Li-Fraumeni Vignette

Question 1

1) Describe the criteria for classifying a hereditary cancer syndrome as Li-Fraumeni syndrome.

Answer 1

First of all what is it:
A very rare inherited cancer susceptibility syndrome.

Huge Range of Presentation:

• Childhood Cancer
• Early onset of breast cancer, present later (after age 50)
• Elevated risk for a wide range of cancers, commonly sarcomas, pre-menopausal breast cancers, adrenocortical tumors and lymphomas
• Must have more than one family member with cancer, reflecting the autosomal dominant nature of the syndrome.
• LFS is associated with a mutation in the tumor supressor p53 (70%)
• 1/5000 to 1/20000 incdidence of LFS
• 40% LFL is p53 mutations in germline
• 5-10% of all cancer may be due to heritable high penetrance mutations

Diagnostic Criteria:

• A PROBAND with a sarcoma diagnosed before 45 years of age
• a FIRST DEGREE RELATIVE with any cancer under 45 years of age
• A FIRST or SECOND DEGREE RELATIVE with any cancer under 45 years of age or a sarcoma at any age

Question 2

2) Describe the Knudson 2-hit hypothesis.

Answer 2

Knudson 2-Hit Hypothesis:
= 2 hits in a TS gene –> cancer. One p53 allele is mutated already at birth = 1st hit. Theoretically, the other needs to get knocked out at some point along the way to cause cancer = 2nd hit. Only the first hit is hereditary.
However, mutation in another gene (not p53) can also be enough to cause cancer, so 1st and 2nd hit don’t have to affect same allele (unlike with retinoblastoma). Ex: 2nd hit can be amplification of Her2 or EGFR exon deletion.
-Cancer “hits” occur via:
-point mutations (that can activate oncogene or break tumor suppressor)
-amplifications and deletions
-epigenetic silencing by methylation
-or insertion of a retrovirus containing an oncogene.

Question 3

3) Describe the function of p53 in response to DNA damage.

Answer 3

P53:
-required to protect us for major carcinogens = guardian.
Protects body from damaging effects of UV radiation exposure because it aids in DNA repair.
Mutation in p53 can thus lead to susceptibility to damage. (This is why we don’t treat p53 mutation-caused cancers with radiation)
It also arrests the cell cycle so DNA can repair.
Can also cause apoptosis if DNA is too damaged. Leads to cellular and genetic stability.
P53 regulates transition into S and M phase, or can cause apoptosis.
P53 is a TF that regulates miRNA and protein coding genes.
Gamma radiation, UV, toxicity, stress, etc. can all affect p53 function.
Most mutations of p53 happen in the DNA binding domain.
On p53 gene, if tetrameric gene is fucked, you cant make tetramer at all, as opposed to when the DNA binding domain is messed, you can still make a tetramer ( right renzo?)
New chemotherapies focused on activating p53 w/o radiation.
In the face of DNA damage, p53 turns on very quickly and levels tail off very quickly = quick/brief response to DNA damage. It’s the most altered gene in cancer.