Von-Hippel-Lindau/Renal cancer (Exam 3)

Question 1

What are four lab tests of interest for potential renal cancer patients? These can help “prognosticate” outcomes.

Answer 1

1. Creatinine
2. Hemoglobin
3. LDH (Lactate dehydrogenase)
4. Calcium

Question 2

What is the prevalence of Von Hippel-Lindau? Penetrance? Main cause of death? Inheritance?

Answer 2

1/36,000; highly penetrant; renal cell carcinoma (RCC); autosomal dominant (LOH)

Question 3

Identify the typical manifestations of von Hippel-Lindau (VHL) disease (6)

Answer 3

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.

Question 4

What is the association with clear cell renal cell carcinoma (ccRCC)? Familial vs sporadic?

Answer 4

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.

Question 5

What is the mutation?

Answer 5

Mutation in VHL tumor suppressor gene.

Question 6

Are hereditary or spontaneous cases more common?

Answer 6

Spontaneous.

Question 7

What is Hif 1-alpha?

Answer 7

Hif 1-alpha stands for Hypoxia-inducible factor 1, alpha subunit. It plays an essential role in cellular and systemic responses to hypoxia.

Question 8

Describe how a mutation in VHL creates oncogenic cells.

Answer 8

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.

Question 9

Under normoxic conditions…..

Answer 9

VHF binds Hif 1-alpha, which is ubiquitylated and degraded.

Question 10

Under anoxic conditions….

Answer 10

VHF does not bind Hif 1-alpha, levels rise and VEGF, PDGF, and TGF are overexpressed.

Question 11

What are VEGF, PDGF, and TGF?

Answer 11

VEGF = Vascular Endothelial Growth Factor (important for high levels of vascularization seen in these tumors)
PDGR = Platelet Derived Growth Factor
TGF = Transcription Growth Factor

Question 12

What are the four classifications of VHL disease?

Answer 12

Type 1, 2A, 2B, 2C

Question 13

Which types of VHL are due to unchecked expression of Hif 1-alpha?

Answer 13

All but type 2C (1, 2A, 2B)

Question 14

Which types are due to missense mutations?

Answer 14

All but type 1 (2A, 2B, 2C). Type 1 is due to truncation or misfolding (or total gene loss)

Question 15

What other genomic alterations, though less common, are also important in clear cell renal cell carcinoma

Answer 15

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

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

Question 16

What are three classes of drugs?

Answer 16

Immunosuppressive, VEGF inhibitors, mTOR inhibitors

Question 17

What are the immunosuppressive drugs? What is the response/outcome for these patients?

Answer 17

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.

Question 18

What are the VEGF inhibitors? How do these work? How good are these drugs at keeping people alive?

Answer 18

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.

Question 19

What are the mTOR inhibitors? How do these work? what are survival rates?

Answer 19

Temsirolimus, Everolimus. mTOR is a parallel pathway that can lead to activation of oncogenic genes.

1 year survival (ongoing study, limited data)