Familial tumour syndromes: von Hippel–Lindau disease

2017 ◽  
Author(s):  
Hiroshi Kanno ◽  
Joachim P. Steinbach
Keyword(s):  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Laboratory Data ◽  
Von Hippel Lindau ◽  
Vhl Protein ◽  
Von Hippel Lindau Disease ◽  
The Central Nervous System ◽  
Microsurgical Techniques ◽  
Vhl Disease ◽  
Hif Pathway

Von Hippel–Lindau (VHL) disease, an autosomal dominant familial tumour syndrome, is often associated with haemangioblastoma of the central nervous system. In the presence of oxygen, VHL protein serves to prevent the accumulation of hypoxia-inducible factor (HIF) protein by targeting it to the proteasomal pathway, while biallelic inactivation of the VHL gene blocks degradation of HIF and leads to constitutive activation of the HIF pathway although oxygen is present. HIF-target genes are involved in angiogenesis, proliferation, and metabolism enabling tumour growth. Haemangioblastoma is a highly vascularized, begin tumour commonly associated with a cyst, but it is linked with neurological morbidity and mortality based on its location and multiplicity. Haemangioblastoma in VHL is diagnosed according to symptoms and signs, past and family histories, laboratory data, neuroradiological findings, pathological findings, and genetic testing. Surgical treatment is usually the most recommended therapy for haemangioblastomas, and using well-defined microsurgical techniques, the majority can be resected safely.

scholarly journals Inactivation of the Arylhydrocarbon Receptor Nuclear Translocator (Arnt) Suppresses von Hippel-Lindau Disease-Associated Vascular Tumors in Mice

2005 ◽  
Vol 25 (8) ◽  
pp. 3163-3172 ◽  
Author(s):  
Erinn B. Rankin ◽  
Debra F. Higgins ◽  
Jacqueline A. Walisser ◽  
Randall S. Johnson ◽  
Christopher A. Bradfield ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Germ Line ◽  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Vascular Tumors ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Arylhydrocarbon Receptor ◽  
Vhl Disease ◽  
Endothelial Growth Factor

ABSTRACT Patients with germ line mutations in the VHL tumor suppressor gene are predisposed to the development of highly vascularized tumors within multiple tissues. Loss of pVHL results in constitutive activation of the transcription factors HIF-1 and HIF-2, whose relative contributions to the pathogenesis of the VHL phenotype have yet to be defined. In order to examine the role of HIF in von Hippel-Lindau (VHL)-associated vascular tumorigenesis, we utilized Cre-loxP-mediated recombination to inactivate hypoxia-inducible factor-1α (Hif-1α) and arylhydrocarbon receptor nuclear translocator (Arnt) genes in a VHL mouse model of cavernous liver hemangiomas and polycythemia. Deletion of Hif-1α did not affect the development of vascular tumors and polycythemia, nor did it suppress the increased expression of vascular endothelial growth factor (Vegf) and erythropoietin (Epo). In contrast, phosphoglycerokinase (Pgk) expression was substantially decreased, providing evidence for target gene-dependent functional redundancy between different Hif transcription factors. Inactivation of Arnt completely suppressed the development of hemangiomas, polycythemia, and Hif-induced gene expression. Here, we demonstrate genetically that the development of VHL-associated vascular tumors in the liver depends on functional ARNT. Furthermore, we provide evidence that individual HIF transcription factors may play distinct roles in the development of specific VHL disease manifestations.

scholarly journals von Hippel-Lindau Disease: an Update

2019 ◽  
Vol 7 (4) ◽  
pp. 227-235 ◽  
Author(s):  
Eamonn R Maher ◽  
Richard N Sandford
Keyword(s):  
Natural History ◽  
Patient Outcomes ◽  
Molecular Characterisation ◽  
Von Hippel Lindau ◽  
Functional Characterisation ◽  
History Of ◽  
Vhl Protein ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease ◽  
Improve Patient

Abstract Purpose of Review In this review, we discuss the key molecular and clinical developments in VHL disease that have the potential to impact on the natural history of the disease and improve patient outcomes. Recent Findings Identifiable mutations in VHL underlie most cases of VHL and define clear genotype-phenotype correlations. Detailed clinical and molecular characterisation has allowed the implementation of lifelong screening programmes that have improved clinical outcomes. Functional characterisation of the VHL protein complex has revealed its role in oxygen sensing and the mechanisms of tumourigenesis that are now being exploited to develop novel therapies for VHL and renal cancer. Summary The molecular and cellular landscape of VHL-associated tumours is revealing new opportunities to modify the natural history of the disease and develop therapies. Drugs are now entering clinical trials and combined with improved clinical and molecular diagnosis, and lifelong surveillance programmes, further progress towards reducing the morbidity and mortality associated with VHL disease is anticipated.

scholarly journals Cardiopulmonary function in two human disorders of the hypoxia‐inducible factor (HIF) pathway: von Hippel‐Lindau disease and HIF‐2α gain‐of‐function mutation

2011 ◽  
Vol 25 (6) ◽  
pp. 2001-2011 ◽  
Author(s):  
Federico Formenti ◽  
Philip A. Beer ◽  
Quentin P. P. Croft ◽  
Keith L. Dorrington ◽  
Daniel P. Gale ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Gain Of Function ◽  
Cardiopulmonary Function ◽  
Von Hippel Lindau ◽  
Human Disorders ◽  
Von Hippel Lindau Disease ◽  
Hif Pathway

scholarly journals Pathology of the Nervous System in Von Hippel-Lindau Disease

2015 ◽  
Vol 2 (3) ◽  
pp. 114-129 ◽  
Author(s):  
Alexander O. Vortmeyer ◽  
Ahmed K. Alomari
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Hypoxia Inducible Factors ◽  
Metastatic Renal Cancer ◽  
Vhl Gene ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
The Central Nervous System ◽  
Vhl Disease ◽  
Common Manifestation

Von Hippel-Lindau (VHL) disease is a tumor syndrome that frequently involves the central nervous system (CNS). It is caused by germline mutation of the VHL gene. Subsequent VHL inactivation in selected cells is followed by numerous well-characterized molecular consequences, in particular, activation and stabilization of hypoxia-inducible factors HIF1 and HIF2. The link between VHL gene inactivation and tumorigenesis remains poorly understood. Hemangioblastomas are the most common manifestation in the CNS; however, CNS invasion by VHL disease-associated endolymphatic sac tumors or metastatic renal cancer also occur, and their differentiation from primary hemangioblastoma may be challenging. Finally, in this review, we present recent morphologic insights on the developmental concept of VHL tumorigenesis which is best explained by pathologic persistence of temporary embryonic progenitor cells. 

scholarly journals The Endothelial Landscape and Its Role in Von Hippel–Lindau Disease

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2313
Author(s):  
Isabel de Rojas-P ◽  
Virginia Albiñana ◽  
Lyudmyla Taranets ◽  
Lucía Recio-Poveda ◽  
Angel M. Cuesta ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Tumor Development ◽  
Vascular Diseases ◽  
Hereditary Disease ◽  
In Vitro Assays ◽  
Second Hit ◽  
Von Hippel Lindau ◽  
Vhl Protein ◽  
Von Hippel Lindau Disease

Von Hippel–Lindau disease (VHL) is a rare hereditary disease characterized by the predisposal to develop different types of highly vascularized tumors. VHL patients carry a VHL mutation that causes partial lack of functional VHL protein (pVHL) in all cells, and a total lack thereof in cells harboring a second hit mutation. Absence of pVHL generates a prolonged state of pseudo-hypoxia in the cell due to accumulation of hypoxia inducible factor, an important transcription factor regulating pro-tumorigenic genes. The work here presented focuses on characterizing the endothelium of VHL patients, by means of blood outgrowth endothelial cells (BOECs). Transcriptome analysis of VHL-derived BOECs, further supported by in vitro assays, shows that these cells are at a disadvantage, as evidenced by loss of cell adhesion capacity, angiogenesis defects, and immune response and oxidative metabolic gene downregulation, which induce oxidative stress. These results suggest that the endothelium of VHL patients is functionally compromised and more susceptible to tumor development. These findings contribute to shedding light on the vascular landscape of VHL patients preceding the second hit mutation in the VHL gene. This knowledge could be useful in searching for new therapies for these patients and other vascular diseases.

scholarly journals pVHL Modification by NEDD8 Is Required for Fibronectin Matrix Assembly and Suppression of Tumor Development

2004 ◽  
Vol 24 (8) ◽  
pp. 3251-3261 ◽  
Author(s):  
Natalie H. Stickle ◽  
Jacky Chung ◽  
Jeffery M. Klco ◽  
Richard P. Hill ◽  
William G. Kaelin ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Tumor Development ◽  
Three Dimensional ◽  
Suppressor Gene ◽  
Matrix Assembly ◽  
Von Hippel Lindau ◽  
Fibronectin Matrix ◽  
Matrix Expression ◽  
Vhl Disease ◽  
Hif Pathway

ABSTRACT Functional inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is the cause of the familial VHL disease and most sporadic renal clear-cell carcinomas (RCC). pVHL has been shown to play a role in the destruction of hypoxia-inducible factor α (HIF-α) subunits via ubiquitin-mediated proteolysis and in the regulation of fibronectin matrix assembly. Although most disease-causing pVHL mutations hinder the regulation of the HIF pathway, every disease-causing pVHL mutant tested to date has failed to promote the assembly of the fibronectin matrix, underscoring its potential importance in VHL disease. Here, we report that a ubiquitin-like molecule called NEDD8 covalently modifies pVHL. A nonneddylateable pVHL mutant, while retaining its ability to ubiquitylate HIF, failed to bind to and promote the assembly of the fibronectin matrix. Expression of the neddylation-defective pVHL in RCC cells, while restoring the regulation of HIF, failed to promote the differentiated morphology in a three-dimensional growth assay and was insufficient to suppress the formation of tumors in SCID mice. These results suggest that NEDD8 modification of pVHL plays an important role in fibronectin matrix assembly and that in the absence of such regulation, an intact HIF pathway is insufficient to prevent VHL-associated tumorigenesis.

Metastases to hemangioblastomas in von Hippel–Lindau disease

2006 ◽  
Vol 105 (2) ◽  
pp. 256-263 ◽  
Author(s):  
S. Taylor Jarrell ◽  
Alexander O. Vortmeyer ◽  
W. Marston Linehan ◽  
Edward H. Oldfield ◽  
Russell R. Lonser
Keyword(s):  
Pancreatic Neuroendocrine Tumor ◽  
Von Hippel Lindau ◽  
Increased Risk ◽  
Age At Surgery ◽  
Von Hippel Lindau Disease ◽  
The Central Nervous System ◽  
Histological Characteristics ◽  
Tumor Metastases ◽  
Vhl Disease

Object Patients with hereditary cancer syndromes may be at increased risk for the development of tumor-to-tumor metastases. To gain insight into the biological nature of these lesions in the central nervous system (CNS), to determine their prevalence in a familial neoplasia syndrome, and to better define their management, the authors retrospectively examined a series of cases in which metastatic lesions developed within hemangioblastomas in patients with von Hippel–Lindau (VHL) disease. Methods The study included all cases of VHL disease in which patients underwent resection of a CNS hemangioblastoma that contained a metastasis or were found at autopsy to have a metastasis to a hemangioblastoma between January 2002 and December 2005 at the National Institute of Neurological Disorders and Stroke (NINDS). Clinical, histopathological, imaging, and surgical and/or autopsy findings were analyzed. Metastasis to a CNS hemangioblastoma was found in six resected tumors (8% of all hemangioblastomas resected from patients with VHL disease at the NINDS during the study period) from six patients (five women, one man; mean age at surgery 42.5 years). The primary site of metastatic disease was the kidney in five patients (renal cell carcinoma) and the pancreas in one (a pancreatic neuroendocrine tumor). Only one patient had systemic metastases at the time of resection of the hemangioblastoma containing the metastasis. Neurologically, all patients had remained at baseline or were improved at last clinical follow-up examination (mean follow-up duration 16.5 months, range 3–40 months). In all cases, postoperative imaging revealed that the hemangioblastoma resection was complete, and there was no evidence of recurrence in any of the patients at the last follow up. Two patients (including one who was also in the surgical group) were found at autopsy to have CNS metastases exclusively to spinal hemangioblastomas. Conclusions Hemangioblastomas are an early and preferred site for metastasis in VHL disease. Emerging histopathological techniques may lead to recognition of an increasing number of cases of tumor-to-hemangioblastoma metastasis. Management of cases involving tumor-to-hemangioblastoma metastases in VHL disease should be based on the histological characteristics of the primary tumor, extent of the primary disease, and completeness of the resection.

scholarly journals A case of von Hippel-Lindau disease with multi-organ involvement: a rare case report

2020 ◽  
Vol 7 (5) ◽  
pp. 1684
Author(s):  
Mrinal Bhuyan ◽  
Debadatta Saha ◽  
Basanta Kumar Baishya ◽  
Ashish Ghanghoria
Keyword(s):  
Early Recognition ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Von Hippel Lindau ◽  
Rare Case Report ◽  
Complete Tumour ◽  
Von Hippel Lindau Disease ◽  
The Central Nervous System ◽  
Vhl Disease

Von Hippel-Lindau (VHL) disease is a rare autosomal dominant syndrome manifested by a spectrum of tumours in the central nervous system (CNS) and other visceral organs. We herein report a case of 35 years aged newly diagnosed diabetic female patient presented with headache, gait instability, loss of vision in both eyes, left sided hearing impairment and subsequently diagnosed to have VHL disease. The pathophysiology involves the inactivation of the VHL tumour suppressor gene. Early recognition and treatment remains the mainstay of management. Even many years after the complete tumour excision, newer neoplasms may develop. Increasing knowledge about the molecular enabled us to investigate the role of anti-angiogenic drugs. Continuous surveillance at regular interval must be conducted in patients with VHL disease. 

A Novel HIFalpha Mutation Associated with Familial Erythrocytosis Supports This Isoform Being the Major Regulator of Erythropoietin in Humans.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. LB5-LB5
Author(s):  
Melanie J. Percy ◽  
Paul W. Furlow ◽  
Guy S. Lucas ◽  
Xiping Li ◽  
Terry R. Lappin ◽  
...  
Keyword(s):  
Target Genes ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Elevated Serum ◽  
Red Cell ◽  
Main Site ◽  
Von Hippel Lindau ◽  
B Subunit ◽  
Vhl Protein ◽  
A Subunit

Abstract Red cell homeostasis is crucial to maintain a sustained tissue oxygen supply. Oxygen is sensed by the kidneys and hypoxia induces renal erythropoietin (Epo) to stimulate red cell production. At the molecular level this process is controlled by the hypoxia inducible factor (HIF) complex, comprised of a labile a-subunit and a constitutively expressed b subunit. Key prolines present in the oxygen-dependent degradation (ODD) domain of the a subunit are hydroxylated by prolyl hydroxylase domain proteins (PHD1-3). The von Hippel Lindau (VHL) protein then binds and targets HIFa to the proteasome. There are 3 isoforms of the a subunit, each of which shows differential tissue distribution. The HIF-1, HIF-2 and HIF-3a subunit, in association with the b subunit, exhibit diverse affinities for the hypoxia response elements (HREs) located in the promoters and enhancers of HIF target genes. It is unclear whether Epo synthesis is under the control of HIF-1 or HIF-2 in humans although recent studies in mice support HIF-2 as the critical regulator. Dysregulation of Epo production can give rise to the red cell disorder of erythrocytosis. Defects in the oxygen sensing pathway are commonly associated with erythrocytosis and mutations in both the VHL and PHD2 genes have been described. Previously, screening the ODD domain of HIF-1a detected a polymorphism, Pro582Ser, that did not impair the function of HIF-1a. Subsequently, when sequencing HIF-2a, a novel heterozygous c.G1609T mutation was uncovered in 3 generations of one family with erythrocytosis. All affected individuals exhibited greatly elevated serum Epo levels. The c.G1609T mutation was absent in other unaffected family members as well as a cohort of 200 normal control samples. The mutation predicts the replacement of Gly by Trp at amino acid 537, which is close to the main site of proline hydroxylation at 531. Functional assays confirmed the Gly537Trp variant was less hydroxylated and exhibited reduced affinity for PHD2. Furthermore, the increased stability in normoxia of the Gly537Trp variant would result in elevated transcription of HIF-2 target genes. Consequently, these findings support a critical role for HIF-2a in control of Epo production in humans.

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