Von Hippel-Lindau Disease Vignette Flashcards
Uncommon familial disease __________
Uncommon familial disease 1:36,000 births
VHL is inherited in
autosomal dominant fashion
heterozygous germ-line mutation
Traditionally, ______ were the most common cause of death in VHL, but now ______ is the most common cause
CNS hemangioblastomas
renal cell carcinoma
VHL is characterized by
formation of cystic and highly vascularized tumors in many organs
common symptoms of VHL
- Cerebellar, spinal cord, and retinal hemangioblastomas.
- Endolymphatic sac (inner ear) tumors.
- Bilateral kidney cysts and renal cell carcinomas.
- Pancreatic cysts and islet cell tumors.
- Pheochromocytomas.
- Cystadenomas of the genitourinary tract.
VHL type 1
mutation
total or partial VHL loss
improper folding
VHL type 1 molecular defect
up-regulation of HIF
VHL type 1 clinical manifestations
- hemangioblastoma
- Renal cell carcinoma
- Low risk of pehochromocytes
VHL type 2A clinical manifestations
hemangioblastoma
low risk of renal cell carcinoma
high risk of pehochromocytoma
VHL type 2B clinical manifestations
- hemangioblastoma
- high risk of renal cell carcinoma
- high risk of pheochromocytoma
VHL 2C clinical maneifestation
pheochromocytoma only
VHL is most common cause of
inherited ccRCC
Familial ccRCC
(4%)- typically multifocal, bilateral, early age onset
Sporadic ccRCC
(96%)- solitary, unilateral, later age of onset.
Goal of surgical management for VHL-associated kidney tumors is
to prevent metastasis while preserving renal function.
VHL is a
tumor suppressor.
VHL protein is part of a complex that
selects proteins for degradation by ubiquitylation.
HIF is a
Transcription factor whose action is oxygen-dependent.
Control of HIF-α by VHL is _____
oxygen- dependent
under normoxic conditions:
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.
Under hypoxic conditions
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.
Processes regulated by HIF
Angiogenesis Erythropoiesis Anaerobic glycolysis Glucose uptake Extracellular matrix turnover pH control Apoptosis Mitogenesis
Accumulaton of HIF-α results in
over-expression of VEGF, TGF, PDGF
Treatment options in metastatic renal cell carcinoma
- Immunotherapy
- vascular endothelial growth factor inhibitors
- mTOR inhibitors
Immunotherapy examples
HD-IL2
IFN
Vascular endothelial growth factor inhibitors examples
sorafenib sunitunib bevacizumab pazopanib axitinb
mTOR inhibitors exampels
temsirolimus
everolimus
Other Genetic Alterations in ccRCC
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.
The protein encoded by HIF1 gene is a
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.
In kidney cancer cell lines with multiple mutations, the reintroduction of VHL _____
dramatically reduces
their growth
It is estimated that 60-70% of sporadic clear-cell kidney cancer have
inactivation of both VHL alleles
o May be by mutation or hyper-methylation of the promoter
Recent drugs have instead focused on
downstream targets of HIF signaling.
• VEGF – controls growth of new blood vessels
• PDGF – Platelet derived growth factor
2 of the tyrosine kinase inhibitors work on
VEGFR and are delivered orally:
• Sunitinib
• Sorafenib
o Also works on PDGFR
