Li-Fraumeni syndrome

Overview

Li-Fraumeni (LEE-frau-MEE-nee) syndrome is a rare inherited condition that increases the risk of many types of cancer. These cancers often happen at younger ages than usual. The syndrome also can lead to more than one cancer throughout life.

In the past, Li-Fraumeni syndrome has been called sarcoma, breast, leukemia and adrenal gland (SBLA) cancer syndrome. You also may see the condition spelled Li Fraumeni, without the hyphen.

Li-Fraumeni syndrome is linked to an inherited harmful change, also called a mutation, in the TP53 gene. The TP53 gene usually helps keep cells with damaged DNA from growing into cancer.

Li-Fraumeni syndrome is different from other inherited cancer syndromes because it involves a different gene. It also may be linked with different cancers. For example, Lynch syndrome is caused by changes in other genes that also play a role in managing DNA damage. Though Lynch syndrome also is linked to many cancers, it's especially linked to colon and endometrial cancers.

A diagnosis of Li-Fraumeni syndrome can feel overwhelming. But knowing about Li-Fraumeni syndrome can help you and your healthcare team take steps to screen for cancer early, when treatment may be more successful.

Causes

Li-Fraumeni syndrome is caused by a harmful change in the TP53 gene, which is located on chromosome 17. The TP53 gene gives the body instructions to make a protein called p53. This protein helps stop cells with damaged DNA from growing and dividing. When TP53 doesn't work well, damaged cells may survive and grow. Over time, they may become cancer.

Li-Fraumeni syndrome often is inherited. When it's inherited, a person needs to inherit only one changed copy of the TP53 gene from a parent to have the syndrome. This is called an autosomal dominant pattern. If a parent has the harmful gene change, each child has a 50% chance of inheriting it.

In Li-Fraumeni syndrome, the TP53 gene change usually is a germline gene change. This means the change was present in the egg or sperm cell that formed a person, so it's found in almost every cell in the body. This is why the TP53 change can increase the risk of many different types of cancer.

Not everyone with Li-Fraumeni syndrome inherits the TP53 change from a parent. In some people, the gene change happens by chance. This is called a de novo variant.

Complications

The main complication of Li-Fraumeni syndrome is cancer. Research has estimated that the lifetime risk of cancer for someone with Li-Fraumeni syndrome is 90%, possibly more.

When it comes to cancer linked to Li-Fraumeni syndrome:

• Cancer can happen at a younger age. Cancer often happens at a younger age than usual for someone without Li-Fraumeni syndrome. In one study of people with Li-Fraumeni syndrome, half of women had cancer by about age 34, and half of men had cancer by age 45.
• Cancer risk is much higher. Cancer also is much more common in those with Li-Fraumeni syndrome. For example, in women with Li-Fraumeni syndrome, the lifetime risk of breast cancer is more than 60%. In the general population, the lifetime risk is 12% to 13%. One study found that, overall, people with Li-Fraumeni syndrome had nearly 24 times the rate of cancer compared with the general population.
• More than one cancer is possible. People with Li-Fraumeni syndrome who get cancer also have a high risk of getting another unrelated cancer later. In one study, the chance of a second cancer was close to 60% within 30 years of the first cancer. Some people later had cancer a third or fourth time.

Cancer risk estimates for Li-Fraumeni syndrome, especially for specific types of cancer, can change depending on the study. Because Li-Fraumeni syndrome is rare, risk estimates may change as more people are studied. Cancer risk also depends on your age and sex and which TP53 change you have.

In general, cancers most strongly linked to Li-Fraumeni syndrome include:

• Adrenal cancer.
• Brain tumors.
• Breast cancer.
• Osteosarcoma.
• Soft tissue sarcoma.

Some TP53 gene changes, also called gene mutations, also increase the risk of certain cancers beyond those traditionally linked with Li-Fraumeni syndrome. They include:

• Colorectal cancer.
• Leukemia.
• Lung cancer.
• Lymphoma.
• Melanoma.
• Ovarian cancer.
• Prostate cancer.
• Stomach cancer.

Diagnosis

Li-Fraumeni syndrome usually is diagnosed when a genetic test finds a harmful TP53 gene change. Before recommending genetic testing, the healthcare team also looks at your personal and family histories of cancer.

Who needs genetic testing

A healthcare team may recommend TP53 genetic testing if:

• Someone in your family is known to have a harmful TP53 gene change. This may include a first-degree relative, meaning a parent, brother, sister or child. It also might include another close blood relative, such as an aunt, uncle, niece, nephew, grandparent or grandchild.
• Your personal or family history suggests Li-Fraumeni syndrome.

Two sets of criteria commonly used to decide if you need genetic testing are the classic Li-Fraumeni syndrome criteria and the Chompret criteria.

If all of these classic criteria apply, a care team may suggest genetic testing.

• You have a sarcoma before age 45.
• A first-degree relative has any cancer before age 45.
• Another first-degree or close blood relative on the same side of the family has any cancer before age 45 or a sarcoma at any age.

The classic criteria look for a pattern of cancer at young ages within a family.

The Chompret criteria aim to include people who may need testing even if their family does not meet the classic criteria.

If any of these Chompret criteria apply, a care team may suggest genetic testing:

• You have a cancer commonly linked to Li-Fraumeni syndrome before age 46 and you also have a first-degree relative or close blood relative who's had one of these cancers before age 56 or who's had more than one cancer. This doesn't apply if you have breast cancer and your family history is limited to breast cancer.
• You've had more than one cancer, with at least two of them linked to Li-Fraumeni syndrome and the first cancer was diagnosed before age 46. This doesn't apply if your cancers were breast cancer.
• You've had adrenal cancer, choroid plexus carcinoma or a certain type of rhabdomyosarcoma at any age, regardless of family history.
• You have breast cancer before age 31.

Genetic testing may be considered in some other situations. These include when:

• You've had a specific type of childhood leukemia.
• You've had a tumor that was tested and results showed a harmful TP53 gene change.

What to expect from genetic testing

Genetic testing often looks for a harmful TP53 gene change using a blood sample.

Sometimes a TP53 gene change is found in only a small number of blood cells. When this happens, it could mean:

• The gene change affects only some cells in the blood — and in the body. This is called mosaicism. A mosaic form of Li-Fraumeni syndrome may still increase cancer risk.
• The gene change affects a group of blood cells and is not found anywhere else in the body. This is not Li-Fraumeni syndrome and does not increase the risk of cancer.

If a blood test shows that only some cells have the gene change, you may need testing of other body tissue, such as the skin. This can show if the gene change is present in other places in the body, which may suggest it's mosaic Li-Fraumeni syndrome.

A genetic counselor or other healthcare professional trained in genetics can help explain what the result means for the person being tested and for family members.

Cancer screening

If you're diagnosed with Li-Fraumeni syndrome, regular cancer screening and medical exams are an important part of managing the risk of cancer. Some screening is recommended as early as infancy, and screening is done throughout life.

Screening may include:

• Physical exams. Children may have an exam every 3 to 4 months. Blood tests may be done in children to check for signs of leukemia or adrenal cancers. Adults may have a physical exam every 6 to 12 months. These exams look for signs of cancer.
• Whole-body MRI. An MRI scan of the body once a year can begin in infants. MRI does not use radiation.
• Brain MRI. This usually is done once a year and can start when a child is an infant.
• Ultrasound of the adrenal glands in children. Young children may have an ultrasound every 3 to 4 months to look at the adrenal glands.
• Skin checks. Both children and adults may need regular skin checks by a dermatologist.

Screening in adults also may include:

• Breast MRI and mammograms. For women with Li-Fraumeni syndrome, annual breast MRI usually starts at age 20. Annual mammograms also may be added starting at age 30. Breast cancer screening may be recommended earlier, depending on family history.
• Upper endoscopy and colonoscopy. These tests may be recommended every 2 to 5 years starting at age 25 or earlier, depending on family history.
• Pancreatic cancer screening. In people with a family history of pancreatic cancer, periodic screening for pancreatic cancer may be recommended starting at age 50 or starting at 10 years younger than the earliest age a family member was diagnosed with it.
• Prostate cancer screening. A PSA test may be recommended yearly starting at age 40.

Your exact screening plan may be adjusted based on your age and personal and family cancer histories. Because Li-Fraumeni syndrome is rare and screening planning is complex, care often is coordinated by a team with experience in inherited cancer syndromes.

Preparing for an appointment

It may help to take steps to prepare for your appointments.

What you can do

Before your appointment, it may help to gather information to bring with you.

• Collect and document your personal and family histories of cancer.
• If someone in your family has had genetic testing that found a TP53 gene change, try to get a copy of that person's genetic test report.

It also may help to prepare a list of questions ahead of time. For Li-Fraumeni syndrome, some basic questions to ask may include:

• What does my genetic test result mean for me?
• If my TP53 test result suggests mosaicism, do I need more testing?
• Should I meet with a genetic counselor?
• What is my risk of cancer?
• What cancer screening tests do I need, and how often do I need them?
• At what age should cancer screening start for me or my child?
• Are there imaging tests or treatments that use radiation that I should avoid or limit?
• Should I consider surgery to lower my risk of breast cancer?
• Are there research studies or clinical trials that I should think about?
• Should children or other family members have genetic testing?
• What are the chances that I will pass Li-Fraumeni syndrome on to my children?
• If I want to have children, what reproductive options are available to me?