What is Li-Fraumeni Syndrome (LFS)?
Li-Fraumeni syndrome is caused by a hereditary genetic variation in the TP53 gene, which weakens the cells’ ability to control various vital systems. This loss of control over critical cell mechanisms increases the likelihood of cancer diagnosis.
Li-Fraumeni syndrome significantly increases the risk of cancer in its carriers. About half of these individuals are likely to develop cancer before the age of 30, and the vast majority face this disease before the age of 70.
When this syndrome manifests in childhood, patients tend to experience multiple types of cancer throughout their lives or develop more than one type of cancer simultaneously when symptoms arise.
Li-Fraumeni syndrome has an increased prevalence in the southern and southeastern regions of Brazil due to the presence of a Brazilian founder genetic variant in the TP53 gene. Therefore, individuals from these regions and with a personal and/or family history of cancer deserve attention regarding genetic counseling.
What is the meaning of the TP53 gene?
The TP53 gene is responsible for preventing tumor formation. It ensures that cells, when dividing, do not suffer DNA damage. When damage occurs, TP53 halts cell division and directs the cell to repair. If the damage is severe, the cell stops dividing or self-destructs to protect other cells.
People with Li-Fraumeni syndrome carry an inherited mutation in a specific gene (TP53), present in one of the copies inherited from their parents.
This genetic mutation can occur in either the maternal or paternal copy, affecting all cells in the body from birth. This significantly increases the risk of developing a variety of cancers throughout life compared to the general population.
Because these individuals still have a normal copy of the gene, another event that causes the normal copy to lose its function would have to affect some cells during life for cancer to occur.
For this reason, there is no certainty that a person with Li-Fraumeni syndrome will develop cancer in life, in which organ, or at what age: the phenomenon of losing the normal copy is unpredictable and, in certain carriers, may never occur.
Cancers associated with Li-Fraumeni syndrome
Li-Fraumeni syndrome is rare and autosomal dominant, meaning it can be passed from either the father or mother to their children. Each offspring has a 50% chance of inheriting the syndrome, and the presence of one mutated copy of the gene is enough to increase the likelihood of developing cancer.
Cancers associated with Li-Fraumeni syndrome include:
- Bone and soft tissue sarcomas;
- Breast cancer;
- Thoracic cancer;
- Brain tumors;
- Adrenocortical cancer;
- Leukemia;
- Lymphoma;
- Glioblastoma; and
- Rhabdomyosarcoma.
Li-Fraumeni Syndrome – who should be tested
As the main sign that a person may have Li-Fraumeni syndrome (LFS) is the development of certain types of cancer, it is important to know who should be tested for the TP53 gene alteration.
There may be suspicion of LFS if someone has a personal or family history of the types of cancer mentioned above. Patients who belong to families with multiple cases of childhood cancers, with members who have multiple cancers, or specific rare cancers, such as adrenocortical carcinoma or choroid plexus tumors, should inform these events to their doctors, asking about possible heredity.
If the professional considers that the patient may have the syndrome, a referral will be made to a genetic counseling specialist. They will explain details about the disease and risks, which vary from family to family. Above all, the genetic counselor will discuss the implications of undergoing a DNA test and the meaning of a positive or negative result.
It will be clarified which family member would be the best candidate for the test (it is not necessary to test everyone initially) and even information about reimbursement for the test before its realization.
If the results are positive (meaning the tested patient has the mutation), the person has a higher risk of developing cancer throughout their life and has a 50% chance of passing the variant to their children.
Diagnosis of Li-Fraumeni syndrome
The possibility of mass screening to identify families with the syndrome is a controversial topic due to the unclear risk-benefit ratio – the same applies to early detection in newborns.
In Brazil, researchers at Unicamp have developed a kit for detecting mutations linked to Li-Fraumeni syndrome in newborns. The idea is to incorporate it into the heel prick test, which identifies over 30 diseases. There is no consensus on the issue. Genetic mapping in patients with a family history of multiple cancers is advisable.
Li-Fraumeni syndrome is diagnosed based on clinical criteria and confirmed by genetic tests for the TP53 gene mutation.
American Society of Clinical Oncology’s criteria for testing:
- A sarcoma diagnosed before age 45;
- A first-degree relative with cancer before age 45; and
- A first- or second-degree relative with any cancer before age 45 or a sarcoma at any age.
Chompret criteria for testing:
Criterion 1 – Individual with a tumor belonging to the Li-Fraumeni syndrome spectrum (osteosarcoma, brain tumor, breast cancer, etc.) before the age of 46 and at least one first- or second-degree family member with a tumor related to Li-Fraumeni syndrome (except breast cancer if the index case was breast cancer) before the age of 56 or with multiple tumors;
Criterion 2 – an individual with multiple tumors, except multiple breast tumors, two of which belong to the LFS tumor spectrum and the first occurred before the age of 46; and
Criterion 3 – a family member diagnosed with adrenocortical carcinoma or a tumor in the choroid plexus, a membrane that surrounds the brain, regardless of family history.
Li-Fraumeni syndrome treatment
There is no standard treatment or cure for LFS. With a few exceptions, cancers in people with LFS are treated similarly to cancers in other patients. There are some differences, such as special care regarding the use of tests and treatments involving radiation.
Radiation Therapy vs. Li-Fraumeni Syndrome
Research indicates that individuals with LFS appear to have an increased risk of radiation-induced cancer. Therefore, the use of radiation therapy should be approached with caution. Computed tomography (CT), mammography, and other diagnostic techniques involving ionizing radiation should be limited. Radiation therapy may be considered only in special situations, preferably involving a multidisciplinary medical discussion.
Prevention
As a syndrome predisposes to the development of various types of cancer, carriers should adopt a healthy lifestyle with measures to reduce the risk of neoplasia. General recommendations are well known, such as not smoking, maintaining a healthy weight, using sunscreen, regular physical activity, etc. An important study showed that female carriers of Li-Fraumeni Syndrome who breastfed for at least 7 months had a significant reduction in the risk of developing breast cancer, etc.
In families where LFS has already been diagnosed, adherence to preventive screening is very useful. Some surveillance recommendations are suggested, such as the use of whole-body magnetic resonance imaging for patients with LFS.
Overall, screening recommendations for families with the syndrome include:
Children (up to 18 years old):
- Complete physical exam every 3-4 months;
- Abdominal and pelvic ultrasound every 3-4 months and blood tests (adrenocortical carcinoma);
- Annual brain MRI (brain cancer);
- Annual whole-body MRI (soft tissue and bone sarcoma).
Adults:
- Complete physical exam every 6 months;
- Clinical breast exam twice a year starting at age 20;
- Annual breast MRI;
- Annual whole-body MRI;
- Annual brain MRI;
- Upper endoscopy and colonoscopy every 2-5 years; and
- Annual dermatological exam.
