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Last updated: 3/14/2025
Years published: 2017, 2021, 2025
NORD gratefully acknowledges Christian Kratz, MD, Department Head of Pediatric Hematology and Oncology, Hannover Medical School, Li-Fraumeni Syndrome Association Medical Advisory Board Member and Germany Chapter Co-chair; Robert Lufkin, DO, Li-Fraumeni Syndrome Association Scientific & Medical Advisor/Co-Founder, Megan Frone, MS, CGC, National Cancer Institute and Li-Fraumeni Syndrome Association Genetic Counseling Advisory Group Co-Chair, and Holly Fraumeni, Vice- President, Li-Fraumeni Syndrome Association, for the preparation of this report.
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Summary
Li-Fraumeni syndrome (LFS) is an inherited genetic syndrome that leads to an increased lifetime risk of a wide range of cancers. This is due to a genetic change (genetic variant) in a tumor suppressor gene known as TP53. The resulting p53 protein produced by the gene is damaged (or otherwise rendered malfunctioning) and is unable to help prevent cancer from developing. Individuals with LFS are at risk of developing many types of cancers including soft-tissue and bone sarcomas, breast cancer, brain tumors, adrenocortical carcinoma and acute leukemia. Other cancers seen in people with LFS include gastrointestinal cancers and cancers of the lung, kidney, thyroid and skin, as well as in gonadal organs (ovarian, testicular and prostate). The risk of developing cancer begins in early childhood and continues throughout the lifetime. Individuals with LFS can develop multiple cancers throughout their lifetime. Both males and females are at risk to develop cancer, and both males and females can pass a TP53 gene variant to their children.
It is important to note that not everyone with a TP53 gene variant will develop cancer, but the lifetime cancer risks are substantially higher than in the general population. A diagnosis of LFS is critically important so that affected families can seek appropriate genetic counseling as well as surveillance for early detection of cancer.
Introduction
LFS was first recognized in 1969 by Drs. Frederick Li and Joseph Fraumeni, Jr. while studying pediatric and familial cancers at the National Cancer Institute. They described four families with multiple early-onset cancers in children and young adults. The syndrome was first reported in a publication as “Li-Fraumeni syndrome” in 1982 by researchers in the United Kingdom who described two families with multiple forms of cancer in young people.
In 1990, inherited variants of the TP53 gene were discovered as the primary cause of LFS. This finding provided a special opportunity for genetic testing and clinical interventions that enable cancer surveillance and management for people with LFS. The finding also fueled further molecular research into TP53 which is commonly found in the tumor tissue of cancer patients.
LFS may be suspected if someone has a personal or family history of cancer, particularly if there are many individuals with cancer and/or those cancers have an early age of onset. In addition, there are certain rare cancers that are characteristic of the syndrome that should alert clinicians to the potential diagnosis of LFS. Patients and families with multiple childhood cancers or specific rare cancers such as adrenocortical, choroid plexus carcinoma, anaplastic rhabdomyosarcoma, sonic hedgehog medulloblastoma, or hypodiploid acute lymphoblastic leukemia should alert doctors to the potential of a hereditary cancer syndrome such as LFS. Although increasingly identified as a hereditary cancer predisposition syndrome, not all physicians are aware of the diagnosis of LFS.
Cancers most closely associated (core cancers) with LFS include:
Other cancers may also appear, but risks are lower than for the core cancers:
Individuals with LFS have an approximately 50% chance of developing cancer by age 40 and up to a 90% chance by age 60. Females have a nearly 100% risk of developing cancer in their lifetime due to their markedly increased risk of breast cancer. Many individuals with LFS develop two or more primary cancers over their lifetimes.
Li-Fraumeni syndrome is caused by an inherited (germline) pathogenic variant of the TP53 tumor suppressor gene on chromosome 17. LFS was first recognized in 1969 and in 1979, TP53 was identified in the tumor tissue of more than 50% of all cancer patients. However, it wasn’t until 1990 that a TP53 germline variant was discovered to be the cause of LFS.
LFS follows autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Most people with LFS have a TP53 gene variant inherited from a parent, but in some individuals, LFS is due to a spontaneous (de novo) genetic variant. In such situations, the syndrome is not inherited from the parents and there is not a family history of the syndrome.
There are many known gene variants that result in malfunctioning p53 protein, and each can affect every person in a family differently. Most families with LFS have very high cancer incidence rates while some others do not, and even within families, the aggressiveness of the syndrome varies. The degree to which a TP53 variant causes cancer in a family or individual is called “penetrance.”
Individuals with LFS may also be prone to the carcinogenic risks associated with certain lifestyle or environmental exposures such as tobacco smoking or radiation exposure. LFS patients should take preventive measures to reduce their exposures to behavioral risk factors and carcinogens.
Though it is challenging to estimate the frequency in the population, there are likely over 1,000 multigenerational families worldwide with LFS. Inquiries to the LFS Association website have been received from 172 countries.
There is no evidence of ethnic or geographic disparity in the occurrence of LFS, but a high prevalence of LFS has been reported in southern and southeastern Brazil. Many people with LFS in this area have been diagnosed with a specific variant of the TP53 gene called p.R337H. This finding has led researchers to suspect that this variant is a “founder variant”. Interestingly, though, as opposed to the 90% lifetime risk of developing cancer in most people with LFS, the population in Brazil with this “founder variant” has roughly a 60% lifetime risk of cancers, which have relatively favorable survival rates.
Li-Fraumeni syndrome is diagnosed based on the presence of a pathogenic or likely pathogenic variant in the TP53 gene.
Genetic testing for TP53 variants is typically considered for people who meet the criteria outlined below. However, the increased use of clinical gene panel sequencing has led to the identification of TP53 pathogenic or likely pathogenic variants in people who did not meet testing criteria.
If an individual meets the clinical definition of the syndrome (e.g. classic LFS or Chompret criteria 1 or 2 below) but a disease-causing variant in TP53 is not identified and there is no other genetic explanation, the diagnosis is “phenotypic LFS”.
The potential benefits of genetic testing and the implications of possible results should always involve discussions with a genetic counselor, medical providers and family.
The American Society of Clinical Oncology recommends the criteria below to determine if genetic testing should be considered:
Classic LFS is diagnosed when a person has all the following criteria:
Chompret Criteria for Clinical Diagnosis of Li-Fraumeni Syndrome is a set of criteria that has been proposed to identify affected families beyond the classic criteria listed above. A diagnosis of LFS and TP53 gene variant testing should be considered for anyone with a personal and family history that meets 1 of the following 3 criteria:
Criterion 1
Criterion 2
Criterion 3
In addition, people with hypodiploid acute lymphoblastic leukemia and SHH medulloblastoma should be tested, regardless of family history.
Other risk factors to consider, specific to breast cancer:
A female who has a personal history of breast cancer, particularly if it was diagnosed at a younger age, and who does not have an identifiable variant in the BRCA1 or BRCA2 gene, may have a TP53 gene variant.
A female who is diagnosed with breast cancer before age 30 and is not found to have a BRCA1 or BRCA2 variant has an estimated 4% to 8% likelihood of having a TP53 variant.
Females with breast cancer diagnosed between ages 30 and 39 may also have a small increased risk of having a TP53 variant.
In younger females with breast cancer, a TP53 variant may also occur with any of the following features: a family history of cancer, especially LFS-related cancers, a personal history of a breast tumor that is positive for estrogen (ER), progesterone (PR) and HER2/neu markers, also known as “triple-positive” breast cancer and a personal history of an additional LFS-related cancer.
Clonal hematopoiesis of indeterminate potential (CHIP) leading to false positive LFS genetic test results:
Occasionally, a person can test positive for a pathogenic TP53 variant on a blood or saliva sample but have a result indicating a low percentage of tumor cells (low variant allele fraction (VAF) and/or they may have a personal or family history not consistent with LFS. This type of result may indicate that the individual does indeed have a germline TP53 variant consistent with a diagnosis of LFS and has mosaic LFS or a de novo gene variant. Alternatively, this result could be an incidental finding restricted to the blood cells and NOT a finding consistent with a germline TP53 variant leading to LFS.
If an individual has a pathogenic or likely pathogenic TP53 variant on a blood or saliva sample and has either a low VAF result or a personal and/or family history not consistent with LFS, additional testing for the TP53 variant on cultured skin cells from skin punch biopsy or nail clippings should be considered to help determine if a diagnosis of LFS can be confirmed. Alternatively, if the TP53 variant is found in other family members, this confirms a diagnosis of LFS.
If the TP53 variant is confirmed on cultured fibroblasts, nail clippings or in other family members, this confirms a diagnosis of mosaic and/or de novo LFS. The person has the pathogenic variant in some but not all cells in their body and may be the first in the family to carry the variant. Individuals with mosaic LFS may be at lower risk of cancer than someone with “classic” LFS depending on how many cells in the body have the disease-causing TP53 gene variant. Since this cannot be determined, all individuals with mosaic LFS are recommended to undergo the same surveillance and management as for individuals with LFS. Individuals with mosaic LFS can pass the variant on to their children, although in some cases this risk may be below 50%.
More information on how to work up individuals with concern for clonal hematopoiesis vs. LFS can be found here: https://pubmed.ncbi.nlm.nih.gov/31533767/
If the TP53 variant is not confirmed on cultured fibroblasts, nail clippings, or in other family members this may still represent a diagnosis of mosaic and/or de novo LFS that was not detected with this testing, or it could represent a TP53 variant restricted just to the blood cells. The scientific term for this is “clonal hematopoiesis” or CH. Further workup is indicated in these individuals to rule out an underlying cancer diagnosis. Individuals with CH have health risks including cardiovascular risk and malignancy risk that may need to be managed. It is very important that individuals with TP53 variants be evaluated by an expert familiar with the follow up evaluations and proper management based on their genetic testing results and clinical history.
More information on how to manage individuals with likely clonal hematopoiesis can be found here: https://pubmed.ncbi.nlm.nih.gov/30403571/
Treatment
At this time, there is no standard treatment or cure for LFS. With some exceptions, cancers in people with LFS are treated the same as for cancers in other people, but research on how to best manage those cancers involved in LFS is ongoing.
Research has indicated that people with LFS appear to be at an elevated risk for radiation-induced cancers, so the use of radiotherapy should be approached with caution. For this reason, computed tomography (CT) scans and other diagnostic techniques involving ionizing radiation should be limited, whenever feasible. However, radiation therapy should not be avoided if the benefits outweigh the risks.
Since people living with LFS are susceptible to the development of several different cancers, individuals should ensure that they incorporate simple measures into a healthy lifestyle such as sun protection and the avoidance of tobacco products.
It has been widely accepted that early cancer detection can greatly increase overall survival and people diagnosed with LFS should have preventive screening. An expert panel of LFS researchers, oncologists and genetic counselors has published surveillance recommendations that recommend whole body MRI screening for people with LFS. The National Comprehensive Cancer Network (NCCN) also has recommendations for surveillance and management for Li Fraumeni syndrome. Screening should begin as soon as the diagnosis of LFS is made. In brief, the screening recommendations involve:
Children (birth to age 18 years)
• General assessment
o Complete physical exam every 3-4 months
o Prompt assessment with primary care physician for any medical concerns
• Adrenocortical carcinoma
o Ultrasound of abdomen and pelvis every 3-4 months
o In case of unsatisfactory ultrasound, blood tests every 3-4 months
• Brain tumor
o Annual brain MRI (first MRI with contrast – thereafter without contrast if previous MRI normal with and no new abnormality
• Soft tissue and bone sarcoma
o Annual whole-body MRI
Adults
• General assessment
o Complete physical exam every 6 months
o Prompt assessment with primary care physician for any medical concerns
• Breast cancer
o Breast awareness (age 18 years and forward)
o Clinical breast exam twice a year (age 20 years and forward)
o Annual breast MRI screening (ages 20-29)
• Annual breast MRI screening alternating with mammogram (one scan every 6 months) (ages 30-75)
• Breast screening on an individual basis >75 years of age
o Consider risk-reducing bilateral mastectomy
• Brain tumor (age 18 years and forward)
o Annual brain MRI (first MRI with contrast – thereafter without contrast if previous MRI normal)
• Soft tissue and bone sarcoma (age 18 years and forward)
o Annual whole-body MRI
o Ultrasound of abdomen and pelvis every 12 months
• Gastrointestinal cancer (age 25 years and forward)
o Upper endoscopy and colonoscopy every 2-5 years)
• Melanoma (age 18 years and forward)
o Annual dermatologic examination
For families in which breast cancer has already been diagnosed at or around age 20, awareness and screening can be considered 5 to 10 years before the earliest age of onset known. The same is recommended for gastrointestinal cancers. Consider screening 5 years before the earliest known onset of gastrointestinal cancer in the family.
For more information see Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome (June 2017).
Please visit the LFS Association website for locations where LFS patient families may obtain care.
Numerous strategies using small molecule drugs to reactivate or modify dysfunctional TP53 protein are being actively studied but not yet in clinical trials with LFS patients.
There is currently great interest in “liquid biopsy” or screening for cancer with a blood draw in individuals with LFS. Many studies are currently ongoing, but it remains to be seen if this will be an effective screening strategy in individuals with LFS.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Li-Fraumeni syndrome was first described at the National Cancer Institute’s Division of Cancer Epidemiology and Genetics (DCEG) and DCEG’s Clinical Genetics Branch continues to research LFS: https://lfs.cancer.gov/
Batalini F, Peacock EG, Stobie L, et al. Li-Fraumeni syndrome: not a straightforward diagnosis anymore-the interpretation of pathogenic variants of low allele frequency and the differences between germline PVs, mosaicism, and clonal hematopoiesis. Breast Cancer Res. 2019;21(1):107. Published 2019 Sep 18. doi:10.1186/s13058-019-1193-1
Druker H, Zelley K, McGee RB, et al. Genetic Counselor Recommendations for Cancer Predisposition Evaluation and Surveillance in the Pediatric Oncology Patient. Clin Cancer Res. 2017;23(13):e91-e97. doi:10.1158/1078-0432.CCR-17-0834 https://aacrjournals.org/clincancerres/article/23/13/e91/80148/Genetic-Counselor-Recommendations-for-Cancer
Kratz CP, Achatz MI, Brugieres L, et al. Cancer screening recommendations for individuals with Li-Fraumeni syndrome. Clin Cancer Res. 2017;June; 23(11):38-45. https://aacrjournals.org/clincancerres/article/23/11/e38/79828/Cancer-Screening-Recommendations-for-Individuals
About LiFraumeni Syndrome. National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. https://lfs.cancer.gov/about.html Accessed Feb 27, 2025.
How a Hereditary Multicancer Syndrome was Discovered. National Cancer Institute, Division of Cancer Epidemiology and Genetics. Feb 15, 2013. https://dceg.cancer.gov/news-events/linkage-newsletter/2012-12/research-publications/hereditary-multicancer-syndrome
Palmero EI, Schüler-Faccini L, Caleffi M, et al. Detection of R337H, a germline TP53 mutation predisposing to multiple cancers, in asymptomatic women participating in a breast cancer screening program in Southern Brazil. Cancer Lett. 2008;261(1):21-25. doi:10.1016/j.canlet.2007.10.044 https://www.sciencedirect.com/science/article/abs/pii/S0304383507005253?via%3Dihub
Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome?. Ann Intern Med. 1969;71(4):747-752. doi:10.7326/0003-4819-71-4-747
Li FP and Fraumeni JF Jr. Rhabdomysosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Institute.1969; Dec;43(6):1365-73.
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