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NCI CANCERLIT® Search: Von Hippel-Lindau Syndrome - April 2002
National Cancer Institute®
Ultima Vez Modificado: 1 de abril del 2002
Table of Contents
1
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.
2
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%).
3
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.
4
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.
5
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.
6
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.
7
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.
8
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.
9
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.
10
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.
11
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.
12
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.
13
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.
14
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.
15
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.
16
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.
17
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.
18
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.
19
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.
20
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
21
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.
22
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. apause@box-a.nih.gov
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.
23
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.
24
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.
25
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.
26
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.
27
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
28
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.
29
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.
d_chung@helix.mgh.harvard.edu
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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