Flashcards in Von-Hippel-Lindau/Renal cancer (Exam 3) Deck (19)
What are four lab tests of interest for potential renal cancer patients? These can help "prognosticate" outcomes.
3. LDH (Lactate dehydrogenase)
What is the prevalence of Von Hippel-Lindau? Penetrance? Main cause of death? Inheritance?
1/36,000; highly penetrant; renal cell carcinoma (RCC); autosomal dominant (LOH)
Identify the typical manifestations of von Hippel-Lindau (VHL) disease (6)
1. Hemangioblastomas (CNS, retinal)
2. Endolymphatic sac (inner ear) tumors.
3. Bilateral kidney cysts and renal cell carcinomas.
4. Pancreatic cysts and islet cell tumors.
5. Pheochromocytomas (catecholamine secreting tumors that arise from the adrenals)
6. Cystadenomas of the genitourinary tract.
What is the association with clear cell renal cell carcinoma (ccRCC)? Familial vs sporadic?
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.
What is the mutation?
Mutation in VHL tumor suppressor gene.
Are hereditary or spontaneous cases more common?
What is Hif 1-alpha?
Hif 1-alpha stands for Hypoxia-inducible factor 1, alpha subunit. It plays an essential role in cellular and systemic responses to hypoxia.
Describe how a mutation in VHL creates oncogenic cells.
VHF is a tumor suppressor. Hif 1-alpha is ubiquitylated when bound by VHL, which marks it for degradation in the proteosome. Without VHF (absent or missense), Hif 1-alpha levels rise. Hif 1-alpha is a transcription factor, that under high concentrations, relocates to the nucleus and promotes transcription of several oncogenes including VEGF, PDGF, and TGF. These genes are responsible for helping the cell grow under anoxic(hypoxic) conditions. Their unregulated expression causes problems, and they are drug targets.
Under normoxic conditions.....
VHF binds Hif 1-alpha, which is ubiquitylated and degraded.
Under anoxic conditions....
VHF does not bind Hif 1-alpha, levels rise and VEGF, PDGF, and TGF are overexpressed.
What are VEGF, PDGF, and TGF?
VEGF = Vascular Endothelial Growth Factor (important for high levels of vascularization seen in these tumors)
PDGR = Platelet Derived Growth Factor
TGF = Transcription Growth Factor
What are the four classifications of VHL disease?
Type 1, 2A, 2B, 2C
Which types of VHL are due to unchecked expression of Hif 1-alpha?
All but type 2C (1, 2A, 2B)
Which types are due to missense mutations?
All but type 1 (2A, 2B, 2C). Type 1 is due to truncation or misfolding (or total gene loss)
What other genomic alterations, though less common, are also important in clear cell renal cell carcinoma
VHL, BAP1, PRBM1 are all located on Chr 3p.
Loss of 3p causes heterozygous loss of BAP1 and PRBM1 too.
What are three classes of drugs?
Immunosuppressive, VEGF inhibitors, mTOR inhibitors
What are the immunosuppressive drugs? What is the response/outcome for these patients?
IL-2, IFN. Powerful, bad side effects (heart failure), but drive 5-7% of people into 5+ year remission, so tried on most patients b/c is far and away the best therapy when it works.
What are the VEGF inhibitors? How do these work? How good are these drugs at keeping people alive?
Most are tyrosine kinase inhibitors that interrupt the signaling pathway of VEGF (Sorafenib, Sunitinib, pazopanib, axitinib). One is an antibody that binds VEGF directly (Bevacizumab).
**ALL are designed to halt/slow angiogenesis, since that is what VEGF gene does.**
Median survival seems to be 1.5-2.5 years for these drugs.