Li-Fraumeni Flashcards
What is Li-Fraumeni syndrome?
A very rare hereditary cancer syndrome (few hundred families in the US)
Has huge range of presentation: cancer may present at any stage of life
Most commonly sarcomas, early onset breast cancers, adrenocortical tumors, leukemias, lymphomas
Patients MUST have more than one family member with cancer. (Autosomal Dominant)
How many Li-Fraumeni cancers involve p53 mutations?
About 70% (As compared to normal incidence of 50% in most cancers)
What are the general difference found in p53 mutations?
Over 250 mutations in p53 are known to exist. Some are common in families, others occur in sporadic tumors. Different types of mutations causing loss of function or gain of function mutations in p53 may in part explain clinical heterogeneity.
How can a diagnosis of LFS be made with certanty, and what advantages does a diagnosis offer?
Identification of a familial mutation in p53 aids in certain diagnosis. Diagnosis of LFS can change care plans to avoid radiation and to increase monitoring of patient for cancer development.
Three diagnostic criteria for LFS
A proband with sarcoma diagnosed under 45 years of age
AND
A FIRST DEGREE relative with any cancer diagnosed under 45 year of age
AND
A FIRST OR SECOND DEGREE relative with any cancer diagnosed under 45 years of age OR a sarcoma diagnosed at any age.
Diagnostic criteria for LFL (Li-Fraumeni-Like syndrome)
A pro band with any childhood cancer or sarcoma, brain cancer, or adrenal cortical tumor diagnosed before age 45
AND
A FIRST OR SECOND DEGREE relative with a typical LFS cancer at any age
AND
a FIRST OR SECOND DEGREE relative with any cancer under the age of 60 years.
How are sequencing tests conducted for p53?
Partial sequencing: “hot spots” in exons 5-9
Entire gene sequencing (thanks to lower cost sequencing)
If no mutations detected, may seq hChk2 & PTEN genes
Research into what cancer resulted in the “Two Hit Model of Knudson” and what does it mean?
Retinobloastoma
Two Hit Model means that both copies of a tumor suppressor gene must be mutated to knock out the gene’s function and allow cancer development.
What is the multiple loci version of the two hit model of Knudson?
A mutation in one copy of a tumor suppressor (such as p53) along with an amplification of an oncogene (such as HER2). May also be achieved through methylation of the tumor suppressor or retroviral insertion of an oncogene.
Why is p53 such an important protein?
It is a DNA damage surveyor. Anything that damages DNA will trigger a response from p53. It is involved in carcinogenesis from every sort of mutation pathway (UV, chemical, cellular processes, etc.)
By what pathway is p53 activated after DNA damage?
ATM -> Chk1 & Chk2 -> p53
ATR -> p53
By what pathway is p53 activated by oncogene activation?
p14arf (alternative reading frame) -| MDM2 -| p53
What process does p53 activate?
p53 acts as a transcription factor for many possible pathways. It is unknown how p53 chooses among the following pathways it activates:
Cell Cycle Arrest, Apoptosis, Inhibition of Angiogenesis & Metastasis, DNA repair and Damage Prevention, Inhibition of mTOR
p53 activity also responsible for tanning.
Types of mutations of p53 in cancer/LFS
Deletion
Loss of function
Dominant negative
Gain of function
What is MDM2 and what is its relevant target? What is a potential consequence of damaging MDM2?
MDM2 is a ubiquitin ligase. Targets p53 for degradation. Knocking out MDM2 may lead to a Gain of Function in p53, also leading to carcinogenesis.
