Von Hippel-Lindau (VHL) disease is a cancer syndrome that is hereditary and affects 1 in 35,000 people. VHL disease is characterized by central nervous system, retinal, kidney, and adrenal gland tumors. Conducting research on VHL disease can be a complicated process; the gene for VHL is expressed in organs throughout the body, not only in those organs affected by the disease.
Patients with VHL are heterozygotes and carry one wild-type and one inactivated VHL allele. VHL gene mutations can be difficult to identify, but more recent diagnostic techniques, such as direct DNA sequencing, Southern blotting, and fluorescence in situ hybridization (FISH), have improved VHL mutation detection. Twenty to 37% of patients with VHL have germline delections, while approximately 23 to 27% have frameshift or nonsense mutations and 30 to 38% have missense mutations. More than 150 germline mutations of the VHL gene have been identified and linked to VHL disease.
Genotype-phenotype correlations have also been identified in VHL disease research. Type 1 VHL families have an absence of adrenal gland tumors and frequently have VHL deletions or truncation mutations. Type 2 VHL families have adrenal gland tumors and frequently have VHL missense mutations. Scientists believe that the genotype-phenotype correlations illustrate the VHL gene product’s alteration by various VHL mutations.
VHL is also associated with an increased risk or renal, or kidney, cell carcinoma. Familial pheochromocytoma is another feature of the VHL disease, and has also been determined to be associated with germline inactivating mutations. Somatic VHL mutations and hypertmethylation appears in approximately 50% and 10-20% of sporadic clear-cell renal carcinomas, respectively. However, VHL germline mutations rarely appear in patients with sporadic clear-cell renal carcinomas.
VHL mRNA encodes a protein, pVHL, which travels between the nucleus and cytoplasm. Researchers have discovered that pVHL lacking cells overproduce hypoxia-inducible RNAS. Vascular endothelial growth factor (VEGF) mRNA is a hypoxia-inducible RNA and is often overproduced by tumors associated with VHL inactivation.
Many genes that are regulated by hypoxia, including VEGF, are controlled by hypoxia-inducible factor (HIF), a transcription factor. It has been shown that pVHL lacking cells do not degrade HIF subunits in the presence of oxygen. Scientists thereby determined that pVHL is a ubiquitin ligase that controls the degradation of HIF subunits in the presence of oxygen. The pVHL and HIF interaction is mediated by a conserved family of Egl-nine (EGLN) enzymes that cause a post-translational hydroxylation of HIF when oxygen is present.
Without pVHL present, HIF is stabilized and can induce gene expression; many of HIF’s target genes are critical to the human body and regulate functions such as angiogenesis, cell growth, and cell survival. Researchers also hypothesize that overexpression of HIF target genes, such as platelet derived growth factor (PDGF) and VEGF, are responsible for the hypervascularity of tumors.
Additional preliminary data suggest that HIF maintains a role in the formation of pVHL defective tumors. Thus, HIF is a viable target for therapeutic research. Testing inhibitors of HIF controlled growth factors could develop potential treatments for renal cell carcinomas and central nervous system tumors.