Li-Fraumeni syndrome (LFS)
Li-Fraumeni syndrome (LFS) is a rare genetic disorder characterized by an increased risk of developing various types of cancer at a young age, often before the age of 30. The syndrome is primarily caused by mutations in the TP53 gene, which plays a crucial role in regulating cell growth and preventing tumor formation. Individuals with LFS have a 50% chance of passing this mutation on to their offspring, and approximately 25% of cases arise from spontaneous mutations without a family history. The most common cancers associated with LFS include breast cancer, soft-tissue sarcomas, leukemia, and osteosarcoma, among others.
Although LFS is inherited in an autosomal dominant manner, it affects men and women equally across all ethnic backgrounds. The condition typically does not present with symptoms until cancer develops; thus, diagnosis often involves family cancer history and genetic testing. Regular screenings and early medical intervention are recommended for individuals with LFS to manage their heightened cancer risk, as they can have an up to 90% lifetime risk of developing malignancies. Despite no available treatment to prevent the mutation itself, timely cancer treatment significantly influences outcomes for affected individuals.
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Li-Fraumeni syndrome (LFS)
RELATED CONDITIONS: Li-Fraumeni-like syndrome, soft-tissue sarcoma, osteosarcoma, breast cancer, leukemia, adrenal cortical carcinoma, brain tumor (high-grade glioblastoma multiforme), Sarcoma family syndrome of Li and Fraumeni, Ssarcoma, breast, leukemia, and adrenal gland (SBLA) syndrome, SBLA syndrome
DEFINITION: Li-Fraumeni syndrome (LFS) is an autosomal dominant genetic abnormality that predisposes individuals to developing cancer at an early age (with 50 percent penetrance by age fifty years) and to developing multiple primary cancers during their lifetime.
Risk factors: In about 70 percent of LFS cases, Li-Fraumeni syndrome-1 develops because of a mutation in the deoxyribonucleic acid (DNA) of the TP53 gene (also called p53) on chromosome 17. This gene can be inherited from either parent, and the mutation is present in all cells in the body. Changes in another gene, CHEK2 (also called CHK2), on chromosome 22 and spontaneous (noninherited) changes in these genes characterize Li-Fraumeni syndrome-2. A small number of LFS cases, Li-Fraumeni syndrome-3, maps to a locus on chromosome 1q23. People with a mutation causing LFS have a 50 percent chance of passing this mutation to their children. However, approximately 25 percent of people with LFS do not have a family history of LFS but have a spontaneous (de novo) mutation of the TP53 gene.
Etiology and the disease process: TP53 is a tumor-suppressor gene. A normal TP53 controls cell growth and cell death. When it mutates, it loses the ability to regulate cell growth, allowing cells to grow wildly and become malignant. The CHEK2 gene controls another step in regulating cell growth, but the result is the same when it mutates.
People inherit one copy of TP53 from each parent. In Li-Fraumeni syndrome, one copy of TP53 is normal, and the other has mutated. People with Li-Fraumeni syndrome have a 50 percent chance of developing malignant tumors in early childhood or by the age of thirty.
The most common types of cancer for people with LFS are breast cancer, soft-tissue sarcomas (cancer arising in cartilage, muscle, fat, or blood vessels), leukemia, osteosarcoma (bone cancer), malignant melanoma, and cancer of the brain, pancreas, esophagus, adrenal cortex, and colon. People with LFS are also at higher risk of developing more than one type of primary cancer during their lives, especially if they grow and are cured of a childhood cancer.
Incidence: Li-Fraumeni syndrome appears to be rare. Only about five in 20,000 families have the mutations responsible for LFS. However, the ability to screen for this mutation is relatively new, so the incidence is not well defined. Men and women are equally affected, as are all races and ethnicities.
Although LFS is rare, for people who have this condition, the chances of developing cancer are staggeringly high, with up to a 90 percent lifetime risk. Various studies have found the following to be true:
- In the general population, the estimated risk of developing cancer before age fifty is one in thirty-five for men and one in twenty for women, while 50 percent of people with LFS develop cancer before age thirty.
- In persons with LFS, there is a 90 percent lifetime risk of developing any kind of cancer.
- Nearly 100 percent of females with LFS will develop breast cancer.
- Approximately 40 percent of people with LFS develop cancer before age sixteen.
- About 15 percent of people with LFS whose cancer is cured develop a second primary cancer. Some 4 percent develop a third cancer, and 2 percent are diagnosed with a fourth cancer.
- People who develop cancer before age sixteen are at highest risk of developing multiple primary cancers.
Symptoms: Li-Fraumeni syndrome has no symptoms. Cancer symptoms depend on the type of cancer the individual develops.
Screening and diagnosis: People are formally diagnosed with Li-Fraumeni syndrome when they meet all three of the following conditions:
- They are diagnosed with sarcoma before age forty-five.
- A first-degree relative is diagnosed with any cancer before age forty-five.
Genetic screening can detect about 95 percent of TP53 mutations that cause LFS. However, genetic screening is normally only offered when a close blood relative is diagnosed with LFS. Screening should be accompanied by genetic counseling so that individuals can make informed decisions about their future and the risks of passing this mutation on to any children they might have. Prenatal screening is possible through chorionic villi sampling or amniocentesis.
Treatment and therapy: No treatment can prevent or reverse this mutation. Cancers are treated as they arise.
Prognosis, prevention, and outcomes: Li-Fraumeni syndrome strongly predisposes individuals to develop cancer, particularly at an early age. Individuals who know they come from a family with LFS are encouraged to have complete annual physical examinations, which may include more frequent mammograms or colonoscopies than the general population, and to get prompt medical care for any symptoms that may be an early warning of cancer. Outcomes depend on the type of cancer the individual develops and how soon it is treated.
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