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.
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.
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.