Von Hippel Lindau and Kidney cancer

Question 1

What mode of inheritance is VHL?

Answer 1

autosomal dominant

Question 2

What mutation gives rise to VHL?

What function gets affected?

Answer 2

mutation in VHL TSG on ch 3p

VHL normally selects proteins for degredation by ubiquitylation - no more =(

Question 3

What are the different classifications of VHL?

Describe VHL mutation

Answer 3

Type I - partial/total VHL loss = improper folding
Type 2A - VHL Missense mut
Type 2B - VHL Missense mut
Type 2C - VHL Missense mut

Question 4

All of the different types of VHL Up-regulates HIF, except which type?

Answer 4

Type 2C

Question 5

All of the different types of VHL have high risk of pheochromocytoma, except which type?

Which type has high risk of RCC?

(recall chart from lecture)

Answer 5

Type I

Type I and 2B

Question 6

VHL association with clear cell renal cell carcinoma (RCC)

Answer 6

Of all RCC, 75% is due to Clear Cell (CC) carcinoma
64% of CCC is sporadic - VHL related
4% of CCC is familial VHL
Sporadic VHL is the most common cause of RCC (75%)

Question 7

hypoxia inducible factor (HIF-1 alpha)

Answer 7

bHLH TF that plays essential role in cellular/systemic response to hypoxia (HIF is not degraded)

-Activates txn of growth factors:
vascular endothelial (VEGF),
platelet derived (PDGF),
transcription (TGF)

downstream activation of:

• angiogenesis
• endothelia prolif
• anaerobic glycolysis
• glucose uptake ect.

If left unchecked = overexpression and cancer

Question 8

Role of VHL in regulation of HIF-1 alpha

Answer 8

under normal oxygen conditions:
VHL directly ubuiquinates alpha subunit and marks for proteosome degredation

cells with mutated VHL gene behave as if they are under hypoxic conditions

Question 9

typical manifestations of VHL disease

Answer 9

cystic (closed sac)
highly vascularized tumors
   -hemangioblastomas
   - endolymphatic sacs
   - bilateral kidney cysts
   - renal cell carcinomas
   - pheochromocytomas

Question 10

What is the different between sporadic CC-RCC and inherited CC- RCC?

Answer 10

1. Sporadic: individual born with no VHL gene mutations
   
   • single renal tumor
2. Inherited: individuals born with 1 VHL gene mut
   
   • mutiple renal tumors

Question 11

What are treatment options for RCC?

Answer 11

1. Immunotherapy
2. VEGF inhibitors
3. mTOR inhibitors
4. bilateral partial nephrectomies (if not metastasized)

Question 12

List Some VEGF inhibitors used to treat RCC

Answer 12

(ends in B!)

sunitinib
bevacizumab
pazopanib
axitinb

Question 13

List some mTOR inhibitors

Answer 13

The LImus!

Temsirolimus
Everolimus

Question 14

What are other genomic alterations, (though less common), are also important in ccRCC?

Answer 14

VHL mutation with either extra mutation of:
BAP1 or PBRM1 mutation on ch 3.

Or heterozygous loss of 3p short arm with subsequent
BAP1 or PBRM1 loss