Li-Fraumeni syndrome is a rare disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults.

The cancers most often associated with Li-Fraumeni syndrome include breast cancer, a form of bone cancer called osteosarcoma, and cancers of soft tissues (such as muscle) called soft tissue sarcomas. Other cancers commonly seen in this syndrome include brain tumors, cancers of blood-forming tissues (leukemias), and a cancer called adrenocortical carcinoma that affects the outer layer of the adrenal glands (small hormone-producing glands on top of each kidney). Several other types of cancer also occur more frequently in people with Li-Fraumeni syndrome.

A very similar condition called Li-Fraumeni-like syndrome shares many of the features of classic Li-Fraumeni syndrome. Both conditions significantly increase the chances of developing multiple cancers beginning in childhood; however, the pattern of specific cancers seen in affected family members is different.

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.

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

1. A person with a sarcoma diagnosed under the age of 45; AND
2. At least one first-degree relative (parents, brothers, sisters and children) with a cancer of any kind diagnosed under the age of 45; AND
3. 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

1. 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
2. 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;
3. A person with adrenocortical carcinoma, choroid plexus carcinoma, or rhabdomyosarcoma of embryonal anaplastic subtype, irrespective of family history OR;
4. A person with breast cancer before 31 years of age

There are two definitions of LFL

Birch Definition of LFL:

1. A person with any childhood cancer or sarcoma, brain tumor, or adrenal cortical tumor diagnosed under the age of 45; AND
2. 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
3. An additional first- or second-degree relative with any cancer diagnosed under the age of 60.

Eeles Definition of LFL:

1. Two first- or second-degree relatives with LFS-related malignancies at any age.
2. 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.

Normal Function

The TP53 gene provides instructions for making a protein called tumor protein p53 (or p53). This protein acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing (proliferating) too fast or in an uncontrolled way.

The p53 protein is located in the nucleus of cells throughout the body, where it attaches (binds) directly to DNA. When the DNA in a cell becomes damaged by agents such as toxic chemicals, radiation, or ultraviolet (UV) rays from sunlight, this protein plays a critical role in determining whether the DNA will be repaired or the damaged cell will self-destruct (undergo apoptosis). If the DNA can be repaired, p53 activates other genes to fix the damage. If the DNA cannot be repaired, this protein prevents the cell from dividing and signals it to undergo apoptosis. By stopping cells with mutated or damaged DNA from dividing, p53 helps prevent the development of tumors.

Because p53 is essential for regulating DNA repair and cell division, it has been nicknamed the "guardian of the genome."

Health Conditions Related to Genetic Changes

Breast cancer

Inherited changes in the TP53 gene greatly increase the risk of developing breast cancer, as well as several other forms of cancer, as part of a rare cancer syndrome called Li-Fraumeni syndrome (described below). These mutations are thought to account for only a small fraction of all breast cancer cases.

Noninherited (somatic) mutations in the TP53 gene are much more common than inherited mutations, occurring in 20 to 40 percent of all breast cancers. These somatic mutations are acquired during a person's lifetime and are present only in cells that become cancerous. The cancers associated with somatic mutations do not occur as part of a cancer syndrome. Most of these mutations change single protein building blocks (amino acids) in the p53 protein, which reduces or eliminates the protein's tumor suppressor function. This altered p53 protein cannot regulate cell proliferation effectively. Specifically, it is unable to trigger apoptosis in cells with mutated or damaged DNA. As a result, DNA damage can accumulate in cells. Such cells may continue to divide in an uncontrolled way, leading to tumor growth.

Compared with breast cancers without TP53 gene mutations, tumors with these genetic changes tend to have a poorer prognosis: They are more likely to be aggressive, to be resistant to treatment with certain anti-cancer drugs and radiation, and to come back (recur) after treatment.

Bladder cancer

Somatic TP53 gene mutations have been found in some cases of bladder cancer. Bladder cancer is a disease in which certain cells in the bladder become abnormal and multiply uncontrollably to form a tumor. Bladder cancer may cause blood in the urine, pain during urination, frequent urination, the feeling of needing to urinate without being able to, or lower back pain.

Bladder cancer is generally divided into two types, non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), based on where in the bladder the tumor is located. About half of NMIBC tumors have TP53 gene mutations. Most of these mutations change single amino acids in p53. This altered p53 protein cannot regulate cell growth and division and is unable to trigger apoptosis in cells with mutated or damaged DNA. As a result, DNA damage can accumulate in cells. If such cells continue to divide in an uncontrolled way, they can lead to the formation of bladder cancer.

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Head and neck squamous cell carcinoma

Somatic mutations in the TP53 gene have been found in nearly half of all head and neck squamous cell carcinomas (HNSCC). This type of cancerous tumor occurs in the moist lining of the mouth, nose, and throat. Most of the TP53 gene mutations involved in HNSCC change single amino acids in p53; these changes impair the protein's function. Without functioning p53, cell proliferation is not regulated. As a result, cells accumulate DNA damage and continue to divide in an uncontrolled way, leading to tumor growth.

Li-Fraumeni syndrome

Although somatic mutations in the TP53 gene are found in many types of cancer, Li-Fraumeni syndrome appears to be the only cancer syndrome associated with inherited mutations in this gene. This condition greatly increases the risk of developing several types of cancer, including breast cancer; bone cancer; and cancers of soft tissues (such as muscle) called soft tissue sarcomas, particularly in children and young adults. At least 140 different mutations in the TP53 gene have been identified in individuals with Li-Fraumeni syndrome.

Many of the mutations associated with Li-Fraumeni syndrome change single amino acids in the part of the p53 protein that binds to DNA. Other mutations delete small amounts of DNA from the gene. These mutations result in an altered p53 protein that cannot regulate cell proliferation effectively and is unable to trigger apoptosis in cells with mutated or damaged DNA. As a result, DNA damage can accumulate in cells. Such cells may continue to divide in an uncontrolled way, leading to the growth of tumors.

Lung cancer

Somatic mutations in the TP53 gene have been found in nearly half of all lung cancers. Lung cancer is a disease in which certain cells in the lungs become abnormal and multiply uncontrollably to form a tumor. Signs and symptoms may not occur in early stages of the disease.

Lung cancer is generally divided into two types, small cell lung cancer and non-small cell lung cancer, based on the size of the affected cells when viewed under a microscope. Small cell lung cancers nearly always have TP53 gene mutations; however, these mutations may also occur in non-small cell lung cancer. TP53 gene mutations change single amino acids in p53, which impair the protein's function. Without functioning p53, cell proliferation is not regulated effectively and DNA damage can accumulate in cells. Such cells may continue to divide in an uncontrolled way, leading to tumor growth. Additional genetic, environmental, and lifestyle factors contribute to a person's cancer risk; in lung cancer, the greatest risk factor is being a long-term tobacco smoker.

Melanoma

MedlinePlus Genetics provides information about Melanoma

Ovarian cancer

Somatic TP53 gene mutations are common in ovarian cancer, occurring in almost half of ovarian tumors. These mutations result in a p53 protein that is less able to control cell proliferation. Specifically, it is unable to trigger apoptosis in cells with mutated or damaged DNA. As a result, DNA damage can accumulate in cells. Such cells may continue to divide in an uncontrolled way, leading to tumor growth.

Wilms tumor

MedlinePlus Genetics provides information about Wilms tumor

Other cancers

Somatic mutations in the TP53 gene are the most common genetic changes found in human cancer, occurring in about half of all cancers. In addition to the cancers described above, somatic TP53 gene mutations have been identified in several types of brain tumor, colorectal cancer, liver cancer, a type of bone cancer called osteosarcoma, a cancer of muscle tissue called rhabdomyosarcoma, and a cancer called adrenocortical carcinoma that affects the outer layer of the adrenal glands (small hormone-producing glands on top of each kidney).

Most TP53 mutations change single amino acids in the p53 protein, which leads to the production of an altered version of the protein that cannot control cell proliferation and is unable to trigger apoptosis in cells with mutated or damaged DNA. As a result, DNA damage can accumulate in cells. Such cells may continue to divide in an uncontrolled way, leading to tumor growth.

Other Names for This Gene

• antigen NY-CO-13
• cellular tumor antigen p53
• P53
• P53 tumor suppressor
• P53_HUMAN
• phosphoprotein p53
• transformation-related protein 53
• TRP53
• tumor protein p53 (Li-Fraumeni syndrome)
• tumor suppressor p53

Genomic Location

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.

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.

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)

Males and Females:

• Physical and neurological exam every 3-4 months
• Ultrasound of abdomen and pelvis every 3-4 months
• Blood tests for adrenocortical carcinoma every 3-4 months
• Annual brain MRI
• Annual whole body MRI