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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name: Clear Cell Renal Cell Carcinoma
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-04-22T20:13:21Z'
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: PARTIAL
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
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
- name: VEGF-Driven Angiogenesis
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: 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: PARTIAL
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
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.
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.
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: 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
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
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.
- name: 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.
- name: 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.
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.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
- name: VEGFR Tyrosine Kinase Inhibitors
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.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
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
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: MAXO:0001002
label: immunotherapy procedure
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
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
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.
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: cancer
- classification_value: solid tumor
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: []
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).
References
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