Lack of VHL along with flanking loci in 50% cRCC patients that included both groups I and II supported the hypothesis of both VHL dependent and VHL independent pathways in cRCC tumorigenesis.
In the investigated patients, VHL promoter hypermethylation, which may play an important role in carcinogenesis of RCC, is significantly associated with an increased risk of RCC.
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.
In order to elucidate the underlying mechanism for tumorigenesis in this family, extensive genetic studies were performed including routine and spectral karyotyping (SKY), fluorescence in situ hybridisation (FISH), comparative genomic hybridisation (CGH), loss of heterozygosity studies (LOH), and VHL mutation analysis.
In addition, since VHL protein is also required for the down-regulation of transcription activity of certain genes for the cell growth and cell cycle, inactivation of VHL gene may contribute to tumorigenesis of the VHL tumors.
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 VHL gene plausibly plays a key role in the initiation and tumorigenesis of both central nervous system and extraneuraxial hemangioblastoma, therefore, the underlying molecular and genetic mechanisms of the tumor growth are initially reviewed.
Genotype-phenotype correlation studies show that patients with a complete deletion mutation of the VHL gene, relative to participants with a missense or protein-truncating mutation, had better visual acuity and decreased tumorigenesis incidence of retinal hemangioblastomas.
Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis.
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.
Because this deletion was not present in adenomas, VHL gene may play a role in colonic carcinogenesis and represent a relatively late event in colonic neoplasia progression.
Dysfunction of the VHL protein causes accumulation and activation of hypoxia inducible factor (HIF) which can be demonstrated in earliest stages of tumorigenesis and is followed by expression of VEGF, erythropoietin, nitric oxide synthase and glucose transporter 1 in VHL-deficient tumor cells.
In conclusion, unlike other hereditary kidney cancer-related genes (i.e., VHL and MET), which are cell type-specific, BHD is involved in the entire spectrum of histological types of renal tumors, suggesting its major role in kidney cancer tumorigenesis.
In this study, in order to investigate whether the VHL gene is involved in gastric carcinogenesis, we have examined the genetic alterations, including somatic mutations and allelic loss, with the two microsatellite markers, D3S1038 and D3S1110, as well as promoter hypermethylation of the VHL gene in 88 sporadic gastric adenocarcinomas.
Role of chromosome 3p12-p21 tumour suppressor genes in clear cell renal cell carcinoma: analysis of VHL dependent and VHL independent pathways of tumorigenesis.
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.
From these results, we concluded that inactivation of VHL gene induced constitutive phosphorylation of MET protein and modified intercellular adherence structure to trigger the cell growth released from contact inhibition, finally resulting in tumorigenesis.