li fraumeni

Question 1

1 . Describe the criteria for classifying a hereditary cancer syndrome as Li‐Fraumeni syndrome. what is li fraumeni?

Answer 1

• A very rare inherited cancer susceptibility syndrome
• Has a huge range of presentation:
– Childhood cancer, early onset breast cancer, present later
(after age 50).
– Elevated risk for a wide range of cancers, but commonly
sarcomas, pre-menopausal breast cancers, adrenocortical
tumors, leukemias and lymphomas.
• Must have more than one family member with
cancer, reflecting the autosomal dominant nature of
this cancer susceptibility syndrome.
• A proband with a sarcoma diagnosed
before 45 years of age AND
• A first-degree relative with any cancer
under 45 years of age AND
• A first- or second-degree relative with
any cancer under 45 years of age or a
sarcoma at any age [Li & Fraumeni
1969].

Question 2

3 . Describe the function of p53 in response to UV exposure.

Answer 2

It can activate DNA repair proteins when DNA has sustained damage. Thus, it may be an important factor in aging.[30]
It can arrest growth by holding the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle).
It can initiate apoptosis (i.e., programmed cell death) if DNA damage proves to be irreparable.

Question 3

How is testing conducted for LFS

or LFL?

Answer 3

Direct sequencing of the entire gene of p53
(more than 2300 base pairs)
• Some groups only sequence the “hot spots”
which include exons 5-9.
• Other groups sequence the entire p53
messenger RNA.
• If there are no detectable p53 mutations they
may go on to other genes i.e. hChk2, PTEN.

Question 4

what are the benefits of early detection?

Answer 4

1) Clinical recognition of LFS can be complicated,
identification of a mutation provides diagnostic
certainty.
2) An informed clinician can avoid delay in diagnosis of
any second tumor.
3) Radiation should be avoided where-ever possible.
4) Prenatal diagnosis may be offered to families.

Question 5

What are the common ways cancer

associated “hits” can occur?

Answer 5

Point mutations – may give oncogene activation
(e.g.. RAS or MYC) or tumor suppressor inactivation
(e.g.. p53 or pRB)
• Amplifications and deletions
• Epigenetic silencing by methylation (eg. CDKN2A)
• Insertion of a retrovirus containing an oncogene
• Hits may be on different genes (unlike
retinoblastoma).

Question 6

What are possible functions of p53?

Answer 6

It regulates the expression of a huge number of other
genes:
• p53 is a transcription factor.
• p53 regulates microRNAs as well as protein coding
genes.
• p53 is a target of conventional chemotherapy, and
specific rationally designed drugs are now available
that can activate p53 without DNA damage.