Von Hippel Lindau (VHL) Flashcards

1
Q

What is the VHL gene? Where is it?

A

tumor suppressor. chromosome 3

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2
Q

What is the penetrance of VHL disease?

A

> 95% by age 65

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3
Q

How is VHL syndrome characterized?

A
  • high variability in disease severity and age of onset
  • formation of cystic and highly vascularized tumors in many organs
  • major causes of death in patients - metastatic renal cell carcinoma (RCC) and CNS hemangioblastomas
  • pancreatic cysts and pancreatic neuroendocrine tumors
  • endolyphatic sac (inner ear) tumors
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4
Q

How is VHL classified?

A

Based on presence or absence of pheochromocytoma (tumor on adrenal gland) and type of VHL mutation

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5
Q

Type 1 VHL

A
  • hemangioblastoma and clear cell renal cell carcinoma

- due to total or partial loss of VHL

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6
Q

Type 2 VHL

A

pheochromocytoma +/- hemangioblastoma +/- clear cell renal cell carcinoma

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7
Q

What does VHL protein do?

A
  • targets unwanted proteins for proteosomal degradation by ubiquitination
  • regulates hypoxia inducible transcription factor (HIF), suppression of aneuploidy, and maintenance of primary cilia and stabilization of microtubules
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8
Q

What happens when VHL is lost or inactivated?

A
  • leads to HIF accumulation -> activates transcription of downstream genes that promote cancer growth and survival in low O2 conditions
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9
Q

What does VHL-HIF protein interactions do in a normal cell?

A

Normoxic conditions - HIF is hydroxylated by proline and asparagine hydroxylase. HIF is ubiquitinated by VHL protein and undergoes proteosomal degradation

Hypoxic conditions - HIF does not get hydroxylated and accumulates -> activates transcription of downstream genes involved in angiogenesis, metabolism, apoptosis, etc

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10
Q

Most clear cell renal cell carcinoma (ccRCC) cases are _______ and have a ______ mutation.

A

sporadic; VHL

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11
Q

Therapies used to treat clear cell renal cel ll carcinoma

A
  • local - surgical resection with either partial or radical nephrectomy
  • management with vascular endothelial growth factor receptor tyrosine kinase inhibitors, mTOR, and immunotherapies
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