About Li Fraumeni Syndrome

Li-Fraumeni syndrome is a genetic syndrome that increases a person’s risk to develop certain cancers including breast cancer, sarcomas (tumors of the soft tissue or bone), brain tumors, adrenocortical carcinoma (a tumor of the adrenal gland), and others. Many individuals with a personal and/or family history of cancer consistent with LFS will be found to have a variant in the TP53 gene causing their LFS. Sometimes a person or family will be diagnosed with LFS based on the pattern of cancers in their family, even if a causative TP53 variant cannot be found on genetic testing.

LFS is diagnosed based on an individual’s personal and family history of cancer. Several different clinical diagnostic criteria for LFS have been published. To receive a diagnosis of “classic” LFS, patients must meet stringent criteria based on a collection of families with similar cancer history to those first described by Drs. Li and Fraumeni. Other individuals who have family and personal cancer histories similar to the classic patterns may meet the diagnostic criteria for Li-Fraumeni-Like (LFL) Syndrome.

Classic Li-Fraumeni Syndrome (LFS)

A minimum of three features must be present within a family to fit the classic LFS criteria.

A person with a sarcoma diagnosed under the age of 45; AND
At least one first-degree relative (parents, brothers, sisters and children) with a cancer of any kind diagnosed under the age of 45; AND
A third family member who is either a first- or second-degree relative (grandparents, aunts, uncles, nieces, nephews, and grandchildren) with any cancer diagnosed under the age of 45, or a sarcoma at any age.

Chompret Criteria

A person with a tumor belonging to the LFS spectrum (breast cancer, sarcoma, central nervous system tumor, adrenocortical carcinoma) before the age of 46 AND at least one first- or second-degree relative with an LFS tumor (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumors OR
A person with multiple tumors (except multiple breast tumors) two of which belong to the LFS tumor spectrum and the first of which occurred before age 46 OR;
A person with adrenocortical carcinoma, choroid plexus carcinoma, or rhabdomyosarcoma of embryonal anaplastic subtype, irrespective of family history OR;
A person with breast cancer before 31 years of age

Li-Fraumeni-Like Syndrome (LFL)

There are two definitions of LFL

Birch Definition of LFL:

A person with any childhood cancer or sarcoma, brain tumor, or adrenal cortical tumor diagnosed under the age of 45; AND
A first- or second-degree relative with a typical LFS cancer (soft tissue and bone sarcomas, brain tumors, breast cancer, adrenocortical carcinomas, leukemia) at any age; AND
An additional first- or second-degree relative with any cancer diagnosed under the age of 60.

Eeles Definition of LFL:

Two first- or second-degree relatives with LFS-related malignancies at any age.
Persons with choroid plexus carcinoma or adrenal cortical tumors may have mutations in the TP53 gene even if there are no other cancers among their relatives.

As genetic testing becomes more common, there has been an increase in individuals identified with disease-causing variants in TP53 that do not have a personal or family history of cancer consistent with LFS. More research needs to be done to understand the cancer risks for these individuals and families and the best screening recommendations for them.

Some people who have genetic testing may be found to have a TP53 variant that is not a part of their DNA, but rather an acquired change isolated in their blood. When this happens, it is called CHIP (clonal hematopoiesis of indeterminate potential) or ACE (aberrant clonal expansion). These types of TP53 variants are not associated with LFS and are not thought to be passed down through a family. This type of change is important to detect as the health risks are different than in LFS, and family members are not thought to be at risk. Sometimes additional testing such as a skin biopsy can help clarify the diagnosis.

What Causes LFS

About 7 out of every 10 individuals (or 70%) meeting the classic LFS, and 4 out of every 10 (40%) meeting the LFL diagnostic criteria, have a detectable disease-causing variant in the TP53 gene.

Disease-causing changes (variants) in the TP53 gene were discovered in 1990 as the main cause of LFS. This gene is classified as a "tumor suppressor gene," meaning that when working correctly, it plays a role in preventing uncontrolled cell division. TP53 remains the only gene shown to be associated with LFS to date. Everyone has two copies of the TP53 gene – one inherited from their mother, the other from their father – in every cell of their body. This gene is very important for the normal growth, function, and division of cells. The protein produced by this gene causes cells that are damaged beyond repair to die, a process that stops damaged cells from becoming cancerous. If there is a change (or variant) in TP53, the gene protein product fails to work properly and cancer may develop. The kind of cancer that develops depends on where in the body the abnormal cells first develop. A TP53 variant may be inherited from either the mother or the father or may arise spontaneously in an individual without a family history of cancer, a phenomenon called a de novo (“new”) variant. The children of an individual with a de novo variant are at risk of inheriting the variant. There is also a small risk that the siblings of an individual with a de novo variant may be at risk of inheriting the variant, as well.

We do not yet fully understand what causes the increased cancer risk in families that meet the clinical diagnostic criteria for LFS but do not have a detectable TP53 variant on genetic testing, but there are several possibilities. For example, there could be an unusual variant in TP53 that is not easily found by the standard testing methods. Alternatively, there may be other, as-yet unidentified genes that can cause LFS.

Risk of Cancer in LFS

The lifetime risk of developing any cancer for a person who carries a TP53 variant ranges from 70% to 90% by age 70. Women with LFS have a higher lifetime cancer risk than men with LFS due to the high risk of female breast cancer. The lifetime cancer risk among women reaches almost 100%. At present, we cannot predict which individuals with a TP53 variant will eventually develop cancer and, if they do develop cancer, which type it will be or when it will occur.

Genetic Testing in LFS

Generally, health care providers can diagnose a family suspected of LFS by first performing genetic testing for TP53 variants on a person with a cancer characteristic of the syndrome. If this person is found to have a variant in the TP53 gene, genetic testing can be used to identify other family members with the same specific variant who would also be at high cancer risk. Family members who do not have the variant are generally not at increased cancer risk.

To date, more than 600 families with a TP53 variant have been reported worldwide. It has been estimated that about 1 person in 5,000 carries a mutation in the TP53 gene. There are generally no specific subgroups within the general population – that is, people of a particular race, heritage, ethnic background, or shared environment – that are more likely to carry variants in this gene. However, some exceptions have been found; a specific TP53 variant is responsible for most LFS families in a population residing in Southeastern Brazil.This variant has been traced back to a single Portuguese ancestor whose descendants helped to settle this geographical area. There is also a more recently discovered variant that appears to be more common in the Ashkenazi Jewish population. Both of these variants are thought to be likely “low penetrance” variants in that the risk of cancer in individuals with these variants seem to be lower than the risks expected in classical LFS. However, as we cannot yet quantify the specific lifetime cancer risks we currently recommend the same surveillance and management for these individuals as those with any other disease-causing TP53 variant.

Screening for LFS

Individuals found to have LFS are recommended to undergo high risk surveillance.

Adults

Males and Females:

Annual whole body MRI
Annual brain MRI (may be performed as part of the whole body MRI or as a separate exam)
Annual dermatological exam
Annual physical and neurological exam
Colonoscopy and upper endoscopy every 2-5 years beginning at age 25 or 5 years before the youngest diagnosis of colon or gastric cancer in the family (whichever is earlier)
Healthy lifestyle including sun protection, avoidance of tobacco products, healthy varied diet, and exercise

Females:

Breast awareness beginning at age 18
Clinical breast exam every 6-12 months beginning at age 20
Annual breast MRI with contrast beginning at age 20-29
Annual breast MRI with contrast alternating with annual mammogram (with consideration of tomosynthesis) beginning at age 30-75years (alternating scans every 6 months)
Consideration of risk-reducing mastectomy (removal of the breast tissue)

Children (Birth to age 16-18)