Li Fraumeni Flashcards
Li Fraumeni is a
very rare inherited cancer susceptibility syndrome
presentation of Li-Fraumeni syndrome?
childhood cancer early on set breast cancer elevated risk for wide range of cancers sarcoma premenosaul breast cancers adrenocortical tumors leukemias lymphomas
Li Fraumeni must have
more than one family member with cancer susceptibility syndrome
LFS is associated with
mutation of tumor suppressor p53 (~70%)
p53 is known as the
guardian of genome
somatic mutations occur in over 50% of all human tumors
Most frequent mutation in solid tumors
Over _____ different mutations in p53 genes
250
some mutations are more common in families, other are more common in sporadic tumors
different properties of each mutation may in part explain clinical heterogeneity
Li-Fraumeni Like syndrome
only 40% associated with p53 mutations
What is the clinical benefit of identifying the molecular basis of LFS?
- clinical recognition of LFS can be complicated, identification of a mutation provides diagnostic certainty
- an informed clinician can avoid delay in diagnosis of any second tumor
- radiation should be avoided wherever possible
- prenatal diagnosis may be offered to families
LFS inheritance
autosomal dominant
diagnostic criteria for LFS?
- pro band with sarcoma diagnosed before 45 AND
- first degree relative with any cancer under 45 AND
- first or second degree relative with any cancer under 45 or a sarcoma at ANY age
diagnostic criteria for Li-Fraumeni Like Syndome (LFL)
- pro band with any childhood cancer or sarcoma brain tumor, adrenal cortical tumor diagnosed before 45 AND
- 1st or 2nd egree relative with typical LFS cancer (sarcoma, breast cancer, brain tumor, adrenal cortical tumor, leukemia) at any age AND
- 1st or 2nd degree relative with any cancer under the age of 60 years
How is testing conducted for LFS or LFL?
- direct sequencing of entire gene of p53
- some groups only sequence the hot spots
- other groups sequence the entire p53 messenger RNA
- if there are no detectable p53 mutations they may go on to other genes like hChk2 or PTEN
two hit model of knudson
1 hit: premalignant
germline p53 point mutation
2 hit: carcinoma
amplification of HER2
what are the common ways cancer associated hits can occur
- point mutations may give oncogene activation or tumor suppressor inactivation
- amplifications and deletions
- epigenetic silencing by methylation (CDKN2A)
- insertion of a retrovirus containing an oncogene
hits may be on
different genes
hit 1:
hit 2:
p53 mutant
Li Fraumeni patient developed EGFR mutant
lung cancer after whole body radiation
p53 protects us from
carcinogens
____ most prevalent carcinogen
UV
if p53 is not functional,
dna damage can occur and accumulate
___% of solid tumors have lost the function or expression of p53
50%
if regulates the expression of a huge number of other genes:
- p53 is transcription factor
- p53 regulates microRNAs as well as protein coding genes
- p53 is target of conventional chemotherapy and specific rationally designed drugs are now available that can activate p53 without DNA damage
In the case of Li-Fraumeni syndrome, the first hit is often a
loss of function in the tumor suppressor p53 (70% of cases).
DNA damage is recognized by a
sensor molecule such as Rad 17 which binds the damaged DNA.
The ATM/ATR molecules transduce the signal by
phosphorylating CHK1/CHK2 which in turn activates p53 through phosphorylation.
P53 binds DNA and activates transcription of
such as p21, Gadd45, Bax and Fas.
P21 is a signal for
cell cycle arrest in G1
Gadd45 is a signal for
cell cycle arrest in G2.
Fas and Bax signal the cell to
commit suicide through apoptosis.
