Li-Fraumeni and Von-Hippel Lindau

Question 1

What is Li-Fraumeni Syndrome?

Answer 1

Very rare inherited cancer susceptibility syndrome

Question 2

What is the presentation of Li-Fraumeni Syndrome?

Answer 2

Large range. Elevated risk for a wide range of cancers; but commonly sarcomas; pre-menopausal breast cancers; adrenocortical tumors; leukemias and lymphomas

Question 3

What is the inheritability of LFS?

Answer 3

Reflects autosomal dominant nature of cancer susceptibility

Question 4

Which gene is LFS usually associated with?

Answer 4

The tumor suppressor p53 (~70%)

Question 5

What kinds of mutations are seen in p53?

Answer 5

Over 250 different mutations. Some more common in families and some more common in sporadic tumors

Question 6

What are the diagnostic criteria for LFS?

Answer 6

1: Proband with sarcoma diagnosed before 45 yo 2: 1st degree relative with any cancer under 45 yo 3: 1st of 2nd degree relative with any cancer under 45 yo (All 3 criteria must be met)

Question 7

What are the diagnostic criteria for Li-Fraumeni Like Syndrome (LFL)?

Answer 7

1: proband with any childhood cancer or sarcoma; brain tumor; or adrenal cortical tumor diagnosed before 45 years of age 2: 1st or 2nd degree relative with a typical LFS cancer (sarcoma; breast cancer; brain tumor; adrenal cortical tumor; or leukemia) at any age 3: 1st or 2nd degree relative with any cancer under the age of 60 (again; need all 3)

Question 8

How is testing conducted for LFS or LFL?

Answer 8

Either direct sequencing of the entire gene of p53 or hot spots (excludes exons 5-9). Some sequencethe entire p53 mRNA. NextGen Sequencing is becoming more common

Question 9

If p53 is hit 1; can hit 2 be on different genes or does it have to be on same gene?

Answer 9

Can be on different genes. Note: this is unlike retinoblastoma

Question 10

Should you give someone with a p53 mutation full body radiation?

Answer 10

No - they are already predisposed to cancer

Question 11

Figure out the diagram for p53 signaling pathway

Answer 11

OK

Question 12

What is the VHL gene?

Answer 12

A tumor suppressor gene.

Question 13

Describe inheritance of Von Hippel-Lindau syndrome

Answer 13

AD pattern of inheritence. 1/36000 live births. Penetrance very high by age 65 (95%) BUT high variability in severity and age of onset

Question 14

What characterizes VHL syndrome?

Answer 14

Characterized by formation of cystic and highly vascularized tumors in many organs. Main cause of death is metastic RCC (renal cell carcinomas) and CNS hemangioblastomas

Question 15

What are the clinical criteria for VHL without family history

Answer 15

Two or more characteristic lesions: 1. 2 or more hemangioblastomas of the retina/spine/brain or a single hemangioblastoma in association with a visceral manifestation (e.g.; multiple kidney or pancreatic cysts) 2. Renal cell carcinoma 3. Adrenal or extra-adrenal pheochromocytomas 4. Less commonly; endolymphatic sac tumors; papillary cystadenomas of the epididymis or broad ligament; or neuroendocrine tumors of the pancreas

Question 16

What are the clinical criteria for VHL with family history?

Answer 16

One or more of the following is present: Retinal angioma; Spinal or cerebellar hemangioblastoma; Adrenal or extra-adrenal pheochromocytoma; Renal cell carcinoma; Multiple renal and pancreatic cysts

Question 17

How are different types of VHL disease classified?

Answer 17

Based on presence or absence of pheochromocytoma and type of VHL mutation

Question 18

What is Type 1 VHL?

Answer 18

Hemangioblastoma + Clear cell renal cell carcinoma. Due to total or partial loss of VHL

Question 19

What is type 2 VHL?

Answer 19

Pheochromocytoma +/- Hemangioblastoma +/- Clear cell renal cell carcinoma. Due to VHL missense mutation

Question 20

What is type 2A VHL?

Answer 20

Hemangioblastoma + Pheochromocytoma

Question 21

What is type 2B VHL?

Answer 21

Hemangioblastoma + Pheochromocytoma + Clear cell renal cell carcinoma

Question 22

What is type 2C VHL?

Answer 22

Pheochromocytoma only

Question 23

Where is VHL gene located?

Answer 23

3p25-26

Question 24

What does VHL protein do in general?

Answer 24

Part of a complex that targets unwanted proteins for proteosomal degradation by ubiquitination

Question 25

What are some specific things VHL protein does? (What does it regulate; suppress; maintain; stabilize)

Answer 25

Regulation of hypoxia inducible transcription factor (HIF). Suppression of aneuploidy. Maintenance of primary cilia. Stabilization of microtubules

Question 26

What does VHL loss or inactivation lead to?

Answer 26

HIF accumulation; a high rate of aneuploidy; a disruption of primary cilia maintenance leading to formation of renal cysts and renal cell carcinoma

Question 27

How do VHL-HIF proteins behave under normoxic conditions?

Answer 27

HIF is hydroxylated by proline and asparagine hydroxylase. In the presence of wild type VHL; HIF is ubiquitinated by VHL protein and undergoes proteosomal degradation

Question 28

How do VHL-HIF proteins behave under hypoxic conditions?

Answer 28

HIF does not get hydroxylated and is not degraded. HIF protein accumulates and activates the transcription of downstream genes that are involved in angiogenesis; metabolism; apoptosis; and other processes that promote cancer growth and survival under low O2 conditions

Question 29

How do cell with mutated VHL gene behave?

Answer 29

As if they are under hypoxic conditions

Question 30

What is the most common histologic subtype of RCC?

Answer 30

Clear cell renal cell carcinoma (ccRCC)

Question 31

What mechanism is responsible for 2/3 of sporadic cases of ccRCC?

Answer 31

VHL loss/mutation. Note: most ccRCC cases are sporadic

Question 32

What therapies are used to treat ccRCC?

Answer 32

If local: surgical resection w/partial or radical nephrectomy. If metastic: vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitors; MTOR inhibitors; immunotherapies