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VHL Disease

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von Hippel-Lindau disease (VHL) disease increases susceptibility to several malignancies, including renal cell carcinoma, haemangioblastomas of the central nervous system or retina and phaeochromocytomas. The VHL tumour suppressor gene, responsible for the disease, encodes for a major regulator of the hypoxic response by targeting the transcription factor hypoxia inducible factor (HIF) for degradation. In this review, we present a synopsis of clinical features of the disease and emphasise unique aspects of VHL syndrome in the paediatric population. Genotype–phenotype associations based on the risk of phaeochromocytoma have pointed to the existence of additional, HIF-independent functions of VHL that remain underexplored. We also examine the progress on these pleiotropic roles of VHL, which contribute to explain clinical features of VHL disease. These advances have important translational implications and are likely to offer a new host of therapeutic options to individuals affected by the disease in the future.

Section snippets

Clinical subtypes of disease

Von Hippel Lindau (VHL) disease is a hereditary familial cancer with an incidence of 1 in 36,000 live births.1, 7 VHL disease predisposes an individual to the development of different types of benign and malignant tumours in bilateral and multicentric forms. It is characterised by central nervous system, especially cerebellum, and retinal haemangioblastomas, clear-cell renal cell carcinoma and phaeochromocytoma or paraganglioma. A variety of other lesions have been associated with VHL disease

Genetic and molecular functions of VHL protein

There has been enormous progress in the past few years on the physiological role of VHL. In this section, we present a summary of the multiple functions ascribed to the VHL protein, which are likely to contribute to its role as a tumour suppressor.

Future of research: therapeutic implications

VHL mutant tumours are highly angiogenic and produce high levels of VEGFA.89 These observations can now be understood in light of the role of VHL in regulating HIF and have naturally developed into targets for therapy in these tumours, especially renal cancers. The use of angiogenic inhibitors (sorafenib and sunitib) or VEGF antibodies are now part of the standard treatment course of these tumours with superior responses compared to conventional chemo- or immunotherapy used for these cancers.89

Conclusions

Accumulating evidence over the past years has established the role of HIFα, especially HIF2α, in VHL-mutant tumours such as haemangioblastomas and renal carcinomas. At the same time, a number of HIF-independent VHL functions are being uncovered. Both spontaneous human mutations and animal models have pointed to a relevant role of these other functions to the pathogenesis of VHL-related tumours, especially phaeochromocytomas/paragangliomas (Fig. 1). While it has been long known that tumoural

Acknowledgements

PLMD is a recipient of a Voelcker Foundation Young Investigator Award and is supported by the Cancer Therapy and Research Center (CTRC) at the University of Texas Health Science Center at San Antonio (NIH-P30 CA54174).

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