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Alterations in VHL as potential biomarkers in renal-cell carcinoma

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.

Key Points

  • Disruption of VHL, by somatic mutation, hypermethylation of its promoter or chromosomal loss, is seen in the majority of cases of clear-cell renal-cell carcinoma

  • The best-documented function of pVHL involves targeting hypoxia-inducible factors (HIFs) for polyubiquitination and proteasomal degradation through its role as the substrate recognition component of a ubiquitin ligase complex

  • Drugs that modulate downstream targets of the VHL/HIF pathway have proven efficacy in treating clear-cell renal-cell carcinoma

  • HIF-independent functions of pVHL are important for its tumor-suppressor action: maintenance of the primary cilium, assembly of extracellular matrix, control of microtubule dynamics, regulation of neuronal apoptosis and transcriptional regulation

  • Future clinical trials should prospectively define the VHL mutation status of study participants and include planned subgroup analyses to assess the importance of mutational status as a stratifying variable

  • Understanding the functional effects of pVHL alterations might facilitate development of a classification system to differentiate high-risk from low-risk patients and identify those who could benefit from targeted therapies

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Figure 1: Oxygen-dependent HIF regulation.
Figure 2: Consequences of VHL mutations in ccRCC pathogenesis.
Figure 3: Oxygen-independent HIF regulatory mechanisms are involved in tumorigenesis.

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Acknowledgements

The authors thank the Cambridge Biomedical Research Centre, Cambridge, UK, for their support.

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L. Gossage declares no competing interests. T. Eisen declares that he has received honoraria and is a member of the advisory boards for Amgen, Astra Zeneca, Aveo, Bayer, Bristol-Myers, GlaxoSmithKline, Immatics, Pfizer and Wyeth, and has received grant or research funding from Astra Zeneca, Bayer and Pfizer.

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Classification systems for genetic mutations. (PDF 355 kb)

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Gossage, L., Eisen, T. Alterations in VHL as potential biomarkers in renal-cell carcinoma. Nat Rev Clin Oncol 7, 277–288 (2010). https://doi.org/10.1038/nrclinonc.2010.42

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