von Hippel-Lindau Disease Flashcards
fibronectin
binds extracellular matrix proteins- important for cell adhesion, growth, migration, and differentiation
Hemangioblastoma
tumors of the CNS composed of stromal cells in small blood vessels
HIF is a _____ whose action is _____-dependent.
transcription factor; oxygen
Accumulation of HIF activates the transcription of ____, _____, and _____.
VEGF, PDGF and TGF alpha and beta.
What is the molecular defect in type 2C VHL disease?
decreased binding of fibronectin and defective fibronectin matrix assembly
What is the clinical action to take from age 16 and beyond in VHL pts?
annual physical, eye exam, ultrasound, and fractionated metanephrines; also ab and brain MRI; hearing exam every 2-3 years
What is the function of normal VHL protein?
it’s a tumor suppressor
In the presence of ____, HIF-alpha is ubiquitinated by VHL protein and undergoes proteosomal degradation.
normal wild type VHL
What is the VHL mutation in type 1 VHL disease?
total or partial loss resulting in improper folding
What is the clinical action to take from birth to age 4 in VHL pts?
annual eye/retinal exam; check for white pupils; check for neuro problems; check for abnormal blood pressure
Of all clear cell renal cell carcinomas, what percentage are due to VHL?
4% of all cases
Of all renal cell carcinomas, what percentage are conventional clear cell?
75%
Patients with VHL are at risk of developing of up to ___ tumors per kidney.
600
Under normal conditions, HIF-alpha is ______ by _____ and ______.
hydroxylated; proline; asparagine hydroxylase
BAP1 and PRBM1 are located on ____ and can also be mutated in _____.
Chr 3p; ccRCC
Cells with a mutated VHL gene behave as if they are ____ and ____ is not degraded.
under hypoxic conditions; HIF
VEGF-targeted therapy aims to block ____ and _____.
vasculogenesis; angiogenesis
What are the clinical manifestations of type 2B VHL disease?
Hemangioblastomas; renal cell carcinoma; pheochromocytomas
What is the molecular defect in type 2A VHL disease?
upregulation of HIF and inability to stabilize microtubules
What is the molecular defect in type 2B VHL disease?
upregulation of HIF
What is the VHL mutation in type 2B VHL disease?
missense mutation
Pheochromocytoma
a neuroendocrine tumor of the medulla of the adrenal gland
What are the clinical manifestations of type I VHL disease?
Hemangioblastomas; Renal cell carcinoma
What is the incidence rate of VHL?
1:36,000
What is the VHL mutation in type 2A VHL disease?
missense mutation
What is the VHL mutation in type 2C VHL disease?
missense mutation
_____ and ____ are located on Chr 3p and can also be mutated in ccRCC.
BAP1; PRBM1
How is VHL inherited?
it’s autosomal dominant
mTOR inhibitors act to block _____ and _____.
cell growth; angiogenesis
fractionated metanephrines
metabolite of epinephrine circulating free in the plasma
VHL is the most common cause of _____.
clear cell renal carcinoma (ccRCC)
At what age should genetic testing for VHL pts be considered?
any age
What is the molecular defect in type 1 VHL disease?
upregulation of HIF
What are the clinical manifestations of type 2A VHL disease?
Hemangioblastomas
VHL protein is part of a complex that ____.
selects proteins for degradation by ubiquitylation
Sporadic ccRCC accounts for about ___% of all cases and is typically _____, _____, and has a _____.
96%; solitary, unilateral, later age of onset
Name 3 treatment options for metastatic renal cell carcinoma.
1) immunotherapy 2) vascular endothelial growth factor inhibitors 3) mTOR inhibitors
Name 8 processes regulated by HIF.
1) Angiogenesis 2) Erythopoeisis 3) Anaerobic glycolysis 4) Glucose uptake 5) Extracellular matrix turnover 6) pH control 7) Apoptosis 8) Mitogenesis
_____ activates the transcription of VEGF, PDGF and TGF alpha and beta.
Accumulation of HIF
What is the goal of surgical management for VHL?
to prevent metastasis while preserving renal function
VHL is characterized by the formation of cystic and ______ tumors in many organs.
highly vascularized
Where is the VHL gene located?
short arm of ch 3
Where do hemangioblastomas usually occur?
in the cerebellum, brain stem or spinal cord
What is the clinical action to take from 5 to age 15 in VHL pts?
annual physical and neuro exam; test for fractionated metanephrines; ab ultrasound; hearing tests; MRI w/ contrast of internal auditory canal
Familial ccRCC accounts for about ___% of all cases and is typically _____, _____, and has a _____.
4%; multifocal, bilateral, early age onset
___ is the most common cause of ccRCC.
VHL
Cells with a _____ behave as if they are under hypoxic conditions and HIF is not _____.
mutated VHL gene; degraded
In the presence of normal wild type VHL, ____ is ubiquitinated by _____ and undergoes proteosomal degradation.
HIF-alpha VHL protein
What are the clinical manifestations of type 2C VHL disease?
Pheochromocytomas only
Hematuria
blood in the urine
