Von Hippel Lindau (VHL)

Question 1

What is the VHL gene? Where is it?

Answer 1

tumor suppressor. chromosome 3

Question 2

What is the penetrance of VHL disease?

Answer 2

> 95% by age 65

Question 3

How is VHL syndrome characterized?

Answer 3

• 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

Question 4

How is VHL classified?

Answer 4

Based on presence or absence of pheochromocytoma (tumor on adrenal gland) and type of VHL mutation

Question 5

Type 1 VHL

Answer 5

• hemangioblastoma and clear cell renal cell carcinoma

- due to total or partial loss of VHL

Question 6

Type 2 VHL

Answer 6

pheochromocytoma +/- hemangioblastoma +/- clear cell renal cell carcinoma

Question 7

What does VHL protein do?

Answer 7

• 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

Question 8

What happens when VHL is lost or inactivated?

Answer 8

• leads to HIF accumulation -> activates transcription of downstream genes that promote cancer growth and survival in low O2 conditions

Question 9

What does VHL-HIF protein interactions do in a normal cell?

Answer 9

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

Question 10

Most clear cell renal cell carcinoma (ccRCC) cases are _______ and have a ______ mutation.

Answer 10

sporadic; VHL

Question 11

Therapies used to treat clear cell renal cel ll carcinoma

Answer 11

• local - surgical resection with either partial or radical nephrectomy
• management with vascular endothelial growth factor receptor tyrosine kinase inhibitors, mTOR, and immunotherapies