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Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
Alterations in VHL as potential biomarkers in renal-cell carcinoma
1Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK. lucygossage@doctors.org.uk
Abstract:
Germ line mutations in the VHL tumor-suppressor gene cause von Hippel-Lindau (VHL) disease, a hereditary neoplastic disease associated with clear-cell renal-cell carcinomas (ccRCCs), central nervous system hemangioblastomas and pheochromocytomas. Disruption of VHL, by somatic mutation, hypermethylation of its promoter or chromosomal loss, is also seen in the majority of cases of sporadic ccRCC. The protein product of VHL, pVHL, has multiple functions, the best-documented of which relates to its ability to target hypoxia-inducible factors (HIFs) for polyubiquitination and proteasomal degradation through its role in substrate recognition as part of a ubiquitin ligase complex. Consequently, pVHL-defective ccRCCs overexpress mRNAs that are under the transcriptional control of HIF. Drugs that modulate the downstream targets of the pVHL/HIF pathway, including sunitinib, sorafenib, temsirolimus and bevacizumab, have proven benefit in treating ccRCC. In VHL disease, clear evidence supports strong genotype-phenotype correlations, but the situation in sporadic ccRCC is less clear. Data indicate that VHL alterations have a potential role as prognostic and predictive markers in ccRCC. Future clinical trials should prospectively define the VHL alteration status of study participants so that the true utility of such markers can be determined.
Insights
Germ line mutations in the VHL tumor-suppressor gene cause von Hippel-Lindau (VHL) disease. VHL gene alterations are also implicated in sporadic clear-cell renal-cell carcinomas (ccRCCs), suggesting their utility as prognostic markers.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations in the VHL tumor-suppressor gene.
- VHL gene disruption, through somatic mutation or other mechanisms, is prevalent in sporadic clear-cell renal-cell carcinomas (ccRCCs).
- The VHL protein (pVHL) regulates hypoxia-inducible factors (HIFs), crucial in ccRCC pathogenesis.
Purpose of the Study:
- To explore the role of VHL gene alterations in both hereditary VHL disease and sporadic ccRCC.
- To investigate the potential of VHL alterations as prognostic and predictive markers in ccRCC.
- To highlight the therapeutic implications of targeting the pVHL/HIF pathway in ccRCC treatment.
Main Methods:
- Review of existing literature on VHL gene mutations and their association with VHL disease and ccRCC.
- Analysis of the functional role of pVHL in regulating HIFs and downstream gene expression.
- Examination of clinical data and therapeutic responses to drugs targeting the pVHL/HIF pathway.
Main Results:
- Germline VHL mutations define VHL disease, linked to specific tumors like ccRCC, hemangioblastomas, and pheochromocytomas.
- Somatic VHL alterations are frequent in sporadic ccRCC, indicating a common pathogenic mechanism.
- pVHL's role in HIF degradation is critical; its dysfunction leads to HIF overexpression and promotes ccRCC development.
- Targeted therapies (sunitinib, sorafenib, etc.) show efficacy by modulating the pVHL/HIF pathway.
Conclusions:
- VHL gene alterations are central to both VHL disease and a majority of sporadic ccRCC.
- VHL alterations may serve as valuable prognostic and predictive biomarkers for ccRCC.
- Prospective clinical trials are needed to definitively establish the utility of VHL markers in ccRCC patient management.
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