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National Cancer Institute®
Ultima Vez Modificado: 1 de abril del 2002
UI - 7604013
AU - Duan DR; Humphrey JS; Chen DY; Weng Y; Sukegawa J; Lee S; Gnarra JR;
TI - Linehan WM; Klausner RD Characterization of the VHL tumor suppressor gene product: localization, complex formation, and the effect of natural inactivating mutations.
SO - Proc Natl Acad Sci U S A 1995 Jul 3;92(14):6459-63
AD - Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
The human VHL tumor suppressor gene has been implicated in the inherited disorder von Hippel-Lindau disease and in sporadic renal carcinoma. The homologous rat gene encodes a 185-amino acid protein that is 88% sequence identical to the aligned 213-amino acid human VHL gene product. When expressed in COS-7 cells, both the human and the rat VHL proteins showed predominant nuclear, nuclear and cytosolic, or predominant cytosolic VHL staining by immunofluorescence. A complicated pattern of cellular proteins was seen that could be specifically coimmunoprecipitated with the introduced VHL protein. A complex containing VHL and proteins of apparent molecular masses 16 and 9 kDa was the most consistently observed. Certain naturally occurring VHL missense mutations demonstrated either complete or partial loss of the p16-p9 complex. Thus, the VHL tumor suppressor gene product is a nuclear protein, perhaps capable of specifically translocating between the nucleus and the cytosol. It is likely that VHL executes its functions via formation of specific multiprotein complexes. Identification of these VHL-associated proteins will likely clarify the physiology of this tumor suppressor gene.
UI - 7552140
AU - Olschwang S; Boisson C; Richard S; Resche F; Thomas G
TI - DNA-based presymptomatic diagnosis for the von Hippel-Lindau disease by linkage analysis.
SO - Eur J Hum Genet 1995;3(2):108-15
AD - Laboratoire de Genetique des Tumeurs, INSERM U434, Institut Curie, Paris, France.
Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited condition characterized by a predisposition to the development of haemangioblastoma, renal cell carcinoma and phaeochromocytoma. The gene which, when altered, causes the disease was cloned in 1993, and maps within a series of known polymorphic loci in the 3p25-p26 region. To optimize a DNA-based presymptomatic diagnosis, we have selected six highly informative microsatellite loci, closely linked to the VHL gene. Genotyping using a multiplex-PCR approach was performed in 26 affected families including 99 asymptomatic relatives born from an affected parent. Ninety-six subjects were informative with one or more markers, 76 being informative with markers on both sides of the gene. Combination of age-related and DNA-based risk information improved the accuracy of risk assessment for 90 at-risk patients (91%) and allowed attribution of risk with a confidence limit higher than 0.98 in 79 cases (88%).
UI - 7563486
AU - Neumann HP; Eng C; Mulligan LM; Glavac D; Zauner I; Ponder BA; Crossey
TI - PA; Maher ER; Brauch H Consequences of direct genetic testing for germline mutations in the clinical management of families with multiple endocrine neoplasia, type II.
SO - JAMA 1995 Oct 11;274(14):1149-51
AD - Department of Nephrology and Hypertension, Albert-Ludwigs-University of Freiburg, Germany.
OBJECTIVE--Multiple endocrine neoplasia, type II (MEN-II) is an autosomal dominant disorder characterized by tumors of thyroid C cells and pheochromocytoma. Recently, germline mutations in the RET proto-oncogene have been identified in patients with MEN-II. The aims of this study were (1) to define the mutations in clinically diagnosed MEN-II families, (2) to compare the results of genetic and biochemical testing, and (3) to evaluate the impact of mutation analyses for the members of these families. DESIGN--Register-based survey study of clinically affected and unaffected members of MEN-II families. SETTING--Register of families from Germany and Spain with pheochromocytomas. Two research laboratories at Cambridge University in the United Kingdom. PATIENTS--We investigated consenting affected and unaffected members belonging to a series of 10 families who met the clinical criteria for MEN-II. MAIN OUTCOME MEASURES--(1) Presence or absence of germline mutation in the RET proto-oncogene in affected and unaffected members of the 10 families, and (2) in the absence of RET mutation in a given family, presence or absence of germline mutation in the von Hippel-Lindau (VHL) gene, which is the susceptibility gene involved in a closely related syndrome, von Hippel-Lindau disease. RESULTS--In eight of these families, RET mutations were identified. The specific mutations were detected in all affected members. The remaining two families without RET mutations were subsequently shown to have a mutation within the VHL gene. The VHL mutations were identified in both families and represent a previously undescribed base change. After identification of the mutation, premorbid genetic testing was performed in all MEN-II and VHL families, resulting in detection of asymptomatic carriers in the MEN-II families. Clinically, the two VHL families differed from the eight MEN-II families by the presence of a C-cell tumor in only one individual from each family and extra-adrenal pheochromocytoma in three of nine affected individuals in the two families combined. CONCLUSIONS--The diagnosis of MEN-II should be confirmed by molecular genetic analysis and the diagnosis of VHL syndrome should be considered for families with an absence of RET mutations and a preponderance of pheochromocytomas.
UI - 7585187
AU - Iliopoulos O; Kibel A; Gray S; Kaelin WG Jr
TI - Tumour suppression by the human von Hippel-Lindau gene product.
SO - Nat Med 1995 Aug;1(8):822-6
AD - Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
A partial cDNA sequence for the gene linked to the von Hippel-Lindau (VHL) syndrome was reported in 1993. Mutation or loss of both VHL alleles has been documented in sporadic renal cell carcinomas and in the neoplasms that arise in von Hippel-Lindau kindreds. We have determined that the protein product of the VHL gene is an approximately 30 kilodalton cytoplasmic protein. The renal carcinoma cell line 786-O is known to harbour a VHL mutation and, as shown here, fails to produce a wild-type VHL protein. Reintroduction of wild-type, but not mutant, VHL into these cells had no demonstrable effect on their growth in vitro but inhibited their ability to form tumours in nude mice.
UI - 8592333
AU - Crossey PA; Eng C; Ginalska-Malinowska M; Lennard TW; Wheeler DC; Ponder
TI - BA; Maher ER Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma.
SO - J Med Genet 1995 Nov;32(11):885-6
AD - Human Molecular Genetics Group, University of Cambridge, Department of Pathology, Addenbrooke's Hospital, UK.
Inherited predisposition to phaeochromocytoma is seen in multiple endocrine neoplasia type 2 syndromes, von Hippel-Lindau (VHL) disease, and neuro-fibromatosis type 1. In addition familial phaeochromocytoma alone has been reported. To investigate the genetic basis for familial phaeochromocytoma alone, we screened three affected kindreds for mutations in the RET proto-oncogene and the VHL tumour suppressor gene. We did not detect MEN 2 associated RET mutations in any family, but missense VHL gene mutations (V155L and R238W) were identified in two kindreds with no clinical evidence of VHL disease. Patients with familial, multiple, or early onset phaeochromocytoma should be investigated for germline VHL and RET gene mutations as the molecular diagnosis of multisystem familial cancer syndromes enables appropriate counselling and screening to be provided.
UI - 8718521
AU - Zbar B
TI - Von Hippel-Lindau disease and sporadic renal cell carcinoma.
SO - Cancer Surv 1995;25():219-32
AD - National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702, USA.
The VHL gene, isolated by positional cloning, encodes a protein of 284 aminoacids that has no homology with other proteins in the databases. The nucleotide sequence lacks domains that would suggest (a) a DNA binding protein, (b) nuclear localization, (c) enzymatic activity or (d) membrane localization. Studies are in progress on the size and cellular localization of the VHL protein and how it may function in growth regulation. How mutations in this small protein lead to a specific tumour spectrum presents an enormous research challenge. Germline mutations in the VHL gene are heterogeneous, and the resulting heterogeneity of mutations in the VHL protein that lead to disease suggests a protein whose function can be compromised by mutations over a large area. Study of the germline mutations and correlation with disease patterns provide the basis for a new clinical classification of von Hippel-Lindau disease. Somatic VHL mutations and hypermethylation of the VHL gene are found in some 75-80% of sporadic clear cell renal carcinomas. About 20% of clear cell renal carcinomas show neither VHL gene mutation or hypermethylation. Whether other chromosome 3 tumour suppressor genes have a pathogenetic role in clear cell renal carcinoma remains to be determined. Sorting out the contributions of different tumour suppressor genes to the pathogenesis of clear cell renal carcinomas will require assays demonstrating somatic mutation of candidate genes and functional assays to determine whether replacement of the mutant gene is associated with suppressed tumour growth.
UI - 7660121
AU - Krumm A; Groudine M
TI - Tumor suppression and transcription elongation: the dire consequences of changing partners.
SO - Science 1995 Sep 8;269(5229):1400-1
AD - Division of Basic Sciences, Hutchinson Cancer Center, Seattle, WA 98104, USA.
UI - 7660122
AU - Duan DR; Pause A; Burgess WH; Aso T; Chen DY; Garrett KP; Conaway RC;
TI - Conaway JW; Linehan WM; Klausner RD Inhibition of transcription elongation by the VHL tumor suppressor protein.
SO - Science 1995 Sep 8;269(5229):1402-6
AD - Urologic Oncology Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Germline mutations in the von Hippel-Lindau tumor suppressor gene (VHL) predispose individuals to a variety of tumors, including renal carcinoma, hemangioblastoma of the central nervous system, and pheochromocytoma. Here, a cellular transcription factor, Elongin (SIII), is identified as a functional target of the VHL protein. Elongin (SIII) is a heterotrimer consisting of a transcriptionally active subunit (A) and two regulatory subunits (B and C) that activate transcription elongation by RNA polymerase II. The VHL protein was shown to bind tightly and specifically to the Elongin B and C subunits and to inhibit Elongin (SIII) transcriptional activity in vitro. These findings reveal a potentially important transcriptional regulatory network in which the VHL protein may play a key role.
UI - 7660130
AU - Kibel A; Iliopoulos O; DeCaprio JA; Kaelin WG Jr
TI - Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C.
SO - Science 1995 Sep 8;269(5229):1444-6
AD - Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Germ-line mutations of the von Hippel-Lindau tumor suppressor gene (VHL) predispose individuals to a variety of human tumors, and somatic mutations of this gene have been identified in sporadic renal cell carcinomas and cerebellar hemangioblastomas. Two transcriptional elongation factors, Elongin B and C, were shown to bind in vitro and in vivo to a short, colinear region of the VHL protein (pVHL) that is frequently mutated in human tumors. A peptide replica of this region inhibited binding of pVHL to Elongin B and C whereas a point-mutant derivative, corresponding to a naturally occurring VHL missense mutation, had no effect. These results suggest that the tumor suppression function of pVHL may be linked to its ability to bind to Elongin B and C.
UI - 8603073
AU - Gnarra JR; Duan DR; Weng Y; Humphrey JS; Chen DY; Lee S; Pause A; Dudley
TI - CF; Latif F; Kuzmin I; Schmidt L; Duh FM; Stackhouse T; Chen F; Kishida T; Wei MH; Lerman MI; Zbar B; Klausner RD; Linehan WM Molecular cloning of the von Hippel-Lindau tumor suppressor gene and its role in renal carcinoma.
SO - Biochim Biophys Acta 1996 Mar 18;1242(3):201-10
AD - Urilogic Oncology Section, Surgery Branch, National Cancer Institute, Bethesda, Maryland 20892-1502, USA.
UI - 8625303
AU - Siemeister G; Weindel K; Mohrs K; Barleon B; Martiny-Baron G; Marme D
TI - Reversion of deregulated expression of vascular endothelial growth factor in human renal carcinoma cells by von Hippel-Lindau tumor suppressor protein.
SO - Cancer Res 1996 May 15;56(10):2299-301
AD - Institute of Molecular Medicine, Tumor Biology Center, Freiburg, Germany.
Mutations or loss of both alleles of the von Hippel-Lindau (VHL) tumor suppressor gene has been documented in sporadic renal cell carcinomas and neoplasms that arise in individuals having the VHL syndrome. The well-vascularized phenotype of tumors that form in VHL disease let us consider vascular endothelial growth factor (VEGF) as a mediator of tumor growth in VHL disease. Human renal carcinoma cells that either lacked endogenous wild-type VHL or were transfected with an inactive mutant VHL showed deregulated expression of VEGF on the mRNA and protein level that was reverted by introduction of wild-type VHL. Stimulation of proliferation of endothelial cells by conditioned medium of cells expressing mutant VHL was almost abolished by neutralizing the VEGF. In contrast, expression of basic fibroblast growth factor and of c-myc proto-oncogene was not affected by VHL. Our data suggest VEGF as the key tumor angiogenesis factor in VHL disease.
UI - 8630511
AU - Bertherat J
TI - Von Hippel-Lindau tumor suppressor protein and transcription elongation: new insights into regulation of gene expression.
SO - Eur J Endocrinol 1996 Feb;134(2):157, 159
AD - Service d'Endocrinologie, INSERM, Paris, France.
UI - 8730290
AU - Maher ER; Webster AR; Richards FM; Green JS; Crossey PA; Payne SJ; Moore
TI - AT Phenotypic expression in von Hippel-Lindau disease: correlations with germline VHL gene mutations.
SO - J Med Genet 1996 Apr;33(4):328-32
AD - Cambridge University Department of Pathology, UK.
Von Hippel-Lindau disease is an autosomal dominantly inherited familial cancer syndrome predisposing to retinal and central nervous system haemangioblastomas, renal cell carcinoma, and phaeochromocytoma. VHL disease shows variable expression and interfamilial differences in predisposition to phaeochromocytoma. In a previous study of 65 VHL kindreds with defined VHL mutations we detected significant differences between VHL families with and without phaeochromocytoma such that missense mutations were more common and large deletions or protein truncating mutations less frequent in phaeochromocytoma positive families. To investigate the significance and cause of this association further, we studied 138 VHL kindreds for germline mutations and calculated the age related tumour risks for different classes of VHL gene mutations. Using SSCP, heteroduplex and Southern analysis we identified a germline VHL gene mutation in 101 families (73%). Direct sequencing of the VHL coding region further increased the mutation detection rate to 81%. In addition to precise presymptomatic diagnosis, identification of a VHL gene mutation can provide an indication of the likely phenotype. We found that large deletions and mutations predicted to cause a truncated protein were associated with a lower risk of phaeochromocytoma (6% and 9% at 30 and 50 years, respectively) than missense mutations (40% and 59%, respectively) and that missense mutations at codon 167 were associated with a high risk of phaeochromocytoma (53% and 82% at ages 30 and 50 years). Cumulative probabilities of renal cell carcinoma did not differ between the two groups (deletion/ truncation mutations: 8% and 60%, and missense mutations: 10% and 64% at ages 30 and 50 years, respectively). Age related risks for haemangioblastoma were similar in the two mutation groups, with the age related risks of cerebellar haemangioblastoma slightly less (35% and 64% v 38% and 75% at ages 30 and 50 years) and retinal haemangioblastoma slightly higher (45% and 72% v 37% and 64% at ages 30 and 50 years) in the missense mutation group than in the deletion/protein truncation group. These results provide valuable data for counselling VHL families and indicate that specific VHL mutations may be associated with different tumour susceptibility risks. There was no evidence of a generalised increase in age related tumour risks for missense mutations, suggesting that missense mutations predisposing to phaeochromocytoma have tissue specific effects, possibly because the VHL protein has several functions, the importance of which varies from tissue to tissue, or because the proteins which interact with VHL differ between different tissues.
UI - 8810329
AU - Takagi Y; Conaway RC; Conaway JW
TI - Characterization of elongin C functional domains required for interaction with elongin B and activation of elongin A.
SO - J Biol Chem 1996 Oct 11;271(41):25562-8
AD - Program in Molecular and Cell Biology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
The Elongin (SIII) complex stimulates the rate of elongation by RNA polymerase II by suppressing transient pausing by polymerase at many sites along DNA templates. The Elongin (SIII) complex is composed of a transcriptionally active A subunit, a chaperone-like B subunit, which promotes assembly and enhances stability of the Elongin (SIII) complex, and a regulatory C subunit, which (i) functions as a potent activator of Elongin A transcriptional activity, (ii) interacts specifically with Elongin B to form an isolable Elongin BC complex, and (iii) is bound and negatively regulated in vitro by the product of the von Hippel-Lindau tumor suppressor gene. As part of our effort to understand how Elongin C regulates the activity of the Elongin (SIII) complex, we are characterizing Elongin C functional domains. In this report, we identify Elongin C mutants that fall into multiple functional classes based on their abilities to bind Elongin B and to bind and activate Elongin A under our assay conditions. Characterization of these mutants suggests that Elongin C is composed of multiple overlapping regions that mediate functional interactions with Elongin A and B.
UI - 8863170
AU - Chen F; Slife L; Kishida T; Mulvihill J; Tisherman SE; Zbar B
TI - Genotype-phenotype correlation in von Hippel-Lindau disease: identification of a mutation associated with VHL type 2A.
SO - J Med Genet 1996 Aug;33(8):716-7
AD - Science Applications International Corp, Frederick, MD 21702, USA.
A family with von Hippel-Lindau disease (VHL) type 2A has been shown to have a T to C missense mutation at nucleotide 547 of the VHL gene. This gives further support for the proposal to associate the 547 T to C mutation with phenotype VHL 2A.
UI - 8952541
AU - Lubensky IA; Gnarra JR; Bertheau P; Walther MM; Linehan WM; Zhuang Z
TI - Allelic deletions of the VHL gene detected in multiple microscopic clear cell renal lesions in von Hippel-Lindau disease patients.
SO - Am J Pathol 1996 Dec;149(6):2089-94
AD - Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892, USA.
Patients with von Hippel-Lindau (VHL) disease develop a spectrum of bilateral clear-cell renal lesions including cysts and renal cell carcinomas (RCCs). VHL gene deletions have been previously reported in VHL-associated macroscopic RCC. Although histological analysis suggests that microscopic cystic lesions in the VHL patients may represent precursors of the RCC, there is at present no direct molecular evidence of their relationship. To investigate the relationship between cystic lesions and RCC, 26 microdissected archival renal lesions from two VHL disease patients were studied for loss of heterozygosity at the VHL gene locus using polymerase chain reaction single-strand conformation polymorphism analysis. The renal lesions included 2 benign cysts, 5 atypical cysts, 5 microscopic RCCs in situ, 5 cysts lined by a single layer of cells, in which RCCs in situ were developing, and 2 microscopic and 7 macroscopic RCCs. Except for a single benign cyst, 25 of 26 renal lesions showed nonrandom allelic loss of the VHL gene. In either of the 2 patients, the same VHL allele was deleted in all of the lesions tested, indicating loss of the wild-type allele and retention of the inherited, mutated VHL allele. The results suggest that all clear-cell lesions in the VHL kidney represent neoplasms and that the loss of the VHL gene occurs early in their development. Atypical and benign cysts most likely represent the initial phenotype in malignant transformation to the RCC.
UI - 8930647
AU - Wizigmann-Voos S; Plate KH
TI - Pathology, genetics and cell biology of hemangioblastomas.
SO - Histol Histopathol 1996 Oct;11(4):1049-61
AD - Neurozentrum der Albert-Ludwigs-Universitat, Abteilung Neuropathologie, Freiburg, Germany.
Hemangioblastomas are highly vascularized tumors of not well-defined histological origin which are frequently associated with cysts. They arise preferentially in cerebellum, medulla and spinal cord and are histologically indistinguishable from vascular lesions in the retina (so-called angiomatosis retinae). Hemangioblastomas are the most frequent manifestations of the von Hippel-Lindau (VHL) disease, an autosomal-dominant inherited cancer syndrome but also occur as sporadic non-hereditary tumors. The VHL tumor suppressor gene has recently been cloned and enormous progress has been made towards the understanding of molecular biology and biological function of the VHL gene. Germline mutations in VHL patients, as well as somatic mutations in different tumors, including hemangioblastomas, have been identified, its ability to act as a tumor suppressor in vivo has been confirmed, and interaction with transcription factors Elongin B and C leading to inhibition of transcriptional elongation has been demonstrated. The mechanism underlying neovascularization and cyst formation in hemangioblastomas and how this is linked to inactivation of the VHL tumor suppressor gene is not known. However, the finding of dramatic up-regulation of vascular endothelial growth factor (VEGF), a potent endothelial cell growth factor with vascular permeability-inducing activity, in stromal cells and the corresponding receptors, VEGFR-1 and VEGFR-2, in tumor endothelial cells suggests that angiogenesis and cyst formation in hemangioblastomas may be regulated by this signaling pathway via a paracrine mechanism.
UI - 8956040
AU - Zbar B; Kishida T; Chen F; Schmidt L; Maher ER; Richards FM; Crossey PA;
TI - Webster AR; Affara NA; Ferguson-Smith MA; Brauch H; Glavac D; Neumann HP; Tisherman S; Mulvihill JJ; Gross DJ; Shuin T; Whaley J; Seizinger B; Kley N; Olschwang S; Boisson C; Richard S; Lips CH; Lerman M; et al Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan.
SO - Hum Mutat 1996;8(4):348-57
AD - Laboratory of Immunobiology, Biological Carcinogenesis and Development Program, SAIC Frederick, Maryland, USA.
Germline mutation analysis was performed in 469 VHL families from North America, Europe, and Japan. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected. Most of the germline VHL mutations (124/137) occurred in 1-2 families; a few occured in four or more families. The common germline VHL mutations were: delPhe76, Asn78Ser, Arg161Stop, Arg167Gln, Arg167Trp, and Leu178Pro. In this large series, it was possible to compare the effects of identical germline mutations in different populations. Germline VHL mutations produced similar cancer phenotypes in Caucasian and Japanese VHL families. Germline VHL mutations were identified that produced three distinct cancer phenotypes: (1) renal carcinoma without pheochromocytoma, (2) renal carcinoma with pheochromocytoma, and (3) pheochromocytoma alone. The catalog of VHL germline mutations with phenotype information should be useful for diagnostic and prognostic studies of VHL and for studies of genotype-phenotype correlations in VHL.
UI - 8733131
AU - Richards FM; Schofield PN; Fleming S; Maher ER
TI - Expression of the von Hippel-Lindau disease tumour suppressor gene during human embryogenesis.
SO - Hum Mol Genet 1996 May;5(5):639-44
AD - Cambridge University Department of Pathology, UK.
The von Hippel-Lindau (VHL) disease product is thought to down-regulate transcription by antagonizing elongin-enhanced transcriptional elongation. Germline VHL gene mutations predispose to the development of retinal, cerebellar and spinal haemangioblastomas, renal cell carcinoma and phaeochromocytoma. In addition, somatic Inactivation of the VHL gene is frequent in sporadic renal cell carcinoma and haemangioblastoma. Regulation of transcript elongation is an important control mechanism for gene expression and the VHL gene might modify the expression of proto-oncogenes and growth suppressor genes during embryogenesis. We therefore investigated the expression of VHL mRNA during human embryogenesis by in situ hybridization studies at 4, 6 and 10 weeks post conception. Although VHL mRNA was expressed in all three germ layers, strong expression was noted in the central nervous system, kidneys, testis and lung. Within the kidney, VHL mRNA was differentially expressed within renal tubules suggesting that the VHL gene product may have a specific role in kidney development. Two alternatively spliced VHL mRNAs characterized by inclusion (isoform I) or exclusion (isoform II) of exon 2 are transcribed in adult tissues. To investigate if the two isoforms are differentially expressed during embryogenesis, VHL mRNA was reverse transcribed from 13 fetal tissues (8-10 weeks gestation). The quantitative distribution of VHL mRNA within fetal tissues reflected that seen by in situ hybridization and the ratio of the two VHL isoforms was similar between tissues. Although the genes regulated by the VHL gene product have not yet been identified, our findings are compatible with the hypothesis that VHL-mediated control of transcriptional elongation may have a role in normal human development.
UI - 9239471
AU - Humphrey JS; Klausner RD; Linehan WM
TI - Von Hippel-Lindau syndrome: hereditary cancer arising from inherited mutations of the VHL tumor suppressor gene.
SO - Cancer Treat Res 1996;88():13-39
UI - 9062583
AU - Decker HJ; Weidt EJ; Brieger J
TI - The von Hippel-Lindau tumor suppressor gene. A rare and intriguing disease opening new insight into basic mechanisms of carcinogenesis.
SO - Cancer Genet Cytogenet 1997 Jan;93(1):74-83
AD - Department of Hematology and Oncology, Johannes-Gutenberg University, Mainz, Germany.
The von Hippel-Lindau (VHL) disease is an inherited tumor susceptibility syndrome featuring a high variety of benign and malignant tumors. The gene has been localized and cloned at 3p25-26. Recent functional analysis defined the VHL gene product as an inhibitor of the transcription elongation process. Its possible involvement in the vascularization process may explain the histologic features of VHL tumors providing insight into basic mechanism of tumorigenesis. Direct genetic testing is available for patients affected with VHL. Seventy to eighty percent of the germline mutations expected could be detected. As first geno/phenotype correlations have been established, we are now beginning to understand the diversity of this fascinating disease at the molecular level. As mutational analysis proved to be of striking prognostic significance, gene testing became an important tool for the management of the disease. The VHL gene was also found to be responsible for tumorigenesis in the corresponding sporadic tumors, especially in the clear cell type of renal cell carcinomas. The understanding of the normal and disturbed function of the VHL gene product will enable us to develop treatment strategies based on and targeted at the molecular cause of the disease. In this review we summarize the current knowledge about genetics, clinics, and function of VHL.
UI - 9122164
AU - Pause A; Lee S; Worrell RA; Chen DY; Burgess WH; Linehan WM; Klausner RD
TI - The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins.
SO - Proc Natl Acad Sci U S A 1997 Mar 18;94(6):2156-61
AD - Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. email@example.com
The inactivation of the von Hippel-Lindau (VHL) gene predisposes affected individuals to VHL syndrome and is an early genetic event associated with sporadic renal cell carcinoma and CNS hemangioblastomas. The VHL protein (pVHL) has been shown to form a stable complex with elongin B and elongin C, two factors that stabilize and activate the transcription elongation factor elongin A. Here, Hs-CUL-2, a member of the recently identified multigene family, the cullins, is shown to specifically associate with the trimeric pVHL-elongin B-C (VBC) complex in vitro and in vivo. Nearly 70% of naturally occurring cancer-predisposing mutations of VHL disrupt this interaction. The pVHL-Hs-CUL-2 association is strictly dependent on the integrity of the trimeric VBC complex. Immunofluorescence studies show Hs-CUL-2 to be a cytosolic protein that can be translocated to the nucleus by pVHL. Recently it has been shown that a yeast Hs-CUL-2 homolog, Cdc53, is part of a ubiquitin protein ligase complex that targets cell cycle proteins for degradation by the ubiquitin proteolytic pathway. In Caenorhabditis elegans, a null mutation of another Hs-cul-2 homolog, Ce-cul-1, results in hyperplasia in all tissues and is required for cell cycle exit. Hence, Hs-cul-2 may be required for VHL function and, therefore, may be a candidate human tumor-suppressor gene.
UI - 9106522
AU - Prowse AH; Webster AR; Richards FM; Richard S; Olschwang S; Resche F;
TI - Affara NA; Maher ER Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors.
SO - Am J Hum Genet 1997 Apr;60(4):765-71
AD - Cambridge University Department of Pathology.
Von Hippel-Lindau (VHL) disease is a dominantly inherited disorder predisposing to retinal and CNS hemangioblastomas, renal cell carcinoma (RCC), pheochromocytoma, and pancreatic tumors. Interfamilial differences in predisposition to pheochromocytoma reflect allelic heterogeneity such that there is a strong association between missense mutations and risk of pheochromocytoma. We investigated the mechanism of tumorigenesis in VHL disease tumors to determine whether there were differences between tumor types or classes of germ-line mutations. Fifty-three tumors (30 RCCs, 15 hemangioblastomas, 5 pheochromocytomas, and 3 pancreatic tumors) from 33 patients (27 kindreds) with VHL disease were analyzed. Overall, 51% of 45 informative tumors showed loss of heterozygosity (LOH) at the VHL locus. In 11 cases it was possible to distinguish between loss of the wild-type and mutant alleles, and in each case the wild-type allele was lost. LOH was detected in all tumor types and occurred in the presence of both germ-line missense mutations and other types of germline mutation associated with a low risk of pheochromocytoma. Intragenic somatic mutations were detected in three tumors (all hemangioblastomas) and in two of these could be shown to occur in the wild-type allele. This provides the first example of homozygous inactivation of the VHL by small intragenic mutations in this type of tumor. Hypermethylation of the VHL gene was detected in 33% (6/18) of tumors without LOH, including 2 RCCs and 4 hemangioblastomas. Although hypermethylation of the VHL gene has been reported previously in nonfamilial RCC and although methylation of tumor-suppressor genes has been implicated in the pathogenesis of other sporadic cancers, this is the first report of somatic methylation in a familial cancer syndrome.
UI - 9145719
AU - Manski TJ; Heffner DK; Glenn GM; Patronas NJ; Pikus AT; Katz D; Lebovics
TI - R; Sledjeski K; Choyke PL; Zbar B; Linehan WM; Oldfield EH Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease.
SO - JAMA 1997 May 14;277(18):1461-6
AD - Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1414, USA.
OBJECTIVES: Isolated reports suggest a possible association of endolymphatic sac tumors (ELSTs), which are extremely rare in the general population, with von Hippel-Lindau disease (VHL). To determine if hearing loss and ELSTs are a component of VHL, we examined prevalence, clinical presentation, and natural history of hearing loss and ELSTs in VHL. DESIGN: Brain magnetic resonance images (MRIs) from 374 patients screened for VHL were reviewed for evidence of ELSTs. The VHL patients with MRI evidence suggestive of ELSTs or a history of hearing loss, tinnitus, or vertigo underwent additional radiologic and audiologic evaluations. To further assess prevalence of hearing loss and ELST in VHL, the next 66 patients screened in the VHL clinic (49 with proven VHL, 17 at risk for VHL) received MRI and audiologic assessment. SETTING: Referral center. PARTICIPANTS: Study subjects comprised 374 persons screened for VHL, 66 consecutive patients with VHL or at risk for VHL, 4 patients with 6 ELSTs, and 13 previously reported patients with VHL and invasive tumors of the temporal bone. INTERVENTION: Magnetic resonance image and computed tomographic (CT) scan of the posterior fossa and audiologic assessment. MAIN OUTCOME MEASURES: Any ELST visible on MRI or CT and hearing loss compatible with ELST. RESULTS: Magnetic resonance imaging revealed evidence of 15 ELSTs in 13 (11%) of 121 patients with VHL, but in none of the 253 patients without evidence of VHL (P<.001). Clinical findings in these 13 patients included hearing loss (13), tinnitus (12), vertigo (8), and facial paresis (1). Mean age at onset of hearing loss was 22 years (range, 12-50 years). Hearing for pure tones was abnormal in all affected ears and in 6 of the 11 additional, allegedly unaffected ears. In 8 patients (62%), hearing loss was the first manifestation of VHL. Presence or absence of hearing loss was associated with duration of symptoms (P<.002) and with tumor size (P<.01). Further, 43 (65%) of the 66 patients from the VHL clinic had pure tone threshold abnormalities, abnormalities that occurred bilaterally in 23 (54%) of the 43 affected subjects; however, evidence is lacking for a definitive association with ELST (3 [6%] of 49 patients with proven VHL had ELST evident on MRI). CONCLUSIONS: Hearing loss and ELSTs are frequently associated with VHL syndrome and should be considered when screening individuals at risk for VHL and when monitoring patients with an established diagnosis of VHL. Many patients with VHL have hearing loss without radiographic evidence of an ELST. Whether it is caused by an ELST that is too small to be detected by MRI or is produced by some other etiology is still unknown. Audiologic evaluation and MRI should allow early detection and enhance management of hearing loss in these patients.
UI - 9027742
AU - Levy AP; Levy NS; Iliopoulos O; Jiang C; Kaplin WG Jr; Goldberg MA
TI - Regulation of vascular endothelial growth factor by hypoxia and its modulation by the von Hippel-Lindau tumor suppressor gene.
SO - Kidney Int 1997 Feb;51(2):575-8
AD - Department of Medicine, Georgetown University Medical School, Washington, D.C., USA.
The regulation of VEGF production is mediated by both transcriptional and post-transcriptional mechanisms. A schematic model of elements involved in hypoxic regulation of VEGF is shown in Figure 1.
UI - 9158701
AU - Vortmeyer AO; Gnarra JR; Emmert-Buck MR; Katz D; Linehan WM; Oldfield
TI - EH; Zhuang Z von Hippel-Lindau gene deletion detected in the stromal cell component of a cerebellar hemangioblastoma associated with von Hippel-Lindau disease.
SO - Hum Pathol 1997 May;28(5):540-3
AD - Laboratory of Pathology and Surgery Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Central nervous system hemangioblastoma is a neoplasm with characteristic and well-described histopathological features, including proliferation of vascular and stromal cells. yet, the histogenesis of the stromal cell component and its neoplastic capacity as compared with the vascular component are still controversial. Stromal cells were selectively procured from formalin-fixed, paraffin-embedded archival tissue from a von Hippel-Lindau (VHL) disease patient with a cerebellar hemangioblastoma and studied for loss of heterozygosity (LOH) of the VHL gene locus and associated microsatellite regions. The stromal cells consistently showed LOH. Analysis of mixed stromal anti vascular areas of this tumor and four other hemangioblastomas of VHL patients showed that loss of heterozygosity was partially obscured. These preliminary results suggest that the stromal component of hemangioblastomas contains genetic alterations consistent with a neoplastic nature. Additional samples of pure stromal cells need to be analyzed to establish the prevalence of VHL gene deletion in stromal cells of capillary hemangioblastoma and, hence, its pathogenetic significance.
UI - 9206740
AU - Brauch H
TI - [Hippel-Lindau syndrome. Clinical and genetic aspects of angiomatosis retinae]
SO - Klin Monatsbl Augenheilkd 1997 Mar;210(3):aA1
UI - 9156283
AU - Fleming S
TI - Genetics of renal tumours.
SO - Cancer Metastasis Rev 1997 Jun;16(1-2):127-40
AD - Department of Pathology, University of Edinburgh, UK.
The two main renal tumours, Wilms' tumour and renal cell carcinoma, are associated with distinct molecular genetic abnormalities. The genes involved behave as Knudson oncosuppressor genes. Further dissection of the molecular biology pathways involving WT1 and VHL genes is providing fascinating insight into the biology of these genes, the development and cell biology of the kidney and its tumours.
UI - 9218518
AU - Chung DC; Smith AP; Louis DN; Graeme-Cook F; Warshaw AL; Arnold A
TI - A novel pancreatic endocrine tumor suppressor gene locus on chromosome 3p with clinical prognostic implications.
SO - J Clin Invest 1997 Jul 15;100(2):404-10
AD - Laboratory of Endocrine Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. firstname.lastname@example.org
The molecular pathogenesis of pancreatic endocrine tumors is largely unknown. Such tumors are more likely to develop in individuals with the von Hippel-Lindau (VHL) syndrome. We sought to determine whether allelic loss of the recently identified VHL tumor suppressor gene on chromosome 3p25-26 occurs in the more common sporadic forms of these tumors. Allelic loss on chromosome 3p was identified in 33% of 43 patients with endocrine tumors of the pancreas. The smallest common region of allelic loss, however, centered not at the VHL locus, but rather at 3p25, centromeric to VHL. Furthermore, no mutations of the VHL gene were identified in thes
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