While HIF activation explains the highly vascularized nature of VHL loss lesions, the relative role of HIF in oncogenesis and loss of growth control remains unknown.
We have used a conditional gene-targeting approach to investigate the relative contributions of HIF-1 and HIF-2 to VHL-associated vascular tumorigenesis in a mouse model of liver hemangiomas.
To identify candidate genes for renal tumorigenesis we characterized a constitutional translocation, t(3;6)(q22;q16.1) associated with multicentric RCC without evidence of VHL target gene dysregulation.
To elucidate the aetiological role of the VHL gene in human kidney tumorigenesis, localized and advanced tumours from 110 patients with sporadic renal carcinoma were analysed for VHL mutations and loss of heterozygosity (LOH).
To determine whether the von Hippel-Lindau (VHL) disease tumor suppressor gene located at 3p25 is responsible for oncogenesis in lung cancer, we searched the known open reading frame using the single-strand conformation polymorphism (SSCP) technique for mutations in the VHL gene in 72 cancer cell lines including small cell (SCLC) and non-small cell (NSCLC) lung cancers, carcinoids, and mesotheliomas.
To delineate more precisely the somatic von Hippel-Lindau disease (VHL) gene alteration as well as to elucidate its etiologic role in renal tumorigenesis, we examined a total of 240 sporadic renal cell carcinomas (RCCs) for somatic VHL gene alterations by DNA-SSCP followed by sequencing, methylation-specific PCR assay, microsatellite LOH study, and Southern blot analysis.
To assess the role of elongin B/C, Rbx1 and HIF-1alpha in RCC tumorigenesis we (a) mapped the genes to chromosomes 8q(cen) (elongin C), 16p13.3 (elongin B) and 22q11.2 (Rbx1) by FISH, monochromosomal somatic cell hybrid panel screening and in silico GenBank homology searching; (b) determined the genomic organisation of elongin C (by direct sequencing of PAC clones), Rbx1 and elongin B (by GenBank homology searching); and (c) performed mutation analysis of exons comprising the coding regions of elongins B, C and Rbx1 and the oxygen-dependent degradation domain of HIF-1alpha by SSCP screening and direct sequencing in 35 sporadic clear cell RCC samples without VHL gene inactivation and in 13 individuals with familial non-VHL clear cell RCC.
Thus, we propose that the decreased C12orf59 expression status is a prognostic biomarker of ccRCC and cooperates with the loss of VHL all the while promoting renal carcinogenesis.
This allowed for reconstructing the life history of individual tumors, identifying somatic mutations as well as copy-number loss of 3p and 11p (VHL subgroup), 1p (Cluster 2), and 17q (NF1 subgroup) as early events in PPGL tumorigenesis.
These results suggest a mechanism for CXCR4 activation during tumour cell evolution and imply that VHL inactivation acquired by incipient tumour cells early in tumorigenesis confers not only a selective survival advantage but also the tendency to home to selected organs.
These results indicate that VHL gene mutations are related to the carcinogenesis of the clear-cell type of primary renal cell carcinomas, whereas alteration of the APC gene is not involved in the pathogenesis of this cancer.
These mutations may cause substitutions of specific amino acid residue and functional change of VHL protein (pVHL), which leads to the oncogenesis of the particular tumor types that characterize the different VHL disease types.
These findings suggest that VHL gene mutations together with methylation associated inactivation of the VHL gene are important events that predispose to renal cell tumorigenesis.
These data suggest that a RET germline mutation is necessary for development of CCH, that allelic imbalance between mutant and wild-type RET may set off tumorigenesis, and that somatic VHL gene alterations may not play a major role in tumorigenesis of MEN2A-associated MTC.
These data indicate separable independent functions for VHL (HIFalpha degradation and differentiation) and suggest a mechanism whereby disruption of both functions is required for renal carcinogenesis.
The results indicate that VHL gene inactivation contributed to the oncogenesis of endolymphatic sac tumor and provide molecular genetic proof that this tumor is associated with VHL disease.
The purpose of this study was to determine whether aberrant expression of the von Hippel-Lindau (VHL) gene in human hyperplastic and malignant endometrial tissues was involved in endometrial carcinogenesis.
The presence of allelic deletions of the VHL gene in pancreatic NETs provides direct molecular evidence for a role of the gene in their tumorigenesis and establishes NET as an independent tumor type of VHL disease.
The observation that other coding VHL variants can exclude exon 2 suggests that dysregulated splicing may be an underappreciated mechanism in VHL-mediated tumorigenesis.