The dependence of transcription for trafficking is lost with a deletion of exon 2, a region with a mutation causing a splice defect in the VHL gene in sporadic renal clear cell carcinoma.
Mutations of the von Hippel-Lindau (VHL) gene had been found in 55-70% of sporadic RCC and appear to be a critical event in the pathogenesis of clear-cell RCC.
The last 30 years of research in renal cell carcinoma (RCC) has revealed that the vast majority of RCC histologies share a recurrent pattern of mutations to metabolic genes, including VHL, MTOR, ELOC, TSC1/2, FH, SDH, and mitochondrial DNA.
Clear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer, characterized by the presence of inactivating mutations in the VHL gene in most cases, and by infrequent somatic mutations in known cancer genes.
The common clear cell subtype of renal cell carcinoma is associated with hereditary or acquired loss of function of the von Hippel-Lindau tumor suppressor, a key component in oxygen sensing, perpetuating a stressed state.
An analysis of clear cell renal carcinoma that manifests mutation of the VHL gene in most cases revealed an association of strong CXCR4 expression with poor tumour-specific survival.
Abnormal accumulation of c-Myc is able to induce excessive proliferation of normal cells. von Hippel-Lindau protein(pVHL) is a key regulator of hypoxia-inducible factor 1α(HIF1α), thus accumulation and hyperactivation of HIF1α is the most prominent feature of VHL-mutated renal cell carcinoma.
In clear-cell renal cell carcinoma (ccRCC), the von Hippel-Lindau (VHL) gene is frequently inactivated leading to constitutive activation of HIF-2 and/or HIF-1, which may be expected to upregulate REDD1 and inhibit mTORC1.
This may have relevance to the development of renal cell carcinoma (RCC), where mutations of the von Hippel-Lindau (VHL) gene are major risk factors for the development of familial and sporadic RCC.
The role of the von-Hippel-Lindeau (VHL) tumour suppressor gene is well established in RCC with a loss of VHL protein leading to accumulated hypoxia-induced factor (HIF) and the subsequent transcriptional activation of multiple downstream targets.
The evolution patterns of ccRCC have great inter-patient heterogeneities, with del(3p) being regarded as the common earliest event followed by three early departure points: VHL and PBRM1 mutations, del(14q) and other somatic copy number alterations (SCNAs) including amp(7), del(1p) and del(6q).
Alcohol was associated with a decreased risk for clear-cell renal cell cancer without VHL gene promoter methylation (hazard ratio for >15 g compared with nondrinkers, 0.58; 95% CI, 0.34-0.99).