What is Li-Fraumeni Syndrome?
In 1969, doctors Li and Fraumeni discovered a unique cancer syndrome, which is now known as Li-Fraumeni syndrome (LFS). This condition is passed down through families and often ties to changes in a gene called the P53 gene (TP53). This gene acts like a bodyguard, stopping tumors, or abnormal growths, from forming in our bodies. LFS is also sometimes referred to as SBLA cancer syndrome, short for sarcoma, breast, leukemia, and adrenal gland cancer syndrome. This syndrome comes in different forms: LFS1, LFS2, and LFSL. In LFS1, the TP53 gene is affected. LFS2 is linked to changes in another tumor-stopping gene called CHEK2. Individuals grouped into LFSL do not show any recognizable changes in the P53 gene.
What Causes Li-Fraumeni Syndrome?
Li-Fraumeni syndrome (a rare disorder that greatly augments the risk of developing certain cancers) is usually linked to mutations in three specific genes, identified as TP53 (found at location 17p13 on our chromosome), 1q23, and a gene called checkpoint kinase 2 (CHEK2, located at 22q12.1). Of these three, TP53 mutations are the most common.
A brief explanation of genes and mutations: Genes are segments of our DNA that hold the instructions to make proteins, which perform various functions in our body. Sometimes, there are changes in these genes (mutations) that can cause problems in how the proteins function.
The P53 protein (formed by the TP53 gene) is a cancer-fighting protein – it helps in a natural process called apoptosis (controlled cell death), keeps our genetic information stable, and hinders angiogenesis (formation of new blood vessels that can help a tumor grow). When our DNA is damaged, the P53 protein can activate other proteins that repair this damage, or it can stop the cell from growing and dividing, giving time for repairs to be made. If the damage is too severe, P53 can trigger apoptosis. The protein made by the CHEK2 gene controls how the P53 protein functions.
In the case of Li-Fraumeni syndrome, typically one mutated copy of the TP53 gene is inherited from one parent. The other copy of this gene is either deleted or also undergoes mutations, leading to loss of a functioning P53 protein. Mutations involving misleading protein instructions (missense mutations) are usually the most common ones and often occur in a specific part of the gene, which controls how the protein binds with DNA. Approximately 70% of the families with Li-Fraumeni syndrome carry these TP53 mutations when tested for them. It has also been observed that the partial loss of the TP53 gene can lead to fewer incidences of family history, fewer tumors, and late onset of the disease.
It’s important to note that not everyone with Li-Fraumeni syndrome has TP53 mutations. The syndrome can also occur because of changes in the gene that affects how much of the protein is made, or due to other mutations that scientists have yet to identify.
Risk Factors and Frequency for Li-Fraumeni Syndrome
Li-Fraumeni Syndrome (LFS) is a rare condition that has been identified in over 500 families in medical literature, but it is thought that there could be over 1,000 families worldwide dealing with this syndrome. Children diagnosed with a type of cancer called adrenocortical carcinoma are the group most often found to have P53 mutations, which are a common characteristic of LFS. This syndrome can also be associated with brain tumors, bone cancer (osteosarcoma), and muscle cancer (rhabdomyosarcoma) during childhood. People with LFS who have more than one primary tumor are likely to have a high incidence of P53 mutations.
- Li-Fraumeni Syndrome is rare but identifiable, seen in over 500 families but potentially affecting over 1,000 families worldwide.
- Children with adrenocortical carcinoma are the most prone to have P53 mutations.
- Childhood brain tumors, osteosarcoma, and rhabdomyosarcoma are frequently associated with this syndrome.
- People with multiple primary tumors are more likely to have P53 mutations.
Changes to the TP53 gene greatly increase the risk of cancer for people with LFS. The risky nature of these P53 mutations is especially evident in women, with a 90% lifetime risk by the age of 60. For men, the estimated lifetime risk is about 73%. People with LFS are at risk for a wide array of cancers, but the syndrom is specifically linked with breast cancer, bone sarcomas, and soft tissue sarcomas. There have been other types of cancer reported in people with LFS, but these occur less frequently.
- LFS patients with TP53 mutations face a high risk of cancer.
- The lifetime cancer risk for women is 90% by age 60 and for men it’s about 73%.
- People with LFS can get a wide variety of cancers, with the most frequent being breast cancer, bone sarcomas and soft tissue sarcomas.
Members of LFS families are more likely to develop multiple primary cancers, compared with the general population. This increased risk is mainly for cancers that are commonly seen in people with LFS. The risk goes up even further for people who have survived childhood cancers, so these individuals need to be closely monitored for any early signs of cancer. Treatment for LFS is usually successful when dealing with an initial cancer occurrence. However, it’s advisable to avoid radiation therapy if possible, due to the increased risk of developing new cancer triggered by radiation in people with LFS. These patients face a high risk of developing a second primary cancer, which is a completely separate type of cancer.
- People with LFS face a higher risk of developing multiple primary cancers.
- This risk is even higher for those who have survived childhood cancers.
- Treatment for the first occurrence of cancer is often successful.
- However, radiation therapy is generally avoided due to the risk of it causing new cancers.
- Patients with LFS are at high risk of developing a second separate type of cancer.
Signs and Symptoms of Li-Fraumeni Syndrome
Hereditary cancer syndromes may be indicated by a family history of cancer, being diagnosed at a young age, and experiencing multiple types of cancer. It’s important for patients to be fully aware of all the signs and symptoms of cancer. They need to know to seek medical advice if they notice any strange signs or symptoms associated with cancer. A detailed family history spanning multiple generations matters significantly as it can highlight an increased risk of cancer in the family. The history should screen for a variety of tumors particularly sarcomas, breast cancer, leukemia, and adrenocortical tumors. It’s crucial to routinely update the family history as risk may become apparent only after several years. It might be tough to gather a comprehensive family history, but it’s a vital step when assessing every child diagnosed with an early age cancer. The focus should be on all the cancers within the Li-Fraumeni syndrome spectrum.
There are no specific physical signs unique to individuals with Li-Fraumeni syndrome, apart from those associated with specific cancers. However, there are particular physical findings to be aware of for different cancers:
- Neurological symptoms such as seizures, vomiting, headaches, and changes in walking pattern related to brain cancers
- A lump in the breast indicating breast cancer
- A soft-tissue mass or a mass linked to a bone in cases of soft tissue sarcoma or bone sarcoma
- A variety of symptoms in acute leukemia such as pancytopenia (a shortage of all blood cells), fatigue, fever, weight loss, appetite loss, swollen lymph nodes, bleeding gums, and infections
- Signs of virilization (developing male sexual characteristics) including early pubic hair, enlargement of the penis, clitoromegaly (an enlarged clitoris), a deep voice, and an abdominal mass in adrenal cortical carcinoma
An annual medical check-up including examinations of the breast, skin, and neurological health is recommended.
Testing for Li-Fraumeni Syndrome
In the past, Li-Fraumeni syndrome, a rare genetic disorder that greatly increases the risk of developing several types of cancer, was diagnosed just by examining the patient’s signs and symptoms and their family history. Now, thanks to the advances in genetic testing, we’re able to identify whether a patient carries a specific mutation in the TP53 gene, which is linked to Li-Fraumeni syndrome, even before they show any signs of illness.
However, genetic testing isn’t perfect and it can only detect the mutated TP53 gene in about 70% to 75% of cases. Because of this, it’s really important to also have genetic counseling. If the counseling concludes that a patient is carrying a mutated TP53 gene, the patient will be advised on proper monitoring procedures and routinely screened for cancers associated with Li-Fraumeni syndrome.
Genetic counseling and TP53 mutation testing should be considered for patients based on the following criteria:
Li-Fraumeni syndrome is suspected if a person has a certain type of cancer called sarcoma before the age of 45, a type of cancer in a close family member before they turn 45, and any type of cancer in another close or distant relative before the age of 45 or a sarcoma at any age. Also, anyone who has certain types of cancer, like a brain tumor, adrenocortical cancer, or breast cancer before turning 31, should be to be considered for diagnosis, especially if family history suggests a risk of LFS.
Li-Fraumeni-like syndrome (LFL) is a term used for families who show similar symptoms to those of Li-Fraumeni syndrome, but don’t meet all the criteria. People who have multiple typical LFS cancers at any age or a close or distant relative with any cancer before age 60 could potentially have LFL.
It is important to know that even if genetic testing doesn’t show a TP53 mutation, it doesn’t rule out LFS at all. Therefore, individuals who are suspected of having LFS or LFL should be treated as if they have the syndrome.
If there’s a known TP53 mutation in your family, it is recommended that you should undergo testing to see if you carry the same mutation. If the test results are negative, this rules out LFS. On the other hand, individuals who choose not to proceed with the testing should still be treated as if they carry the TP53 mutation until they turn 50.
Patients with certain types of cancer, like adrenocortical carcinoma, choroid plexus carcinoma, rhabdomyosarcoma, osteosarcoma, and childhood sarcoma (except Ewing sarcoma), should undergo genetic testing for TP53 mutations regardless of their age or family history. When a TP53 mutation has been identified in a family, prenatal testing should also be considered.
If you are diagnosed with LFS, regular monitoring for cancer development is crucial. This includes annual full body checkups, whole-body MRIs, regular ultrasound scans, frequent blood tests, and biochemical checks for indicating signs of cancer. For women, starting at age 20, monthly self-breast examinations, biannual clinical exams, and annual breast imaging (preferably MRI because mammograms use radiation) are all necessary. Starting from around age 25 to 30, it’s also advisable to begin having colonoscopy every 2 to 5 years, or earlier if there is a history of colon cancer in the family.
Treatment Options for Li-Fraumeni Syndrome
At present, there’s no method or treatment available to fix mutations in the P53 gene, which are often seen in Li-Fraumeni syndrome (LFS). This means we cannot specifically target this gene with any drug therapies. Typically, it’s recommended to avoid radiation treatments in people with LFS because they are at a much higher risk of developing additional cancers related to radiation. This also means it’s best to avoid exposure to scans or X-rays that use radiation.
Li-Fraumeni syndrome can have a widespread impact on individuals and their families. Therefore, it’s often suggested that patients with (or suspected to have) LFS consult with a medical professional or medical service with expertise in managing this specific syndrome. These professionals can also assist with genetic counseling and providing other special supportive services.
Just because you have LFS does not mean your cancer should be treated differently from the same type of cancer in other patients. For example, when it comes to treating breast cancer in LFS patients, the complete removal of the breast (or mastectomy) is generally advised over partial removal (or lumpectomy) followed by radiation therapy, because of the heightened risk of a second breast cancer forming or radiation-induced cancers. That said, the need for risk-reducing mastectomy varies from patient to patient, taking into account the level of cancer risk and possible reconstructive options.
Patients with LFS often experience anxiety, depression, and emotional distress. It’s important for these patients to be regularly monitored for psychological issues, and that they receive adequate support.
What else can Li-Fraumeni Syndrome be?
Some genetic conditions that are known to increase the risk of certain kinds of cancer include:
- Hereditary Breast and Ovarian Cancer syndrome (HBOC)
- Lynch syndrome
- Multiple Endocrine Neoplasia
What to expect with Li-Fraumeni Syndrome
The treatment for cancers associated with Li-Fraumeni Syndrome (LFS), a rare genetic disorder that greatly increases the risk of developing several types of cancer, is the same as the treatment for other, randomly occurring cancers. The success of treatments for childhood cancers has significantly improved, meaning most children now survive in the long term. However, survivors of these cancers often face complications, including the development of a second, completely different type of cancer, which is most likely to occur 6 to 12 years after the initial cancer.
Second cancers can emerge due to genetic factors, like changes in a gene called TP53 which is common in individuals with LFS. Diagnosing the first cancer at a younger age or exposure to radiation increases the risk of a second cancer. Therefore, individuals who have had cancer should try to avoid or cut down on exposure to diagnostic and therapeutic radiation when possible. They are more prone to develop new primary tumors, especially a type called sarcomas, in areas on the body that have previously been exposed to radiation.
The overall likelihood of a person with LFS developing a second cancer is nearly 60% within 30 years after the first cancer diagnosis.
Possible Complications When Diagnosed with Li-Fraumeni Syndrome
People who have Li-Fraumeni syndrome may stop responding to chemotherapy. These individuals also have a higher risk of developing other primary cancers if a mutation in the germline has occurred. Studies show that a mutation in the TP53 gene can make a person more sensitive to ionizing radiation. Therefore, people with germline TP53 mutations should try to limit their exposure to diagnostic and therapeutic radiation whenever they can.
Common complications include:
- Resistance to chemotherapy
- Increased risk of other primary cancers if they have a germline mutation
- Increased sensitivity to ionizing radiation if a TP53 genetic mutation is present
- Risks associated with exposure to diagnostic and therapeutic radiation
Preventing Li-Fraumeni Syndrome
Parents and patients need to be thoroughly educated about all the possible signs and symptoms of cancer. They should be encouraged to seek medical attention whenever they experience any unusual signs or symptoms that might be related to cancer. Starting at 18 years old, individuals should learn and regularly perform a self-exam of their breasts every month. This can help in early detection of any abnormal changes. Moreover, paying attention to mental health is crucial, as dealing with these health concerns can lead to anxiety or depression.