Li-Fraumeni Syndrome

Question 1

What is Li-Fraumeni Syndrome?



Answer 1

A very rare inherited cancer susceptibility syndrome

Question 2

What are the diagnostic criteria for Li-Fraumeni?

Answer 2

1. A proband with a sarcoma diagnosed before 45 y/o

AND

2. A first-degree relative with any cancer under 45 y/o

AND

3. A first- or second-degree relative with any cancer under 45 years of age
   OR
   a sarcoma at any age

Question 3

Li-Fraumeni Syndrome (LFS) is usually associated with a mutation in _____ (___%).

Answer 3

the tumor suppressor p53 (~70%)

Question 4

What is the deal with Li-Fraumeni Like Syndrome?

Answer 4

– Only 40% associated with p53 mutations.

Question 5

What are the diagnostic criteria for Li-Fraumeni Like (LFL)? (not a LO)

Answer 5

A proband with any childhood cancer or sarcoma, brain tumor, or adrenal cortical tumor diagnosed before 45 years of age AND
• A first- or second-degree relative with a typical LFS cancer (sarcoma, breast cancer, brain tumor, adrenal cortical tumor, or leukemia) at any age AND
• A first- or second-degree relative with any cancer under the age of 60 years.

Question 6

How is LFS diagnosed?

Answer 6

Direct sequencing of p53 (entire gene, usually)

Question 7

Knudson two-hit hypothesis?

Answer 7

Inherit mutation in p53, second event knocks out good copy in a single cell which then goes bad. UNLIKE Rb, the second hit may be on a DIFFERENT GENE.

Question 8

What are four ways the second hit may occur?

Answer 8

1. Point mutations – may give oncogene activation (e.g.. RAS or MYC) or tumor suppressor inactivation (e.g.. p53 or pRB)
2. Amplifications and deletions
3. Epigenetic silencing by methylation (eg. CDKN2A)
4. Insertion of a retrovirus containing an oncogene

Question 9

___% of solid tumors have lost p53.

Answer 9

50%

Question 10

Describe the function of p53 in response to UV exposure.

Answer 10

UV damage–>
Path 1: ATM phosphorylates CHK2, which activates p53
Path 2: ATR activates p53 directly, or activates CHK1 which activates p53

p53 induces p21 (cell cycle arrest), or induces apoptosis, or any number of other mechanisms to prevent oncogenesis.