TP53-Associated Li-Fraumeni Syndrome

TP53-Associated Li-Fraumeni Syndrome

Article
Brain & Nerve
Digestive Health
+8
Contributed byKrish Tangella MD, MBAFeb 26, 2022

What are other Names for this Condition? (Also known as/Synonyms)

  • TP53-Associated LFS

What is Li-Fraumeni Syndrome, TP53-Associated? (Definition/Background Information)

  • Li-Fraumeni syndrome (LFS) is a hereditary syndrome causing cancer predisposition; meaning it increases one’s risk for cancer development. LFS is inherited in an autosomal dominant manner. The most common types of cancer found in families with Li-Fraumeni syndrome include, osteosarcoma, soft tissue sarcoma, acute leukemia, breast cancer, brain cancer, and adrenal cortical tumors
  • TP53-Associated Li-Fraumeni Syndrome is caused by a mutation in the gene called TP53. TP53 is the genetic blueprint for the p53 protein. When an individual has a mutation in the TP53 gene, the gene is not able to function properly and ultimately leads to cell overgrowth and the development of cancer. Breast cancer is the most frequent malignancy associated with TP53-Associated Li-Fraumeni Syndrome
  • Approximately 70% of all cases of Li-Fraumeni syndrome are caused by mutations in the TP53 gene. It is most commonly found in individuals with a family history of the condition. Developing cancer at a younger age may increase the risk of developing TP53-Associated LFS. Certain environmental factors, such as tobacco smoke and radiation exposure, can also increase one’s risk
  • The signs and symptoms of TP53-Associated Li-Fraumeni Syndrome are related to the malignancies the individual is predisposed to. These include breast cancer, brain/central nervous system tumors, leukemia, colon cancer, or melanoma. TP53-Associated LFS can be diagnosed with standard gene sequence testing
  • Individuals who develop malignancies from TP53-Associated Li-Fraumeni Syndrome are treated for the specific cancer types that arise in them. This may include surgery, chemotherapy, and radiation therapy based on the consideration of the healthcare experts. The prognosis depends on several factors and can vary from one individual to another

Who gets TP53-Associated Li-Fraumeni Syndrome? (Age and Sex Distribution)

  • It is difficult to estimate the frequency of TP53-Associated Li-Fraumeni Syndrome. However, there are likely over 1,000 multigenerational families worldwide with Li-Fraumeni syndrome to date
  • There does not appear to be any gender predilection for TP53-Associated LFS; it can occur in both males and females
  • There does not appear to be any ethnic of geographic disparity in the occurrence of the syndrome. However, some studies have found a higher incidence of the condition in southern and southeastern Brazil. The individuals in this region have a specific variant of TP53 known as R337H

What are the Risk Factors for TP53-Associated Li-Fraumeni Syndrome? (Predisposing Factors)

The following risk factors are noted for TP53-Associated Li-Fraumeni Syndrome: 

  • Having a personal history of breast cancer at a younger age without an identifiable mutation in the BRCA1/BRCA2 genes
  • Being of Brazilian heritage
  • A sarcoma diagnosis before the age of 45
  • Positive family history of cancer
  • Exposure to certain carcinogens including tobacco smoke or radiation exposure

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one's chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of TP53-Associated Li-Fraumeni Syndrome? (Etiology)

TP53-Associated Li-Fraumeni Syndrome is caused by an inherited variant of the TP53 tumor suppressor gene which is located on chromosome 17. In a particular study, TP53 was discovered in tumor tissue of more than 50% of all cancer patients in 1979.

  • TP53-Associated LFS is inherited in an autosomal dominant manner. The risk of passing the altered gene from an affected parent to the offspring is 50% for each pregnancy. Even if a mutation only happens in one of the two TP53 genes, the individual will still develop TP53-Associated LFS
  • Although most cases are caused by a family history of the condition, some individuals can develop the syndrome spontaneously. The spontaneous (de novo) mutation of the TP53 gene is rare but possible for some individuals with TP53-Associated LFS 

A related condition, CHEK2-associated Li-Fraumeni syndrome, is caused by a mutation in the CHEK2 gene located on chromosome 22.

  • TP53-Associated LFS is far more common than CHEK2-Associated LFS
  • Although both conditions can increase the risk for developing cancers, CHEK2-associated Li-Fraumeni syndrome may also lead to the development of thyroid, kidney, and prostate cancers

Autosomal dominant mode of inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of TP53-Associated Li-Fraumeni Syndrome?

The following are possible signs and symptoms associated with TP53-Associated Li-Fraumeni Syndrome:

  • Soft tissue sarcoma
    • Can lead to internal bleeding
    • Enlarged lymph nodes
  • Osteosarcoma
    • Internal hemorrhages
    • Lesions under skin
  • Breast cancer (lumps in breast/tissue thickening)
    • Bleeding from the nipple
    • Breast pain
    • Inverted nipple
  • Colon cancer
    • Persistent change in bowel habits
    • Blood in stool
  • Brain and central nervous system tumors
    • Headaches
    • Hearing and vision impairment
    • Loss of sensation
  • Melanoma
    • Presence of pigmented skin patches
    • Itching and redness around the skin patch
  • Leukemia or lymphoma
    • Swollen glands (lymph nodes) that are not usually painful
    • Easy bruising
    • Fever

How is TP53-Associated Li-Fraumeni Syndrome Diagnosed?

The following tests and exams may be used to diagnose TP53-Associated Li-Fraumeni Syndrome:

  • Complete physical exam and evaluation of family medical history
  • Genetic testing
  • Blood tests, as suitable
  • Radiological scans, as needed
  • Tissue biopsies

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the Possible Complications of TP53-Associated Li-Fraumeni Syndrome?

Individuals with TP53-Associated Li-Fraumeni Syndrome who develop cancer may experience the following complications:

  • Depression
  • Secondary cancers
  • Malignancy of the cancer - invasion and spread of cancer to other body regions
  • Increased sensitivity to radiation and external carcinogens
  • Heart damage
  • Bone pain
  • Surgical complications
  • Lymphedema, or the swelling of an arm, can occur after surgery or radiation therapy

How is TP53-Associated Li-Fraumeni Syndrome Treated?

  • There is currently no standard treatment or cure available for TP53-Associated Li-Fraumeni Syndrome. In most cases, the cancers are treated similar to cancers in other patients. The treatment modalities may include surgery, chemotherapy, and radiation therapy, among others, and is based on the healthcare provider’s evaluation
  • Some research has indicated that individuals with TP53-Associated LFS are more at risk for radiation-induced cancers; and so, radiation therapy has to be considered carefully in individuals with LFS

How can TP53-Associated Li-Fraumeni Syndrome be Prevented?

Currently, there are no available preventative measures for TP53-Associated Li-Fraumeni Syndrome. However, in those with an increased susceptibility to these cancers, the following measures may be considered:

  • One can take certain preemptive measures to be on the lookout for the development of TP53-Associated LFS including, self-breast examinations, annual brain MRIs, regular colonoscopies, annual dermatology examinations, complete blood count tests, abdomen ultrasounds, etc.
  • In general, it is also important to maintain a healthy lifestyle and take measures to prevent unnecessary exposure to environmental carcinogens

What is the Prognosis of TP53-Associated Li-Fraumeni Syndrome? (Outcomes/Resolutions)

There is currently no definitive data on the prognosis for individuals who have been diagnosed with TP53-Associated Li-Fraumeni Syndrome. The prognosis may vary from one individual to another.

  • The prognosis may be similar to those with non-LFS associated cancers compared suitably on a stage-by-stage (and other factors) basis
  • However, because individuals with TP53-Associated LFS are more sensitive to radiation, there may be a greater likelihood of developing malignancies from cell overgrowth/proliferation in those undergoing radiation therapy

In general, the following factors are used to determine each individual’s prognosis

  • Type of cancer
  • Staging of the cancer
  • Location and size of the tumor
  • Cell growth rate
  • Likelihood of cancer returning
  • Age of the individual

Additional and Relevant Useful Information for TP53-Associated Li-Fraumeni Syndrome:

It is estimated that 1 in 8 women will be diagnosed with Breast Cancer during their lifetime. This means that approximately 220,000 women (in the US) will be diagnosed with the disease and fatalities may be around 40,000.

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Krish Tangella MD, MBA picture
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Krish Tangella MD, MBA

Pathology, Medical Editorial Board, DoveMed Team

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