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NCI CANCERLIT^® Search: Von Hippel-Lindau Syndrome - May 2002

Imprima English

National Cancer Institute^®
Ultima Vez Modificado: 1 de mayo del 2002

High frequency loss of heterozygosity in von Hippel-Lindau (VHL)-associated and sporadic pancreatic islet cell tumors: evidence for

The HIF pathway: implications for patterns of gene expression in cancer.

Down-regulation of von Hippel-Lindau protein in N-nitroso compound-induced rat non-clear cell renal tumors.

Germ-line mutations in nonsyndromic pheochromocytoma.

How many pathways to pheochromocytoma?

Solitary retinal capillary hemangioma: lack of genetic evidence for von Hippel-Lindau disease.

Clinical and molecular analysis of disseminated hemangioblastomatosis of the central nervous system in patients without von Hippel-Lindau

Table of Contents

1
UI - 11929809
AU - Lott ST; Chandler DS; Curley SA; Foster CJ; El-Naggar A; Frazier M;
TI - Strong LC; Lovell M; Killary AM High frequency loss of heterozygosity in von Hippel-Lindau (VHL)-associated and sporadic pancreatic islet cell tumors: evidence for a stepwise mechanism for malignant conversion in VHL tumorigenesis.
SO - Cancer Res 2002 Apr 1;62(7):1952-5
AD - Department of Molecular Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Germ-line mutation of the von Hippel-Lindau (VHL) gene predisposes to the development of multifocal, benign lesions, including retinal and central nervous system hemangioblastomas, pheochromocytomas, and renal and pancreatic cysts. Progression to malignancy in VHL disease is associated primarily with the development of renal cell carcinoma (RCC) and pancreatic islet cell tumors (PICT). Although many reports have documented the multiple functions of the VHL protein, few have investigated the intriguing question related to the tissue-specificity of malignant conversion in VHL disease, a problem not easily explained by strict genotype-phenotype correlations. We investigated a novel VHL kindred with a preponderance of PICTs to determine whether loss of additional genetic loci associated with the sporadic forms of RCC and PICTs might play a role in malignant conversion in this disease. We report the high frequency loss of heterozygosity (LOH) of genetic loci distinct from and mapping proximal to VHL within human chromosome 3p in the VHL kindred under study. Furthermore, chromosome 3p LOH occurs subsequent to VHL mutation and cyst formation, and correlates with malignant progression in VHL-associated PICTs. High frequency LOH was also observed in sporadic PICTs in regions of 3p associated with LOH in sporadic clear cell RCC as well as homozygous deletion in lung cancer. A stepwise model for malignant conversion in VHL disease is herein proposed.

2
UI - 11727931
AU - Wykoff CC; Pugh CW; Harris AL; Maxwell PH; Ratcliffe PJ
TI - The HIF pathway: implications for patterns of gene expression in cancer.
SO - Novartis Found Symp 2001;240():212-25; discussion 225-31
AD - Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.
Regulation of the growth and metabolism of large organisms is tightly constrained by the need for precise oxygen homeostasis. Work on control of the haematopoietic growth factor erythropoietin has led to the recognition of a widespread transcriptional response to hypoxia which provides insights into how this is achieved. The central mediator of this response is a DNA binding complex termed hypoxia inducible factor 1 (HIF-1), which plays a key role in the regulation by oxygen of a large and rapidly growing panel of genes. In cancer, activity of the HIF system is up-regulated both by microenvironmental hypoxia and by genetic changes. The clearest example of genetic activation is seen in the hereditary cancer syndrome von Hippel-Lindau (VHL) disease. In normal cells the product of the VHL tumour suppressor gene targets the regulatory HIF subunits (HIF-1alpha and HIF-2alpha) for oxygen-dependent proteolysis, acting as the substrate recognition component of an E3 ubiquitin ligase. In pVHL defective cells this process is blocked leading to constitutive up-regulation of HIF-1alpha subunits, activation of the HIF complex and overexpression of HIF target genes. Using gene array screens we have defined a large number of VHL-regulated genes. The majority of these show hypoxia-inducible responses, supporting the central involvement of pVHL in gene regulation by oxygen. In addition to known HIF target genes involved in angiogenesis, glucose metabolism and vasomotor control, these new targets include examples with functions in matrix metabolism, apoptosis, carbon dioxide metabolism and secondary cascades of transcriptional control. Thus activation of HIF provides insights into the classical metabolic alterations in cancer cells, and into the mechanisms by which microenvironmental hypoxia might influence tumour behaviour. In the case of VHL disease, this activation can be linked to mutations in a defined tumour suppressor gene. Equally regulation of the HIF-1alpha/pVHL interaction in normal cells should provide insights into the physiological mechanisms operating in cellular oxygen sensing.

3
UI - 11880179
AU - Shiao YH; Ramakrishna G; Anderson LM; Perantoni AO; Rice JM; Diwan BA
TI - Down-regulation of von Hippel-Lindau protein in N-nitroso compound-induced rat non-clear cell renal tumors.
SO - Cancer Lett 2002 May 8;179(1):33-8
AD - Laboratory of Comparative Carcinogenesis, Building 538, Room 205, National Cancer Institute at Frederick, Frederick, MD 21702, USA. shiao@mail.ncifcrf.gov
Non-clear cell rat kidney tumors, inducible by N-nitroso compounds but lacking mutations in the von Hippel--Lindau (VHL) coding sequence, were examined for other VHL alterations. Neither mutations nor DNA methylation was detected in a putative promoter region. By immunohistochemistry, however, VHL protein level was evidently reduced in six of the eight eosinophilic renal epithelial tumors and in all the ten nephroblastomas. Immunoblotting of normal kidney detected two VHL proteins of 20 and 22kDa in a 16-day-old fetal rat but only 20kDa protein in an adult rat. This is the first demonstration of VHL alteration at the protein level.

4
UI - 12000816
AU - Neumann HP; Bausch B; McWhinney SR; Bender BU; Gimm O; Franke G;
TI - Schipper J; Klisch J; Altehoefer C; Zerres K; Januszewicz A; Smith WM; Munk R; Manz T; Glaesker S; Apel TW; Treier M; Reineke M; Walz MK; Hoang-Vu C; Brauckhoff M; Klein-Franke A; Klose P; Schmidt H; Maier-Woelfle M; Peczkowska M; Szmigielski C; Eng C; The Freiburg-Warsaw-Columbus Pheochromocytoma Study Group Germ-line mutations in nonsyndromic pheochromocytoma.
SO - N Engl J Med 2002 May 9;346(19):1459-66
AD - Department of Nephrology and Hypertension, Albert Ludwigs University, Freiburg, Germany. neumann@mm41.ukl.uni-freiburg.de
BACKGROUND: The group of susceptibility genes for pheochromocytoma that included the proto-oncogene RET (associated with multiple endocrine neoplasia type 2 [MEN-2]) and the tumor-suppressor gene VHL (associated with von Hippel-Lindau disease) now also encompasses the newly identified genes for succinate dehydrogenase subunit D (SDHD) and succinate dehydrogenase subunit B (SDHB), which predispose carriers to pheochromocytomas and glomus tumors. We used molecular tools to classify a large cohort of patients with pheochromocytoma with respect to the presence or absence of mutations of one of these four genes and to investigate the relevance of genetic analyses to clinical practice. METHODS: Peripheral blood from unrelated, consenting registry patients with pheochromocytoma was tested for mutations of RET, VHL, SDHD, and SDHB. Clinical data at first presentation and follow-up were evaluated. RESULTS: Among 271 patients who presented with nonsyndromic pheochromocytoma and without a family history of the disease, 66 (24 percent) were found to have mutations (mean age, 25 years; 32 men and 34 women). Of these 66, 30 had mutations of VHL, 13 of RET, 11 of SDHD, and 12 of SDHB. Younger age, multifocal tumors, and extraadrenal tumors were significantly associated with the presence of a mutation. However, among the 66 patients who were positive for mutations, only 21 had multifocal pheochromocytoma. Twenty-three (35 percent) presented after the age of 30 years, and 17 (8 percent) after the age of 40. Sixty-one (92 percent) of the patients with mutations were identified solely by molecular testing of VHL, RET, SDHD, and SDHB; these patients had no associated signs and symptoms at presentation. CONCLUSIONS: Almost one fourth of patients with apparently sporadic pheochromocytoma may be carriers of mutations; routine analysis for mutations of RET, VHL, SDHD, and SDHB is indicated to identify pheochromocytoma-associated syndromes that would otherwise be missed.

5
UI - 11891502
AU - Neumann HP; Hoegerle S; Manz T; Brenner K; Iliopoulos O
TI - How many pathways to pheochromocytoma?
SO - Semin Nephrol 2002 Mar;22(2):89-99
AD - Nephrology Section, Department of Medicine, Albert-Ludwigs University, Freiburg, Germany. neumann@mm41.ukl.uni-freiburg.de
Pheochromocytomas, like several other tumors, may be either sporadic or the manifestation of a familial cancer syndrome. Recently, major advances have occurred in both the understanding of diverse molecular mechanisms leading to pheochromocytoma and the diagnostic modalities available for detection of the disease. Familial pheochromocytoma may be a manifestation of multiple endocrine neoplasia type 2 (MEN-2), von Hippel-Lindau (VHL), or neurofibromatosis-1 (NF 1) disease. Tumor-suppressor genes responsible for the familial occurrence of extra-adrenal pheochromocytoma, called paraganglioma, have been identified. This wealth of genetic information, coupled with the availability of sensitive and specific biochemical tests as well as imaging studies, allows for genetic screening and early diagnosis of pheochromocytoma. In addition, genetic screening of relatives at risk is now feasible. In this article, we review recent clinical and molecular advances in our understanding of pheochromocytoma. Copyright 2002, Elsevier Science (USA). All rights reserved.

6
UI - 11910555
AU - Singh AD; Ahmad NN; Shields CL; Shields JA
TI - Solitary retinal capillary hemangioma: lack of genetic evidence for von Hippel-Lindau disease.
SO - Ophthalmic Genet 2002 Mar;23(1):21-7
AD - Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA 19107, USA. arunsingh@eyetumors.com
PURPOSE: To report the results of genetic testing for von Hippel-Lindau (VHL) disease in patients presenting with solitary retinal capillary hemangioma (RCH). METHODS: Ten patients with solitary RCH, who were excluded clinically as having VHL disease, underwent genetic testing using a combination of Southern blot, conformation sensitive gel electrophoresis, and direct sequence analysis. The results of the genetic tests were used to refine the empiric risk for VHL disease using principles of probability. RESULTS: Genetic testing for VHL disease was negative for mutation in all patients. The negative results of the genetic tests diminished the empiric risk for VHL disease by 100-fold. CONCLUSIONS: Solitary RCH can occur sporadically or be associated with VHL disease. In addition to clinical evaluation, genetic testing should be considered to exclude VHL disease with a high level of certainty.

7
UI - 11990821
AU - Weil RJ; Vortmeyer AO; Zhuang Z; Pack SD; Theodore N; Erickson RK;
TI - Oldfield EH Clinical and molecular analysis of disseminated hemangioblastomatosis of the central nervous system in patients without von Hippel-Lindau disease. Report of four cases.
SO - J Neurosurg 2002 Apr;96(4):775-87
AD - Surgical Neurology Branch, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1414, USA.
Hemangioblastomas of the central nervous system (CNS) may occur sporadically or in association with von Hippel-Lindau (VHL) syndrome. The authors present four patients with no family history or clinical evidence of VHL syndrome in whom extensive, progressive, en plaque coating of the brainstem and spinal cord with hemangioblastomas developed 1 to 8 years after complete resection of a solitary cerebellar hemangioblastoma. Analysis included detailed physical, biochemical, radiological, and pathological examinations in all four patients, combined with family pedigree analysis. In addition, a detailed investigation of the VHL gene was undertaken. Allelic loss, comparative genomic hybridization (CGH), single-stranded conformational polymorphism screening, CpG island methylation status, and X chromosome inactivation clonality analyses were performed. Although there was no evidence of germline alterations in the VHL gene on clinical and radiological examination or in the family history (all four patients) or analysis of peripheral blood (three patients), somatic deletion of one copy of the VHL gene occurred in these tumors. These findings indicate that the multiple, separate deposits of tumors were likely derived from a single clone. Results of CGH indicate that one or several additional genes are probably involved in the malignant behavior of the hemangioblastomas in these patients. Furthermore, the malignant biological and clinical behavior of these tumors, in which multiple sites of subarachnoid dissemination developed 1 to 8 years after initial complete resection, followed by progressive tumor growth and death of the patients, occurred despite a histological appearance typical of benign hemangioblastomas. Malignant hemangioblastomatosis developed 1 to 8 years after resection of an isolated cerebellar hemangioblastoma. Alterations of the VHL gene may be permissive in this setting, but other genes are likely to be the source of the novel biological and clinical presentation of the disseminated hemangioblastomas in these patients. This appears to represent a novel condition in which the product of one or more mutations in several genes permits malignant tumor behavior despite retention of a benign histological picture, a circumstance previously not recognized in CNS tumors.

The above citations and abstracts reflect those newly added to CANCERLIT for the month and topic listed in the title. The citations have been retrieved from CANCERLIT using a predefined search strategy of indexed subject terms. Although the search strategy has been refined as best as possible, citations may appear that are not directly related to the topic, and occasionally relevant references may be omitted.

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