About this Study
- Classic Li-Fraumeni Syndrome (LFS)
- Li-Fraumeni-Like Syndrome (LFL)
- What Causes LFS
- Risk of Cancer in LFS
- Genetic Testing in LFS
Li-Fraumeni Syndrome (LFS) was first described in 1969 by Drs. Frederick Li and Joseph F. Fraumeni, Jr., who were working in the intramural research program at the NCI. Their study identified four families with sarcomas, breast cancer, brain tumors, and leukemia, many of which were diagnosed much earlier in life than typically expected. Additional studies showed that other tumors, including cancers of the adrenal cortex, choroid plexus carcinoma, gastrointestinal tract, lung, and non-Hodgkin lymphoma, also occurred more often than expected in these families. Identifying this unique pattern of cancer in families was the first step towards determining the genetic cause of LFS (see below).
LFS is diagnosed based on an individual’s personal and family history of cancer. 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.
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.
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 change in the TP53 gene
Disease-causing changes (mutations) in a gene called TP53 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 the mother, the other from the 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 mutation) 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 mutation may be inherited from either the mother or the father or may arise spontaneously in an affected individual without a family history of cancer, a phenomenon called a de novo mutation. Descendants of an individual with a de novo mutation are at risk of inheriting the mutated gene.
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 change in the TP53 gene. We do not yet fully understand what causes the increased cancer risk in families that meet the diagnostic criteria without a TP53 mutation, but there are several possibilities. For example, there could be an unusual mutation 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 mutation ranges from 70% to 90% by age 70. Women with LFS have a higher lifetime cancer risk than men with LFS, likely 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 mutation 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 mutations on a person affected with a cancer characteristic of the syndrome. If this person is found to have a mutation in the TP53 gene, genetic testing can be used to identify other family members with the same specific mutation who would also be at high cancer risk. Family members who do not have the mutation are not at increased cancer risk.
To date, more than 600 families with a TP53 mutation have been reported worldwide. It has been estimated that about 1 person in 20,000 carries a mutation in the TP53 gene. There are 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 mutations in this gene. One exception does exist; a specificTP53 mutation is responsible for most LFS families in a population residing in Southeastern Brazil. This mutation has been traced back to a single Portuguese ancestor whose descendants helped to settle this geographical area.
For those at high cancer risk due to a TP53 mutation, early cancer detection and risk reduction strategies are desirable, but not yet standardized. Among the common LFS-related cancers, screening is available only for breast cancer. Currently, management recommendations are based on a healthcare provider’s best clinical judgment. Doctors can try to find cancers as early as possible in the hope that finding cancer early will lead to more successful treatment. However, using unproven screening strategies has the potential to harm patients. Misleading test results may lead to invasive procedures to rule out malignancy (so-called "false positives"), or can provide false reassurance (so called "false negatives"). Consequently, we believe LFS-related cancer screening is best done as part of a clinical trial, in which the effectiveness of the strategy can be formally and rigorously evaluated. We also need to develop ways to decrease the chance that cancers will occur in the first place, an approach called "risk-reduction."