What is Li-Fraumeni syndrome (LFS)?
A syndrome is a group of features that often occur together. A person with Li-Fraumeni syndrome (LFS) may develop multiple types of cancer, usually at an early age. If a person inherits a mutation in the p53 gene, they have Li-Fraumeni syndrome and are at increased risk for developing certain types of cancer over their lifetime.
The cancers seen most often in LFS include:
- Soft-tissue sarcomas – tumors that develop in tissue that connects, supports, or surrounds muscles, fat, blood vessels, nerves, and joints
- Osteosarcomas – tumors that form in the bone
- Breast cancer
- Brain cancer
- Adrenocortical tumors – tumors that form in the adrenal gland (a small organ that sits above each kidney and secretes hormones)
- Melanoma (cancer of the skin) and lung, stomach, and pancreatic cancers
Families where LFS might be suspected include those with one or more of the following:
- A person diagnosed with a bone or soft tissue sarcoma under the age of 46
- A person with an adrenocortical tumor or choroid plexus tumor (type of brain tumor)
- A person with multiple tumors associated with LFS, the first of which occurred before the age of 46
- In some cases, a woman diagnosed with breast cancer under the age of 30
The age, number, and type of cancers that develop can vary among people who have LFS, even within the same family. Many of the cancers seen in LFS families, like breast cancer, are also common in the general population. Most of the time, people with these common cancers do not have LFS.Back to top
What does a negative p53 test result mean?
A negative test result means that no p53 mutation was found. This can happen if:
- You have a mutation in the p53 gene that cannot be detected with the method that was used. No one gene testing method can find all mutations in a gene.
- You have a mutation in a different gene. For example, even if you tested negative for a p53 mutation, your genetic counselor may recommend testing for mutations in a different gene that could cause cancers related to LFS. Testing for rare mutations or for panels of multiple predisposition genes is available and may be covered by insurance in some cases. We suggest you talk with your genetic counselor about this. In addition, more genes will probably be discovered in the future.
- Your personal or family history of cancer happened by chance. For instance, breast cancer can be associated with LFS but it is a common cancer in general. It can develop in several people in a family without being caused by a genetic mutation.
- There is a genetic mutation in your family, but you did not inherit it.
What does a positive p53 test result mean?
People with a p53 mutation have LFS and are at an increased risk of developing the associated cancers. These risks may vary, but studies have shown that the risk of developing cancer among carriers of p53 mutations approaches 50% by 30 to 40 years of age, and 90% by 60 to 70 years of age.
It is important to understand that having LFS does not mean that you will definitely develop cancer; it means that you have an increased risk of developing certain cancers. Some people with a p53 mutation never develop cancer.Back to top
What does a “variant of uncertain significance” (or “ambiguous”) test result mean?
Genes are written in letters called bases. A wrong spelling of a gene can cause an increased risk of cancer. However, changes in the spelling of a gene bases may differ in people without cancer. We are still learning which spellings are normal (harmless) and which can cause an increased risk for disease. These kinds of uncertain changes are called “variants of uncertain significance.”
If you have a variant of uncertain significance in the p53 gene, we may not be able to tell you whether or not you are at increased risk for cancer. We will make cancer screening recommendations for you based on your family history. We may suggest testing certain relatives to learn more about the variant but this information will probably not be helpful in predicting cancer risks for your relatives. Future research may make it clearer whether or not a variant of uncertain significance leads to increased risks of cancer.Back to top
How should people with a p53 mutation manage their risk of cancer?
People with a p53 mutation have several options for managing their cancer risk. They can choose to undergo additional cancer screening that is not usually available to people at population risk for cancer. The goal of screening is to try to detect cancer at an early stage if it develops. Pediatricians and other doctors seen by people with LFS should be knowledgeable about the cancer risks associated with this syndrome. Screening includes:
- Children should have a yearly physical exam, urine test, complete blood count, and ultrasound of the abdomen.
- Adults (male and female) should have a yearly physical exam (including the skin and nervous system), urine test and complete blood count. Yearly chest x-ray can be considered to screen for lung cancer, although the risks and benefits should be discussed with a doctor. A colonoscopy should be done to screen for colon cancer starting at the age of 30 to 40. The optimal age to start and frequency of colonoscopies should be discussed with the gastroenterologist.
- Adult females should have yearly PAP smears. Breast cancer screening is recommended starting at the age of 20 to 25 (or earlier depending on family history), and includes clinical breast exams every 6 months, and yearly mammogram and breast MRI. There is controversy about whether females with a p53 mutation should have mammogram and breast MRI, or just breast MRI, before the age of 40. Females with LFS in this age range should discuss the risks and benefits of mammograms with a doctor.
- Screening for many of the other cancers seen in LFS has not proven to be helpful, but you and your doctor may wish to consider new screening approaches such as investigational whole-body MRI. The effectiveness of a yearly whole-body MRI is currently being studied.
It is important to realize that screening does not prevent cancer. Current tests cannot always find cancers when they are small enough to be treated successfully.
Females with a p53 mutation may choose to undergo surgery to try to prevent certain cancers. For instance, surgery to reduce the risk of breast cancer is called prophylactic or preventive mastectomy. During this surgery, as much breast tissue as possible is removed. Since not all breast tissue can always be removed, prophylactic mastectomy may not be 100% effective at preventing cancer.Back to top
If I have a p53 mutation, what are the risks to my children?
If you have a p53 mutation, each of your children (or future children) has a 50% (1 in 2) chance of inheriting that mutation. A child who inherits the mutation will also inherit the associated cancer risks. It is important to remember that just inheriting the mutation does not automatically mean that a person will develop cancer.
Some of the cancers associated with LFS can develop in childhood. Therefore, it may be appropriate to do genetic testing in children at risk to carry a p53 mutation. Your genetic counselor can help determine the risk for your children and other family members, and will also determine what would be an appropriate age for them to have their own genetic testing.Back to top
If I have a p53 mutation, what are my options for having children?
If you are found to carry a p53 mutation, you may want to learn about family planning options (starting a family or having more children). For example, embryos can be tested for the family’s genetic mutation before they are even implanted in a woman’s uterus. This process is called preimplantation genetic diagnosis (PGD). PGD is performed with in vitro fertilization, and may be an option for families who wish to have children without the hereditary cancer risk. To learn more, ask for a referral to a specialist before attempting pregnancy.
Having children with the assistance of donor eggs or donor sperm and adoption are other possible family planning options.Back to top
Who should I call if I have questions?
If you have any questions or concerns, please contact MSK’s Clinical Genetics Service at 646-888-4050.Back to top