Von Hippel Lindau (VHL) Flashcards
What is the VHL gene? Where is it?
tumor suppressor. chromosome 3
What is the penetrance of VHL disease?
> 95% by age 65
How is VHL syndrome characterized?
- high variability in disease severity and age of onset
- formation of cystic and highly vascularized tumors in many organs
- major causes of death in patients - metastatic renal cell carcinoma (RCC) and CNS hemangioblastomas
- pancreatic cysts and pancreatic neuroendocrine tumors
- endolyphatic sac (inner ear) tumors
How is VHL classified?
Based on presence or absence of pheochromocytoma (tumor on adrenal gland) and type of VHL mutation
Type 1 VHL
- hemangioblastoma and clear cell renal cell carcinoma
- due to total or partial loss of VHL
Type 2 VHL
pheochromocytoma +/- hemangioblastoma +/- clear cell renal cell carcinoma
What does VHL protein do?
- targets unwanted proteins for proteosomal degradation by ubiquitination
- regulates hypoxia inducible transcription factor (HIF), suppression of aneuploidy, and maintenance of primary cilia and stabilization of microtubules
What happens when VHL is lost or inactivated?
- leads to HIF accumulation -> activates transcription of downstream genes that promote cancer growth and survival in low O2 conditions
What does VHL-HIF protein interactions do in a normal cell?
Normoxic conditions - HIF is hydroxylated by proline and asparagine hydroxylase. HIF is ubiquitinated by VHL protein and undergoes proteosomal degradation
Hypoxic conditions - HIF does not get hydroxylated and accumulates -> activates transcription of downstream genes involved in angiogenesis, metabolism, apoptosis, etc
Most clear cell renal cell carcinoma (ccRCC) cases are _______ and have a ______ mutation.
sporadic; VHL
Therapies used to treat clear cell renal cel ll carcinoma
- local - surgical resection with either partial or radical nephrectomy
- management with vascular endothelial growth factor receptor tyrosine kinase inhibitors, mTOR, and immunotherapies