Li-Fraumeni Syndrome (LFS)

What Li-Fraumeni syndrome is

The TP53 gene makes a protein called p53, often called the "guardian of the genome". When a cell's DNA is damaged, p53 pauses cell division so the damage can be repaired, or triggers the cell to self-destruct. Everyone has two copies of TP53. People with LFS are born with one faulty copy in every cell. If the second copy is damaged in any cell during life, that cell loses this protection and can grow into a tumor.

LFS was first described in 1969 by Drs. Frederick Li and Joseph Fraumeni, who noticed families with unusual clusters of sarcomas, breast cancer and childhood cancers.

How it is inherited

LFS is autosomal dominant. A parent with a TP53 variant has a 50% chance of passing it to each child, regardless of sex. In about 7% to 20% of people, the variant arises new (de novo) with no family history. Some people carry milder TP53 variants with lower cancer risk, which is why the broader term "heritable TP53-related cancer syndrome" is now used.

Cancers linked to Li-Fraumeni syndrome

Other cancers occur more often and at younger ages too, including colorectal, lung, pancreatic, stomach, prostate, thyroid and skin cancers. People with LFS also have a high chance of developing a second, separate cancer, especially in areas treated with radiation.

Signs that suggest LFS in a family

LFS has no physical features. It is suspected from the pattern of cancers. Testing is recommended when:

• Classic LFS criteria: a person with sarcoma before age 45, plus a parent, sibling or child with any cancer before 45, plus another first- or second-degree relative with any cancer before 45 or sarcoma at any age.
• Chompret criteria (broader), for example: - a person with an LFS-type cancer before 46 and at least one close relative with an LFS-type cancer before 56 - multiple tumors in one person, with the first before 46 - adrenocortical carcinoma, choroid plexus carcinoma or a specific type of rhabdomyosarcoma at any age - breast cancer before age 31

If you are unsure, a genetic counselor can review your family history.

Testing and diagnosis

Diagnosis is made by a genetic blood or saliva test for germline TP53 variants, usually as part of a multigene cancer panel. Pre-test genetic counseling explains what a result means for you and your relatives, including implications for insurance and children.

Sometimes a TP53 variant is found unexpectedly in tumor testing or in a blood test for other reasons. Variants found only in blood cells of older adults can be due to clonal hematopoiesis (age-related changes in blood cells) rather than LFS, so confirmation on another tissue such as skin may be needed.

Once a family variant is known, relatives can have targeted testing. Testing of children is generally offered from birth or early childhood, because screening starts in infancy.

Screening: the Toronto protocol

Regular surveillance finds cancers earlier, when they are more treatable. Studies have shown better survival in people who follow it. A typical schedule, based on the modified Toronto protocol, includes:

Children (from birth to 18):

• full physical exam every 3 to 4 months, including blood pressure and checks for early puberty signs
• abdominal and pelvic ultrasound every 3 to 4 months for adrenal tumors
• yearly whole-body MRI
• yearly brain MRI

Adults:

• full physical exam every 6 months
• yearly whole-body MRI and brain MRI
• breast awareness from age 18, clinical breast exam every 6 to 12 months from 20, and yearly breast MRI from age 20
• colonoscopy and upper endoscopy every 2 to 5 years from about age 25
• yearly skin exam
• blood tests in some programs

MRI is used rather than CT or X-ray-based scans to avoid radiation, which can trigger new cancers in people with LFS. Mammograms are generally not recommended.

Treatment and risk reduction

Cancers in people with LFS are treated with the same basic approaches as in others, with some adjustments:

• Avoid radiation therapy when a good alternative exists, because it raises the risk of a second cancer in the treated area.
• Breast cancer: mastectomy is usually preferred over lumpectomy, since lumpectomy requires radiation.
• Risk-reducing mastectomy: many women with LFS consider removing both breasts, which greatly lowers breast cancer risk.
• General measures: not smoking, sun protection, a healthy weight and limiting alcohol.

Research is exploring medicines that might lower risk, such as metformin, but none is standard yet.

Living with LFS

Knowing you carry a TP53 variant can bring anxiety, grief and decisions about family planning. Options include prenatal testing and in vitro fertilization with preimplantation genetic testing to avoid passing it on. Support from genetic counselors, psychologists and patient groups such as the LFS Association helps many families.

Outlook

Life expectancy with LFS is shorter on average because of cancer risk, but it varies greatly between families and individuals. Many people do not develop cancer until adulthood, and some carriers of lower-risk variants never do. Following the screening protocol and avoiding unnecessary radiation are the most effective ways to improve outcomes.

Frequently asked questions

What cancers are associated with Li-Fraumeni syndrome?

The core cancers are breast cancer, soft tissue sarcoma, osteosarcoma, brain tumors and adrenocortical carcinoma. Leukemia, colorectal, lung, pancreatic and several other cancers are also more common. They often appear at much younger ages than usual, including in childhood.

How is Li-Fraumeni syndrome inherited?

It is autosomal dominant. A parent with a TP53 variant has a 50% chance of passing it to each child. About 7% to 20% of people have a new variant not inherited from either parent, so a family history is not always present.

What is the life expectancy with Li-Fraumeni syndrome?

It varies widely. Cancer risk is very high and often starts early, which lowers average life expectancy. However, regular whole-body MRI screening finds tumors earlier and has been shown to improve survival, and some carriers never develop cancer.

What is the Toronto protocol?

It is a cancer screening schedule for people with LFS. It combines frequent physical exams, abdominal ultrasound in childhood, yearly whole-body and brain MRI, breast MRI from age 20 and regular colonoscopy, avoiding radiation-based imaging wherever possible.

Should children be tested for Li-Fraumeni syndrome?

Testing is usually offered in early childhood when a parent carries the family variant, because adrenal and brain tumors can appear in infancy and screening starts from birth. The decision is made with a genetic counselor and the child's doctors.