Von Hippel- Lindau

Question 1

What are the most common manifestations of von Hippel-Lindau?

Answer 1

• Hemangioblastoma (tumor of CNS originating from vascular system
• Renal cell carcinoma
• pheochromocytoma (rare tumor of adrenal gland)
• Multiple tumors in single organ
• retinoblastoma

Question 2

How can VHL be applied to other diseases?

Answer 2

help researchers to better understand carcinogenesis

ex) recently developed biologically targeted agents for renal cell carcinoma are based on pathophysiology of VHL mutation
- VEGFR tyrosine kinase inhibitors (sunitinib & sorafenib)

Question 3

Are VHL mutations always associated with inherited VHL disease?

Answer 3

No

- sporadic mutations- inactivation of both VHL genes- present in 60-70% of cases of renal cell carcinoma

Question 4

Where is the VHL mutation located?

Answer 4

short arm of chormosome 3

deletion

Question 5

What is the normal function of VHL?

Answer 5

• part of multiprotein complex that tags proteins for degredation by proteasome- > binds with substrate and recruits it to the complex
• normally controls HIF

Question 6

What is HIF?

Answer 6

Heterodimeric transcription factor

- oxygen dependent (controlled by alpha subunit -beta is constituitievely expressed)

Question 7

How is HUF affected by VHL mutations?

Answer 7

control of alpha subunit is lost -> binds to the promoter of “hypoxix inducible genes” (i.e. vascular endothelial growth factor (VEGF) & platelet derived growth factor (PDGF)) => uncontrolled growth!

Question 8

How does VHL disease affect development of drugs to treat other cancers?

Answer 8

Understanding the mechanism of cancers caused by VHL gave researchers targets for drugs :

• VEGFR and PDGFR
• HIF also obvious target but no success yet