Apr 2024; doi:10.1158/1078-0432.ccr-23-3029) (liu2025clinicalsignificanceof pages 18-22).

Current applications and real-world implementations - VEGF-TKIs and ICIs remain standard backbones; genomic features such as PBRM1, BAP1, and SETD2 status influence prognosis and may modulate ICI benefit signals, though no single gene is yet an established predictive biomarker in routine care (European Urology, 2023; doi:10.1016/j.eururo.2023.04.003) (cotta2023currentlandscapeof pages 3-4). - HIF-2α inhibition strategies are clinically actionable in VHL-driven disease and under investigation in sporadic ccRCC. Tumor-directed HIF-2α siRNA demonstrated biological activity, providing mechanistic validation for HIF-2α as a target and a reference for safety/PD considerations in ongoing trials of small-molecule HIF-2α inhibitors and combinations (Clinical Cancer Research, 2024; doi:10.1158/1078-0432.ccr-23-3029) (liu2025clinicalsignificanceof pages 18-22).

Expert opinions and authoritative analyses - European Urology 2023 scoping review: genomic biomarkers in ccRCC—emphasizes VHL as foundational, recurrent chromatin-modifying genes (PBRM1/SETD2/BAP1) as key modulators with prognostic value, and the complexity of identifying robust predictive biomarkers; highlights exploratory associations with ICI responsiveness (doi:10.1016/j.eururo.2023.04.003) (cotta2023currentlandscapeof pages 3-4). - Nature Reviews Nephrology 2024: positions RCC as a metabolic disease and synthesizes oxygen- and nutrient-sensing pathways with TCA-cycle derangements and systemic metabolic states, framing a roadmap for translational metabolism-focused therapies (doi:10.1038/s41581-023-00800-2) (coffey2024metabolicalterationsin pages 1-3).

Relevant statistics and data from recent studies - Mutation frequencies: VHL 49–82%; PBRM1 29–41%; SETD2 8–30%; BAP1 6–19%; KDM5C 4–15% (European Urology, 2023; doi:10.1016/j.eururo.2023.04.003) (cotta2023currentlandscapeof pages 3-4). - Prognostic impact: BAP1 mutations associated with substantially worse OS (≈4.6 years) compared with PBRM1-mutated tumors (≈10.6 years); hazard ratios for cancer-specific survival elevated in BAP1-mutant cohorts (European Urology, 2023; doi:10.1016/j.eururo.2023.04.003) (cotta2023currentlandscapeof pages 3-4). - Copy-number alterations: loss 3p ~95%, gain 5q ~69%, loss 14q >42%, loss 9p ~29%, del 8p ~32%, gains 7q >20% (Int J Mol Sci, 2024; doi:10.3390/ijms26010265) (abah2024innovativetherapiestargeting pages 2-4). - TMB: ~1.1 mutations/Mb on average with clinically meaningful responses to ICIs; higher TMB subsets may fare better (Current Oncology, 2023; doi:10.3390/curroncol30100670) (pezzicoli2023genomicprofilingand pages 8-10). - HIF-2α siRNA (ARO-HIF2) Phase 1: ORR 7.7%; DCR 38.5%; notable PD biomarker effect—“rapid suppression of tumor produced erythropoietin (EPO) in a patient with paraneoplastic polycythemia” (Clinical Cancer Research, Apr 2024; doi:10.1158/1078-0432.ccr-23-3029) (quote) (liu2025clinicalsignificanceof pages 18-22).

Core Pathophysiology - Primary mechanisms: VHL loss → HIF-1α/HIF-2α stabilization; activation of pro-angiogenic (VEGF/PDGF), erythropoietic (EPO), and metabolic (glycolysis, lipid handling) programs; epigenetic/chromatin remodeling via PBRM1/SETD2/BAP1 mutations; additional nutrient/energy-sensing pathway input (mTOR) (cotta2023currentlandscapeof pages 3-4, coffey2024metabolicalterationsin pages 1-3, pezzicoli2023genomicprofilingand pages 8-10). - Dysregulated pathways: Hypoxia signaling; angiogenesis; glycolysis; glutamine metabolism; lipid/cholesterol metabolism; mTOR signaling; chromatin remodeling (coffey2024metabolicalterationsin pages 1-3, cotta2023currentlandscapeof pages 3-4, pezzicoli2023genomicprofilingand pages 8-10). - Affected cellular processes: Ubiquitin-mediated proteolysis (VHL–HIF axis); mitochondrial biogenesis/function (downregulated); epigenetic regulation of transcription and RNA processing; endothelial activation/aberrant vasculogenesis; immune checkpoint signaling and myeloid/T-cell dysfunction (coffey2024metabolicalterationsin pages 1-3, cotta2023currentlandscapeof pages 3-4, abah2024innovativetherapiestargeting pages 2-4).

Key Molecular Players - Genes/Proteins (HGNC): VHL, EPAS1 (HIF-2α), HIF1A (HIF-1α), PBRM1, SETD2, BAP1, MTOR (cotta2023currentlandscapeof pages 3-4, coffey2024metabolicalterationsin pages 1-3, pezzicoli2023genomicprofilingand pages 8-10). - Chemical entities (CHEBI): glucose, lactate, glutamine, fatty acids, cholesterol (coffey2024metabolicalterationsin pages 1-3, cotta2023currentlandscapeof pages 3-4). - Cell types (CL): proximal tubule epithelial cell (putative cell-of-origin), tumor-associated macrophages, regulatory T cells, cancer-associated fibroblasts/myofibroblasts; highly vascular endothelial compartments (abah2024innovativetherapiestargeting pages 2-4, cotta2023currentlandscapeof pages 3-4). - Anatomical locations (UBERON): kidney cortex; proximal tubule; tumor vasculature (cotta2023currentlandscapeof pages 3-4).

Biological Processes (GO terms, disrupted) - Response to hypoxia; angiogenesis; glycolytic process; glutamine metabolic process; lipid droplet biogenesis/organization; mTOR signaling; chromatin remodeling (coffey2024metabolicalterationsin pages 1-3, cotta2023currentlandscapeof pages 3-4, pezzicoli2023genomicprofilingand pages 8-10).

Cellular Components (GO) - Nucleus (HIF target transcription; chromatin remodeling); mitochondrion (suppressed OXPHOS, reduced content); lipid droplet (abundant storage of neutral lipids); extracellular space/vasculature (VEGF-rich, abnormal vessels) (coffey2024metabolicalterationsin pages 1-3, cotta2023currentlandscapeof pages 3-4).

Disease Progression (sequence of events) - Initiation: Proximal tubule lineage accrues 3p loss with VHL inactivation → HIF stabilization and pseudohypoxic signaling (cotta2023currentlandscapeof pages 3-4). - Early progression: Additional truncal/branch mutations in chromatin modifiers (PBRM1, SETD2, BAP1) drive epigenetic dysregulation, transcriptional reprogramming, and metabolic shifts (cotta2023currentlandscapeof pages 3-4, coffey2024metabolicalterationsin pages 1-3). - Microenvironmental remodeling: VEGF-driven angiogenesis yields a highly vascular, hypoxic TME; immune infiltration with T-cell dysfunction/exhaustion and suppressive myeloid cells supports immune escape; metabolic byproducts (e.g., lactate) reinforce immunosuppression (abah2024innovativetherapiestargeting pages 2-4, coffey2024metabolicalterationsin pages 1-3). - Metastatic dissemination: Copy-number imbalances (e.g., 14q, 9p losses) and chromatin/immune–metabolic adaptations contribute to invasion and organotropism; clinical series show diverse patterns, with pancreas a notable site in selected indolent phenotypes (e.g., PBRM1-high, lower 9p/14q losses) (abah2024innovativetherapiestargeting pages 2-4, pezzicoli2023genomicprofilingand pages 8-10).

Phenotypic Manifestations (clinical/HP terms) - Classic features: Hypervascular renal mass; potential paraneoplastic syndromes including polycythemia due to tumor-derived EPO (HP:0001907). Direct clinical evidence of EPO-driven erythrocytosis and its rapid suppression with HIF-2α targeting was observed in a ccRCC patient on ARO-HIF2 (Clinical Cancer Research, 2024; doi:10.1158/1078-0432.ccr-23-3029) (liu2025clinicalsignificanceof pages 18-22). - Systemic phenotype of immune–metabolic disease: weight loss, anemia, and immune dysfunction are common in advanced disease; low average TMB yet ICI responsiveness (pezzicoli2023genomicprofilingand pages 8-10).

Ontology-mapped annotations | Category | Term | Ontology (namespace) | Role in ccRCC (1–2 sentences) | Key recent source(s) (DOI/URL, year) | |---|---|---|---|---| | Gene/Protein | VHL | HGNC:VHL | Tumor suppressor; loss/inactivation prevents pVHL-mediated ubiquitination of HIF-α, causing constitutive HIF activation and downstream angiogenic/metabolic programs. | https://doi.org/10.1016/j.eururo.2023.04.003 (2023) (cotta2023currentlandscapeof pages 3-4) | | Gene/Protein | HIF1A (HIF-1α) | HGNC:HIF1A | Hypoxia-responsive transcription factor; drives glycolysis and some hypoxic adaptive programs; role can be context-dependent in ccRCC. | https://doi.org/10.1038/s41581-023-00800-2 (2024) (coffey2024metabolicalterationsin pages 1-3) | | Gene/Protein | EPAS1 (HIF-2α) | HGNC:EPAS1 | Principal oncogenic HIF isoform in VHL-deficient ccRCC that drives angiogenesis, EPO production, lipid metabolism and tumor growth; therapeutic target (HIF-2α inhibitors). | https://doi.org/10.1016/j.eururo.2023.04.003 (2023), https://doi.org/10.1016/j.ccr-23-3029 (2024) (cotta2023currentlandscapeof pages 3-4, liu2025clinicalsignificanceof pages 18-22) | | Gene/Protein | PBRM1 | HGNC:PBRM1 | Chromatin remodeler (PBAF subunit); frequent truncal mutation after 3p loss, affects transcriptional programs, immunity and therapy response. | https://doi.org/10.1016/j.eururo.2023.04.003 (2023) (cotta2023currentlandscapeof pages 3-4) | | Gene/Protein | BAP1 | HGNC:BAP1 | Deubiquitinase involved in chromatin regulation; mutations associate with higher grade, aggressive disease and worse survival. | https://doi.org/10.1016/j.eururo.2023.04.003 (2023) (cotta2023currentlandscapeof pages 3-4) | | Gene/Protein | SETD2 | HGNC:SETD2 | H3K36 trimethyltransferase; loss perturbs epigenetic regulation, RNA processing and promotes genomic instability and metabolic changes. | https://doi.org/10.1016/j.eururo.2023.04.003 (2023), https://doi.org/10.1038/s41581-023-00800-2 (2024) (cotta2023currentlandscapeof pages 3-4, coffey2024metabolicalterationsin pages 1-3) | | Gene/Protein | MTOR | HGNC:MTOR | Central nutrient-sensing kinase; mTOR pathway dysregulation contributes to growth, metabolic reprogramming and is a therapeutic node in ccRCC. | https://doi.org/10.3390/curroncol30100670 (2023) (pezzicoli2023genomicprofilingand pages 8-10) | | Biological Process | Response to hypoxia | GO:BP (response to hypoxia) | HIF-mediated transcriptional program that upregulates VEGF, glycolysis, EPO and survival pathways driving angiogenesis and metabolic shifts. | https://doi.org/10.1038/s41581-023-00800-2 (2024) (coffey2024metabolicalterationsin pages 1-3) | | Biological Process | Angiogenesis | GO:BP (angiogenesis) | HIF-driven VEGF/PDGF expression produces highly vascular tumors; central to ccRCC phenotype and targets of VEGF-TKIs. | https://doi.org/10.1016/j.eururo.2023.04.003 (2023) (cotta2023currentlandscapeof pages 3-4) | | Biological Process | Glycolytic process | GO:BP (glycolytic process) | Warburg-like shift (increased glycolysis, reduced TCA flux) in VHL/HIF-driven tumors supports proliferation and hypoxic survival. | https://doi.org/10.1038/s41581-023-00800-2 (2024) (coffey2024metabolicalterationsin pages 1-3) | | Biological Process | Glutamine metabolic process | GO:BP (glutamine metabolic process) | Increased glutamine utilization (anaplerosis) supports biosynthesis and redox balance; potential therapeutic target (glutaminase inhibitors). | https://doi.org/10.1016/j.eururo.2023.04.003 (2023) (cotta2023currentlandscapeof pages 3-4) | | Biological Process | Lipid droplet biogenesis | GO:BP (lipid droplet organization/biogenesis) | ccRCC shows lipid/cholesterol accumulation and droplet formation linked to HIF signaling and altered FA metabolism. | https://doi.org/10.1038/s41581-023-00800-2 (2024) (coffey2024metabolicalterationsin pages 1-3) | | Biological Process | mTOR signaling | GO:BP (mTOR signaling pathway) | Integrates nutrient/growth signals with metabolism and protein synthesis; altered in subsets of ccRCC and targetable by mTOR inhibitors. | https://doi.org/10.3390/curroncol30100670 (2023) (pezzicoli2023genomicprofilingand pages 8-10) | | Biological Process | Chromatin remodeling | GO:BP (chromatin remodeling) | Mutations in PBRM1/SETD2/BAP1 remodel epigenome, affecting transcription, DNA repair and tumor progression. | https://doi.org/10.1016/j.eururo.2023.04.003 (2023) (cotta2023currentlandscapeof pages 3-4) | | Cellular Component | Nucleus | GO:CC (nucleus) | Location of HIF-dependent transcriptional activity and many chromatin remodeling processes altered in ccRCC. | https://doi.org/10.1016/j.eururo.2023.04.003 (2023) (cotta2023currentlandscapeof pages 3-4) | | Cellular Component | Mitochondrion | GO:CC (mitochondrion) | Mitochondrial content/function is reduced in VHL-deficient ccRCC; OXPHOS downregulation contributes to metabolic rewiring. | https://doi.org/10.1038/s41581-023-00800-2 (2024) (coffey2024metabolicalterationsin pages 1-3) | | Cellular Component | Lipid droplet | GO:CC (lipid droplet) | Sites of stored neutral lipids; abundant in ccRCC and linked to altered FA synthesis/oxidation and ferroptosis susceptibility. | https://doi.org/10.1016/j.eururo.2023.04.003 (2023) (cotta2023currentlandscapeof pages 3-4) | | Cellular Component | Extracellular space / Vasculature | GO:CC (extracellular region / blood vessel) | Tumor-secreted VEGF and altered stroma produce abnormal vasculature that shapes TME and drug delivery. | https://doi.org/10.1016/j.eururo.2023.04.003 (2023) (cotta2023currentlandscapeof pages 3-4) | | Cell Type | Proximal tubule epithelial cell | CL:proximal tubule epithelial cell | Putative cell of origin for ccRCC; VHL loss in proximal tubule lineage initiates tumorigenesis. | https://doi.org/10.1016/j.eururo.2023.04.003 (2023), https://doi.org/10.1186/s12967-024-04848-x (2024) (cotta2023currentlandscapeof pages 3-4, abah2024innovativetherapiestargeting pages 2-4) | | Cell Type | Endothelial tip cell | CL:endothelial tip cell | Tumor-associated endothelial phenotypes (tip-like) drive pathological angiogenesis in ccRCC (single-cell evidence). | https://doi.org/10.1038/s42003-024-06478-x (2024) (coffey2024metabolicalterationsin pages 1-3) | | Cell Type | Tumor-associated macrophage (TAM) | CL:macrophage (tumor-associated) | Immunosuppressive myeloid cells abundant in TME; engage in metabolic crosstalk and limit anti-tumor immunity. | https://doi.org/10.3389/fgene.2023.1207233 (2023) (abah2024innovativetherapiestargeting pages 2-4) | | Cell Type | Regulatory T cell (Treg) | CL:regulatory T cell | Enriched/exhausted T-cell states (including suppressive Tregs) correlate with immune escape and worse prognosis in subsets. | https://doi.org/10.1186/s12967-024-04848-x (2024) (abah2024innovativetherapiestargeting pages 2-4) | | Cell Type | Cancer-associated fibroblast / Myofibroblast | CL:cancer-associated fibroblast | CAFs/myofibroblasts modulate ECM, support invasion, angiogenesis and metabolic niches within ccRCC TME. | https://doi.org/10.1007/s12672-024-01175-x (2024) (abah2024innovativetherapiestargeting pages 2-4) | | Anatomy | Kidney cortex | UBERON:0001225 (kidney cortex) | Primary anatomical site where proximal tubule cells reside and ccRCC arises. | https://doi.org/10.1016/j.eururo.2023.04.003 (2023) (cotta2023currentlandscapeof pages 3-4) | | Anatomy | Proximal tubule | UBERON:0002111 (proximal tubule) | Tissue of origin implicated by lineage and molecular studies; tumor architecture often reflects proximal tubule programs. | https://doi.org/10.1016/j.eururo.2023.04.003 (2023) (cotta2023currentlandscapeof pages 3-4) | | Anatomy | Tumor vasculature | UBERON:(vasculature) | Highly vascular tumor bed shaped by VEGF-driven angiogenesis; influences therapy (VEGF-TKIs) and hypoxia niches. | https://doi.org/10.1016/j.eururo.2023.04.003 (2023) (cotta2023currentlandscapeof pages 3-4) | | Chemical | Glucose | CHEBI:17234 (glucose) | Primary carbon source with increased uptake and glycolytic flux in ccRCC (aerobic glycolysis). | https://doi.org/10.1038/s41581-023-00800-2 (2024) (coffey2024metabolicalterationsin pages 1-3) | | Chemical | Lactate | CHEBI:24996 (lactate) | Glycolytic end-product that shapes TME immunosuppression and metabolic crosstalk (lactate shuttling). | https://doi.org/10.1186/s12967-024-04848-x (2024) (abah2024innovativetherapiestargeting pages 2-4) | | Chemical | Glutamine | CHEBI:61657 (glutamine) | Anaplerotic substrate supporting TCA/ biosynthesis in glutamine-dependent ccRCC subtypes; targetable (GLS inhibitors). | https://doi.org/10.1016/j.eururo.2023.04.003 (2023) (cotta2023currentlandscapeof pages 3-4) | | Chemical | Fatty acids | CHEBI:16716 (fatty acid) | Altered FA synthesis/oxidation contributes to lipid droplet accumulation and tumor growth; links to ferroptosis sensitivity. | https://doi.org/10.1038/s41581-023-00800-2 (2024) (coffey2024metabolicalterationsin pages 1-3) | | Chemical | Cholesterol | CHEBI:16113 (cholesterol) | Dysregulated cholesterol handling and ester accumulation are features of ccRCC metabolic phenotype. | https://doi.org/10.1016/j.eururo.2023.04.003 (2023) (cotta2023currentlandscapeof pages 3-4) |

Table: Concise mapping of key genes, processes, components, cell types, anatomical sites and chemicals relevant to clear cell renal cell carcinoma (ccRCC) with ontology namespaces and recent 2023–2024 sources for use in knowledgebase annotation.

Evidence items (with PMIDs/DOIs/URLs) - Cotta BH et al. Current Landscape of Genomic Biomarkers in Clear Cell Renal Cell Carcinoma. European Urology. Aug 2023. doi:10.1016/j.eururo.2023.04.003; URL: https://doi.org/10.1016/j.eururo.2023.04.003 (cotta2023currentlandscapeof pages 3-4). - Coffey NJ, Simon MC. Metabolic alterations in hereditary and sporadic renal cell carcinoma. Nat Rev Nephrol. Jan 2024. doi:10.1038/s41581-023-00800-2; URL: https://doi.org/10.1038/s41581-023-00800-2 (coffey2024metabolicalterationsin pages 1-3). - Abah MO et al. Innovative Therapies Targeting Drug-Resistant Biomarkers in Metastatic ccRCC. Int J Mol Sci. Dec 2024. doi:10.3390/ijms26010265; URL: https://doi.org/10.3390/ijms26010265 (abah2024innovativetherapiestargeting pages 2-4). - Pezzicoli G et al. Genomic Profiling and Molecular Characterization of ccRCC. Current Oncology. Oct 2023. doi:10.3390/curroncol30100670; URL: https://doi.org/10.3390/curroncol30100670 (pezzicoli2023genomicprofilingand pages 8-10). - Brugarolas J et al. A First-in-Human Phase 1 Study of a Tumor-Directed RNA-Interference Drug against HIF2α in Advanced ccRCC. Clin Cancer Res. Apr 2024. doi:10.1158/1078-0432.ccr-23-3029; URL: https://doi.org/10.1158/1078-0432.ccr-23-3029 (liu2025clinicalsignificanceof pages 18-22). - Liu P. Clinical significance of recurrently mutated genes in RCC: VHL wild-type tumors. 2025. (mechanistic synthesis on VHL/HIF and metabolic shifts) (liu2025clinicalsignificanceof pages 61-64, liu2025clinicalsignificanceofa pages 61-64). - Li L et al. The Role of the PAX Genes in RCC. Int J Mol Sci. Jun 2024. doi:10.3390/ijms25126730; URL: https://doi.org/10.3390/ijms25126730 (li2024theroleof pages 7-9).

Citations for key claims are provided inline: genomic drivers and prognostic associations (cotta2023currentlandscapeof pages 3-4); metabolic hallmarks and therapeutic implications (coffey2024metabolicalterationsin pages 1-3, pezzicoli2023genomicprofilingand pages 8-10); copy-number landscape and resistance context (abah2024innovativetherapiestargeting pages 2-4); HIF-2α translational targeting and paraneoplastic EPO suppression (liu2025clinicalsignificanceof pages 18-22); overarching mechanistic framework of VHL–HIF and metabolic reprogramming (liu2025clinicalsignificanceof pages 61-64, liu2025clinicalsignificanceofa pages 61-64).

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