Li-Fraumeni Syndrome Explained

Li-Fraumeni syndrome (LFS) is an inherited condition that greatly raises the risk of several cancers. It affects children and young adults far more than most inherited cancer syndromes do. It is rare: it is thought to occur in 1 in 5,000 to 1 in 20,000 people worldwide.

This page covers the gene, the cancers, who should be tested, and the surveillance program that has changed what the diagnosis means.

TP53 is a tumor suppressor gene. Its job is to help control the growth and division of cells. When one copy is faulty from birth, that brake is weakened in every cell of the body.

Nearly three-quarters of families with Li-Fraumeni syndrome carry a germline change in TP53. "Germline" means the change is in every cell, and can be passed to children.

LFS is inherited in an autosomal dominant pattern. One altered copy in each cell is enough to raise cancer risk. Each child of a person with LFS has a 50% chance of inheriting it.

Not everyone inherits it from a parent. In 7% to 20% of cases the change is new in that person, so there is no family history at all.

Five cancers make up the core spectrum:

• Adrenocortical carcinoma (ACC), a cancer of the outer layer of the adrenal gland.
• Breast cancer.
• Central nervous system tumors, meaning brain and spinal cord tumors.
• Osteosarcoma, a bone cancer.
• Soft-tissue sarcoma, a cancer of muscle, fat, or connective tissue.

Other cancers occur more often too. These include leukemia, colorectal cancer, gastric cancer, lung cancer, melanoma, pancreatic cancer, and prostate cancer.

Choroid plexus carcinoma, a rare brain tumor, is strongly tied to LFS. So is adrenocortical carcinoma in a child. Either one, on its own, is a reason to think about TP53 testing.

The numbers are high, and it does not help anyone to soften them.

In classic LFS, the lifetime cancer risk is about 90% for women and about 70% for men. The higher figure in women reflects breast cancer risk.

Half of the cancers occur before age 40.

By age 70, the risk of cancer is about 80%. Of those cancers, 22% occur between ages 0 and 15, 51% between ages 16 and 50, and 27% between ages 51 and 80.

People with LFS are also at real risk of a second, separate cancer later. That fact shapes both treatment choices and lifelong follow-up.

Two sets of criteria are used.

Classic LFS criteria. All three must be present:

• A sarcoma diagnosed before age 45.
• A first-degree relative with any cancer before age 45.
• A first- or second-degree relative with any cancer before age 45, or a sarcoma at any age.

Modified Chompret criteria. Any one of these four is enough:

• A tumor in the LFS spectrum before age 46, plus a first- or second-degree relative with a classic LFS cancer before age 56, or with more than one tumor.
• More than one tumor in the same person, two of them in the classic LFS spectrum, with the first before age 46. Multiple breast cancers do not count here.
• Adrenocortical carcinoma, choroid plexus tumor, or anaplastic embryonal rhabdomyosarcoma, whatever the family history.
• Breast cancer before age 31.

The Chompret criteria matter because they catch people with no family history. That covers the 7% to 20% whose change is new.

Testing should be done alongside genetic counseling. The result affects relatives, insurance decisions, and family planning, not just the person tested.

This is the surveillance schedule used for people with a TP53 change.

Physical examination. Every 3 to 4 months from birth to age 18. Every 6 months from age 18.

Whole-body MRI. Annually, at all ages.

Brain MRI. Annually. The first scan uses contrast. Later scans can be done without contrast if the first is normal.

Abdominal and pelvic ultrasound. Every 3 to 4 months from birth to age 18, mainly to catch adrenocortical carcinoma. Annually from age 18, to look for sarcomas.

Breast surveillance. Clinical breast exam every 6 to 12 months, starting between ages 20 and 25. Breast MRI annually, starting between ages 20 and 30. From age 30 to 75, mammogram and breast MRI alternating every 6 months.

Upper endoscopy and colonoscopy. Every 2 to 5 years from age 25.

Skin examination. Annually from age 18.

Ask your center which parts of this schedule they follow, and who is responsible for booking each one. Surveillance falls apart when no single person owns the calendar.

MRI uses magnetic fields, not ionizing radiation. CT scans and x-rays do use ionizing radiation. In LFS, the same faulty TP53 that raises cancer risk also makes cells less able to repair radiation damage.

So the whole approach is built to find cancers early without adding radiation exposure. In the National Cancer Institute's LFS screening study, the protocol deliberately avoided imaging with ionizing radiation, apart from mammography.

The same logic applies to treatment. Radiation therapy should be avoided if possible, to reduce the risk of a second cancer. This does not mean radiation is forbidden. When it is clinically needed, treating the cancer effectively comes first. It does mean the option should be discussed openly, and that close surveillance of the treated area is recommended afterwards.

Say clearly at every appointment, including dental and emergency visits, that you have Li-Fraumeni syndrome. It should change how casually a scan is ordered.

The National Cancer Institute studied 116 people with LFS and a germline TP53 change.

At the first round of screening, 40 people (34%) had an abnormality found. Eight of them (7%) were diagnosed with a new primary cancer. All but one of those cancers were fully removed with surgery.

An international analysis of 578 participants across 13 groups confirmed the same 7% cancer detection rate.

That is the argument for the schedule. Cancers found small are more often removable.

Surveillance runs on a calendar. Cancer does not. Contact the team promptly, without waiting for the next scan, for:

• Swelling over a bone or a bony part of the body.
• Pain in a bone or joint, pain in the arm when lifting, stiffness in a joint, a limp or trouble walking, or a bone that breaks for no known reason. These are the listed signs of osteosarcoma.
• In a child: pain in the abdomen or back, a lump in the abdomen, a feeling of fullness, high blood pressure, acne, growing body hair, deepening of the voice, or growing faster than normal. These are listed signs of childhood adrenocortical carcinoma.
• A new lump anywhere that persists or grows.

Call 911 for a first seizure, sudden weakness or numbness on one side, a sudden severe or unfamiliar headache, repeated vomiting with headache, or new confusion. These need an ambulance rather than a drive to the hospital.

• Which specific TP53 variant do I have, and is it classified as pathogenic?
• Who coordinates my surveillance schedule, and how are results tracked over time?
• Which of my relatives should be offered testing, and at what age?
• If I need treatment, how will radiation exposure be weighed?
• Is there an LFS study or registry I can join?

• Li-Fraumeni Syndrome — MedlinePlus Genetics, National Library of Medicine
• Li-Fraumeni Syndrome — GeneReviews, National Center for Biotechnology Information
• Cancer Screening Protocol for Patients with Li-Fraumeni Syndrome — National Cancer Institute
• Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment (PDQ) — National Cancer Institute
• Childhood Adrenocortical Carcinoma — National Cancer Institute