The Importance of a Specialized Care Center
The high cancer risks seen with LFS and often with other TP53+ results make it important for children, adolescents, and adults to be cared for by medical providers who are experts in LFS and TP53+ results. Dana-Farber's Li-Fraumeni Syndrome and TP53 Center is the first comprehensive multi-disciplinary center in the world that specializes in coordinating the care of people with LFS and TP53+ results, as well as provides psychological and social support for patients and their families. We do so in partnership with LFS advocacy groups. At the Li-Fraumeni Syndrome and TP53 Center, our mission is to:
- Provide the best care possible for people with LFS and TP53+ results and their families
- Increase the awareness of LFS and TP53+ results among healthcare providers and the public
- Conduct clinical research that will further the understanding and medical management of LFS and of TP53+ results
Our team of internationally renowned experts develops personalized cancer risk management plans for children, adolescents, and adults with LFS and TP53+ results and will work with their health care providers - oncologists, pediatricians, primary care physicians, and others - to provide ongoing care.
Learn about our Center's research studies and clinical trials for people with LFS and TP53+ results.
Experts in Lifelong Care of Adults and Children
We strive to maintain the most up-to-date comprehensive care for people with LFS and TP53+ results, providing recommendations for ways to detect cancers early, to reduce cancer risk, and to consider special issues in cancer treatment because of LFS and TP53+ results. We are one of the few groups who sees patients and families on a regular, long-term basis. Our group has been involved in the development of several internationally-recognized guidelines that prescribe the best ways to manage LFS, and we offer the services that help bring the recommended care to our patients.
The Li-Fraumeni Syndrome and TP53 Center specializes in caring for people with diagnoses of LFS and with TP53+ genetic test results, or those who have a family history of Li-Fraumeni syndrome. We recommend our services to people who:
- Had genetic testing and have a TP53+ (aka pathogenic or likely pathogenic variant [mutation]) result
- Have a relative who has a TP53+ result
- Have a cancer diagnosis suggestive of LFS
- Rarely, had tumor testing that found a possible hereditary TP53+ result
- Have a family history suggestive of LFS
- Have had negative or inconclusive genetic testing results, but are still concerned about LFS
- Have physicians concerned that they have LFS
- Are seeking information about LFS and TP53+ results
What Is Li-Fraumeni Syndrome?
Li-Fraumeni syndrome (LFS) is an inherited condition that increases one's chance for developing a range of different cancers. In the general U.S. population, it is estimated that 1 in 400 to 1 in 5,500 people carry a pathogenic or likely pathogenic variant (mutation) in the TP53 gene (TP53 positive genetic test result or TP53+ result). People who have LFS may develop cancer at unusually young ages, two or more separate cancers, and rare types of cancers. However, some men and women with LFS or TP53+ results will never develop cancer.
People with LFS can develop rare tumors, such as:
- Soft tissue sarcomas (cancers of muscle, fat, and other tissues)
- Osteosarcomas (cancers of the bone)
- Adrenocortical carcinomas (cancers of the adrenal gland)
- Choroid plexus carcinomas (malignant brain tumors)
People with LFS can also develop more common tumors at unusually young ages, such as:
- Brain tumors (various types)
- Breast cancer
- Colorectal cancer, stomach cancer, and other cancers of the digestive tract
- Leukemia (cancer of the blood)
- Lung cancer
- Melanoma (skin cancer)
- Thyroid cancer
Women with typical LFS have about a 90% risk of developing cancer over their lifetimes. Men with typical LFS have about a 70% risk of developing cancer over their lifetimes. One hallmark feature of LFS is that the cancers often occur at young ages. About one-third of the cancers in LFS occur before age 18, about half of the cancers occur before age 30, and most cancers occur by age 50. This is very different from the general population where cancer occurs most frequently in people who are over age 60.
Another feature of LFS is that some people can develop two or more separate cancers. The risk of developing two or more cancers is up to 50%. These separate cancers may occur at the same time or they may occur many years apart. People who had radiation treatments seem to have higher risks of developing a second cancer. For comparison, the risk of a second cancer in the general population is 6%.
Some families with LFS appear to have lower cancer risks than are usually seen in typical families. However, these cancer risks are still higher than general population risks, so these lower risk LFS families will still be advised to have extra cancer monitoring.
What Causes Li-Fraumeni Syndrome?
Li-Fraumeni syndrome is a hereditary condition. LFS is usually caused by a significant DNA change or alteration (pathogenic or likely pathogenic variant, or mutation) in the TP53 gene. Most people with LFS are found to carry a mutation in the TP53 gene (TP53+ result). Less commonly, people are diagnosed with LFS based on their medical and family history, even if they do not carry a detectable mutation in the TP53 gene.
All of us have about 22,000 genes in almost every cell in our body. We have two copies of each gene (one from each parent). Each gene is the instruction set or blueprint made of a series of four chemical letters called DNA. The DNA pattern is important to create the specific protein which performs a particular job in the body. If there is a mutation in the DNA pattern of a gene, then it will not be able to create that protein, which means that the job it was supposed to do either does not happen as well or does not happen at all. The TP53 gene tells the body to make the very important protein called p53. The p53 protein helps to fix DNA damage in our cells and keeps our cells growing normally. When there is an alteration in the TP53 gene, no protein is made.
Most people with LFS are born with a mutation in one copy of the TP53 gene that does not work and one normal copy of the TP53 gene that does work correctly. If the one working copy of the TP53 gene is doing its job, then cancer is unlikely to occur. This is why some people with TP53+ results never develop cancer. But over time, there is a chance that the working copy of the TP53 gene will get damaged in a single cell. This happens by chance or because of exposures to cancer-causing agents. Then the cell has no TP53 gene to protect its DNA. Cancer can eventually develop when this happens.
How Is Li-Fraumeni Syndrome Inherited?
Li-Fraumeni syndrome is a dominantly inherited condition. This means that inheriting one altered TP53 gene is enough to cause LFS. Thus, LFS is typically passed through the family from grandparent to parent to child. Since some people with LFS do not develop cancer, it may not be obvious which side of the family carries the altered TP53 gene.
Men and women carrying a mutation in the TP53 gene have a 50% (1 in 2) chance of passing it on to each of their children. Sometimes, a child is born with an altered TP53 gene as a new genetic event. People with LFS do not always inherit an altered TP53 gene from one of their parents. About 7-20% of people with LFS have an altered TP53 gene that occurs as a brand-new change in them. This is as called a de novo mutation.
The de novo mutation will occur at some point during a person's development before they are born. This may result in the altered TP53 gene in some but not all cells of the body, which may be referred to as mosaic LFS. People with mosaic LFS may still have LFS cancer risks, although we cannot predict which cell types have the mutation and which do not. If the mutation is present in egg or sperm cells, it can be passed down to future generations.
An altered TP53 gene detected in a blood sample may not represent LFS or mosaic LFS. This may happen if the TP53+ gene alteration occurs later in life in only a subset of cells. It will be easiest to find if it occurred in the blood cells. This is known as clonal hematopoiesis (often referred to as clonal hematopoiesis of indeterminate potential or CHIP). As we age, our blood cells can make mistakes in copying their DNA and acquire mutations. New research has shown that CHIP is common in older populations and may also occur after chemotherapy or radiation treatment. People with CHIP do not have an altered TP53 gene in other cells of their body and therefore do not have LFS cancer risks. Rarely, other conditions can look like CHIP. We may recommend special ways to tell the difference, since each condition may require some particular care.
A genetic testing report may identify a "mosaic TP53" or "low level TP53" result that may indicate the person has mosaic LFS or CHIP. Further testing to confirm the mutation in a different tissue type may be discussed. Rarely, other conditions can look like CHIP. We may recommend some tests to tell the difference, since each condition may require some special care. We are here to help resolve these complex testing results.
Who Should Be Tested for Li-Fraumeni Syndrome and TP53?
Our criteria for people who should be tested for LFS and TP53+ results includes people who have or have not had cancer themselves but have:
- A relative with a TP53+ result
- Personal or family cancer history that meets established criteria
- A rare cancer that may be linked to LFS
- An unusual family cancer history that includes rare cancers, childhood or young adult cancers, or people with more than one cancer type
- A person who has not had cancer but whose family history suggests LFS
People who meet the above criteria are recommended for genetic counseling to consider genetic testing.
