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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 Access through your

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BEING VIEWED BY OTHERS GENOMIC PROFILING IN RENAL CELL CARCINOMA Article 19 June 2020 PBRM1, SETD2 AND BAP1 — THE TRINITY OF 3P IN CLEAR CELL RENAL CELL CARCINOMA Article 17 October 2022

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references ACKNOWLEDGEMENTS The authors thank the Cambridge Biomedical Research Centre, Cambridge, UK, for their support. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Cancer Research UK

Cambridge Research Institute, Li Ka Shing Centre, Hills Road, CB2 0RE, Cambridge, UK Lucy Gossage * Department of Oncology, University of Cambridge, Box 193, Addenbrookes Hospital, CB2 0QQ,

Cambridge, UK Tim Eisen Authors * Lucy Gossage View author publications You can also search for this author inPubMed Google Scholar * Tim Eisen View author publications You can also search

for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Lucy Gossage. ETHICS DECLARATIONS COMPETING INTERESTS 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. SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIGURE 1 Classification systems for genetic mutations. (PDF 355 kb) RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Gossage, L., Eisen, T. Alterations in _VHL_ as potential biomarkers in renal-cell carcinoma. _Nat Rev Clin Oncol_

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