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.
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