• Genetic and functional analysis of the von Hippel-Lindau (VHL) tumour suppressor gene promoter.

• Comorbid VHL and SCA2 mutations in a large kindred: confounding diagnosis of neurological dysfunction caused by CNS VHL vascular tumours

• Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire

• Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study.

• Germ-line mutations in nonsyndromic pheochromocytoma.

• HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron.

1
UI - 12114475
AU - Zatyka M; Morrissey C; Kuzmin I; Lerman MI; Latif F; Richards FM; Maher
TI - ER Genetic and functional analysis of the von Hippel-Lindau (VHL) tumour suppressor gene promoter.
SO - J Med Genet 2002 Jul;39(7):463-72
AD - Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, The Medical School, Edgbaston, Birmingham B15 2TT, UK.
The VHL gatekeeper tumour suppressor gene is inactivated in the familial cancer syndrome von Hippel-Lindau disease and in most sporadic clear cell renal cell carcinomas. Recently the VHL gene product has been identified as a specific component of a SCF-like complex, which regulates proteolytic degradation of the hypoxia inducible transcription factors HIF-1 and HIF-2. pVHL is critical for normal development and mRNA expression studies suggest a role in nephrogenesis. Despite the importance of VHL in oncogenesis and development, little is known about the regulation of VHL expression. To investigate VHL promoter activity, we performed comparative sequence analysis of human, primate, and rodent 5' VHL sequences. We then proceeded to deletion analysis of regions showing significant evolutionary conservation between human and rat promoter sequences, and defined two positive and one negative regulatory regions. Analysis of specific putative transcription factor binding sites identified a functional Sp1 site, which was shown to be a regulatory element. Overlapping Sp1/AP2 sites were also identified and candidate E2F1 binding sites evaluated. Three binding sites for as yet unidentified transcription factors were mapped also. These investigations provide a basis for elucidating the regulation of VHL expression in development, the molecular pathology of epigenetic silencing of VHL in tumourigenesis, and suggest a possible link between Sp1, VHL, and nephrogenesis.

2
UI - 12114494
AU - McNeil DE; Linehan WM; Glenn GM
TI - Comorbid VHL and SCA2 mutations in a large kindred: confounding diagnosis of neurological dysfunction caused by CNS VHL vascular tumours versus SCA2 atrophic neurodegeneration.
SO - J Med Genet 2002 Jul;39(7):E37

3
UI - 12114495
AU - Cybulski C; Krzystolik K; Murgia A; Gorski B; Debniak T; Jakubowska A;
TI - Martella M; Kurzawski G; Prost M; Kojder I; Limon J; Nowacki P; Sagan L; Bialas B; Kaluza J; Zdunek M; Omulecka A; Jaskolski D; Kostyk E; Koraszewska-Matuszewska B; Haus O; Janiszewska H; Pecold K; Starzycka M; Slomski R; Cwirko M; Sikorski A; Gliniewicz B; Cyrylowski L; Fiszer-Maliszewska L; Gronwald J; Toloczko-Grabarek A; Zajaczek S; Lubinski J Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene.
SO - J Med Genet 2002 Jul;39(7):E38
AD - Department of Genetics and Pathology, Pomeranian Academy of Medicine, Szczecin, Poland. cezaryc@priv6.onet.pl

4
UI - 12202531
AU - Dollfus H; Massin P; Taupin P; Nemeth C; Amara S; Giraud S; Beroud C;
TI - Dureau P; Gaudric A; Landais P; Richard S Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study.
SO - Invest Ophthalmol Vis Sci 2002 Sep;43(9):3067-74
AD - Federation de Genetique, Ophthalmology Department, Hopitaux Universitaires de Strasbourg, Strasbourg, France. helene.dollfus@medecine.u-strasbg.fr
PURPOSE: To assess the natural history of retinal manifestations in von Hippel-Lindau (VHL) disease and to study the genotype-phenotype correlation. METHODS: Data concerning 103 patients with VHL retinal manifestations and 108 patients without VHL retinal manifestations were extracted from the French VHL database. A retrospective study was performed by questionnaire. Patients were classified into three visual morbidity groups. Molecular analysis of the VHL gene was performed in 196 patients. RESULTS: The mean age of ocular manifestations detection was 24.8 years. In half of the cases, the ocular manifestations revealed the disease. Half of the cases had bilateral involvement. Visual morbidity was significantly associated with the retinal hemangioblastoma count but not with other ocular or general characteristics. One third of the patients were classified in the worst visual morbidity group at the end of follow-up. Mutations were detected in 81% of patients with retinal hemangioblastomas and in 71% of patients without retinal involvement. Using a Poisson model and a marginal approach, the number of hemangioblastomas, age-adjusted, was 2.1 times higher in patients who had a substitution than in patients with a truncation (95% CI, 1.05-4.44; P < 0.05). CONCLUSIONS: Visual loss remains one of the major complications of VHL disease, confirming the importance of early ophthalmologic screening. Visual morbidity was not related to the type of extraocular manifestation but appeared to be related to the type of germline mutation. However, only further genetic and clinical studies in a larger series of patients will clearly determine the genotype-phenotype relationship.

5
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; Eng C; 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.

6
UI - 12124175
AU - Mandriota SJ; Turner KJ; Davies DR; Murray PG; Morgan NV; Sowter HM;
TI - Wykoff CC; Maher ER; Harris AL; Ratcliffe PJ; Maxwell PH HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron.
SO - Cancer Cell 2002 Jun;1(5):459-68
AD - Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, United Kingdom.
Mutations in the von Hippel-Lindau (VHL) gene are associated with hereditary and sporadic clear cell renal carcinoma. VHL acts in a ubiquitin ligase complex regulating hypoxia-inducible factor-1 (HIF-1), but the link between this function and cancer development is unclear. Here we show that in the kidneys of patients with VHL disease, HIF activation is an early event occurring in morphologically normal single cells within the renal tubules. In comparison, dysplastic lesions, cystic lesions, and tumors showed evidence of additional mechanisms that amplify HIF activation. Detection of cells with constitutive HIF activation identified a large number of previously unrecognized foci of VHL inactivation. In proximal tubules these were almost entirely unicellular, whereas multicellular foci were almost exclusively seen in the distal nephron.

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