Von Hippel-Lindau Disease Vignette

Question 1

Uncommon familial disease __________

Answer 1

Uncommon familial disease 1:36,000 births

Question 2

VHL is inherited in

Answer 2

autosomal dominant fashion

heterozygous germ-line mutation

Question 3

Traditionally, ______ were the most common cause of death in VHL, but now ______ is the most common cause

Answer 3

CNS hemangioblastomas

renal cell carcinoma

Question 4

VHL is characterized by

Answer 4

formation of cystic and highly vascularized tumors in many organs

Question 5

common symptoms of VHL

Answer 5

1. Cerebellar, spinal cord, and retinal hemangioblastomas.
2. Endolymphatic sac (inner ear) tumors.
3. Bilateral kidney cysts and renal cell carcinomas.
4. Pancreatic cysts and islet cell tumors.
5. Pheochromocytomas.
6. Cystadenomas of the genitourinary tract.

Question 6

VHL type 1

mutation

Answer 6

total or partial VHL loss

improper folding

Question 7

VHL type 1 molecular defect

Answer 7

up-regulation of HIF

Question 8

VHL type 1 clinical manifestations

Answer 8

1. hemangioblastoma
2. Renal cell carcinoma
3. Low risk of pehochromocytes

Question 9

VHL type 2A clinical manifestations

Answer 9

hemangioblastoma
low risk of renal cell carcinoma
high risk of pehochromocytoma

Question 10

VHL type 2B clinical manifestations

Answer 10

1. hemangioblastoma
2. high risk of renal cell carcinoma
3. high risk of pheochromocytoma

Question 11

VHL 2C clinical maneifestation

Answer 11

pheochromocytoma only

Question 12

VHL is most common cause of

Answer 12

inherited ccRCC

Question 13

Familial ccRCC

Answer 13

(4%)- typically multifocal, bilateral, early age onset

Question 14

Sporadic ccRCC

Answer 14

(96%)- solitary, unilateral, later age of onset.

Question 15

Goal of surgical management for VHL-associated kidney tumors is

Answer 15

to prevent metastasis while preserving renal function.

Question 16

VHL is a

Answer 16

tumor suppressor.

Question 17

VHL protein is part of a complex that

Answer 17

selects proteins for degradation by ubiquitylation.

Question 18

HIF is a

Answer 18

Transcription factor whose action is oxygen-dependent.

Question 19

Control of HIF-α by VHL is _____

Answer 19

oxygen- dependent

Question 20

under normoxic conditions:

Answer 20

HIF-alpha is hydroxylated by proline and asparagine hydroxylase.

In the presence of normal wild type VHL, this HIF-alpha is ubiquated by VHL protein and undergoes proteosomal degradation.

Question 21

Under hypoxic conditions

Answer 21

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

HIF is not degradated.

Accumulation of HIF activates the transcription of VEGF, PDGF and TGF alpha and beta.

Angiogenesis, endothelial proliferation and autocrine growth and survival of cancer cells results.

Question 22

Processes regulated by HIF

Answer 22

Angiogenesis
Erythropoiesis
Anaerobic glycolysis
Glucose uptake
Extracellular matrix turnover
pH control
Apoptosis
Mitogenesis

Question 23

Accumulaton of HIF-α results in

Answer 23

over-expression of VEGF, TGF, PDGF

Question 24

Treatment options in metastatic renal cell carcinoma

Answer 24

1. Immunotherapy
2. vascular endothelial growth factor inhibitors
3. mTOR inhibitors

Question 25

Immunotherapy examples

Answer 25

HD-IL2

IFN

Question 26

Vascular endothelial growth factor inhibitors examples

Answer 26

sorafenib
sunitunib
bevacizumab
pazopanib
axitinb

Question 27

mTOR inhibitors exampels

Answer 27

temsirolimus

everolimus

Question 28

Other Genetic Alterations in ccRCC

Answer 28

VHL, BAP1, PRBM1 are all located on Chr 3p.

Loss of 3p causes heterozygous loss of BAP1 and PRBM1 too.

Subsequent PRBM1 or BAP1 mutations results in ccRCC with different features and outcomes.

Question 29

The protein encoded by HIF1 gene is a

Answer 29

basic helix-loop-helix
- PAS transcription factor found in mammalian cells growing at low oxygen concentrations.
It plays an essential role in cellular and systemic responses to hypoxia.

Question 30

In kidney cancer cell lines with multiple mutations, the reintroduction of VHL _____

Answer 30

dramatically reduces

their growth

Question 31

It is estimated that 60-70% of sporadic clear-cell kidney cancer have

Answer 31

inactivation of both VHL alleles

o May be by mutation or hyper-methylation of the promoter

Question 32

Recent drugs have instead focused on

Answer 32

downstream targets of HIF signaling.
• VEGF – controls growth of new blood vessels
• PDGF – Platelet derived growth factor

Question 33

2 of the tyrosine kinase inhibitors work on

Answer 33

VEGFR and are delivered orally:
• Sunitinib
• Sorafenib
o Also works on PDGFR