Li-Fraumeni syndrome: what is it, symptoms, treatment, prognosis

What is Li-Fraumeni syndrome?

Li-Fraumeni syndrome (SLF) is a hereditary family history of a wide range of certain, often rare cancers (carcinomas). It is associated with a change (mutation) in a tumor suppressor gene known as TP53. The resulting p53 protein produced by the genome is damaged (or otherwise malfunctioning) and cannot help prevent the development of malignant tumors. Children and young patients are susceptible to the development of several types of cancer, primarily sarcoma of soft tissues and bones breast cancer, brain tumors, adrenal cortex carcinoma and acute leukemia. Other types of malignant tumors observed in patients with Li-Fraumeni syndrome include cancers of the gastrointestinal tract and lungs, kidneys, thyroid gland and skin, and gonadal organs (ovarian cancer, testicles and prostate).

It is important to note that not everyone with a gene mutation 

TP53 cancer will certainly develop, but the risks are much higher than in the general population. The diagnosis of SLF is critical so that affected families can seek appropriate genetic counseling and follow-up for early detection of tumors.

SLF was first recognized in 1969. Frederick Lee and Joseph Fraumeni Jr. while studying pediatric and familial cancers at the National Cancer Institute. They described four families with multiple early cancers in children and young patients. The syndrome was first described in a publication titled "Li-Fraumeni Syndrome" in 1982 by researchers from the United Kingdom, who described two families with multiple forms of cancer.

In 1990, the inherited variants of the gene TP53 have been found to be the main cause of SLF. This discovery has provided a special opportunity for genetic testing and clinical interventions that can prevent cancer, detect it early, and treat it in people with SLF. This discovery also served as an impetus for further molecular research. TP53, which is usually found in the tumor tissue of cancer patients.

Signs and symptoms

Li-Fraumeni syndrome can be suspected if someone has a personal or family history of cancer. In addition, there are certain rare cancers associated with this syndrome that should alert clinicians to the possibility of a diagnosis of SLF. Patients and families with multiple childhood cancers or specific rare cancers such as adrenal cortex cancer, carcinoma of the choroid plexus, anaplastic rhabdomyosarcoma, medulloblastoma subtype SHH (sonic hedgehog) or hypodiploid acute lymphoblastic leukemiashould alert practitioners to the potential of hereditary cancer syndrome such as Li-Fraumeni. Although it is increasingly referred to as hereditary cancer syndrome, not all doctors are aware of the diagnosis of SLF.

The malignant tumors most closely associated (major cancers) with SLF include:

• sarcoma of soft tissues;
• steosarcoma;
• breast cancer;
• brain and central nervous system tumors (glioma, carcinoma of the choroid plexus, medulloblastoma subtype SHH, neuroblastoma);
• adrenocortical carcinoma;
• acute leukemia.

Other types of tumors may appear, but the risks are lower than for the main types of cancer:

• adenocarcinoma of the lung;
• melanoma;
• tumors of the gastrointestinal tract (for example, colon cancer or pancreas cancer);
• renal carcinoma;
• thyroid carcinoma;
• carcinomas of the gonadal organs (for example, testicular cancer, ovaries, prostate).

In patients with SLF, approximately 50% of cancers will develop by age 40 and up to 90% likely by age 60, while how women have an almost 100% risk of developing cancer during their lifetime due to their markedly increased risk of cancer breasts. Many people with SLF develop two or more primary cancers in their lifetime.

Causes and risk factors

Li-Fraumeni syndrome is caused by an inherited (embryonic) pathogenic variant of a tumor suppressor gene TP53 on chromosome 17. SLF was first discovered in 1969, and in 1979, more than 50% of all cancer patients were found in tumor tissue. TP53However, it was not until 1990 that it was discovered that the germline variant TP53 is the cause of Li-Fraumeni syndrome.

SLF follows autosomal dominant inheritance. Most genetic diseases are determined by the status of two copies of a gene, one from the father and one from the mother. Dominant genetic disorders occur when only one copy of an altered gene is needed to cause a specific disease. The abnormal gene can be inherited from either parent and can result from a new mutation (gene change) in the affected person. The risk of passing the altered gene from the affected parent to the offspring is 50% with every pregnancy. The risk is the same for men and women.

Most patients with SLF have a gene mutation TP53 germline, but in some, Li-Fraumeni syndrome occurs due to a spontaneous (new) genetic variant that occurs in the egg or sperm. In such situations, the disorder is not inherited from the parents.

There are many known malfunctions. TP53and each of them can affect each family member differently. Most families with SLF have a very high incidence of cancer, while some others do not, and even the aggressiveness of the syndrome varies across families. The extent to which the option TP53 causes tumors in a family or in an individual, is called "penetrance" - an indicator of the phenotypic manifestation of an allele in a population.

People with SLF may also be predisposed to carcinogenic risks associated with a particular lifestyle or environmental exposure, such as tobacco smoking or radiation exposure. Patients with SLF should take preventive measures to reduce exposure to behavioral risk factors and carcinogens.

Affected populations

Although it is difficult to estimate the incidence in a population, there are probably over 1000 multigenerational families worldwide with SLF. To date, the SLF website has been requested from 172 countries.

There is no evidence of ethnic or geographic difference in the occurrence of Li-Fraumeni syndrome. but a uniquely high prevalence of the disease has been reported in the southern and southeastern Brazil. The SLF population in this area was associated with a highly specific variant TP53, designated as R337H. This particular change in the region has led researchers to suspect a single point of origin, with family lines tracing back to a common ancestor who migrated from Portugal long ago. Interestingly, however, in contrast to the 90% lifetime risk of developing carcinomas in most patients with Li-Fraumeni syndrome, the population Brazil with this "founder mutation" has an approximately 60% lifelong cancer risk, which has a relatively favorable rate. survival rate.

Diagnostics

Li-Fraumeni syndrome is diagnosed based on the presence of a so-called pathogenic or probable pathogenic variant in the gene TP53.

Genetic testing TP53 is usually considered based on the following criteria.

- Clinical research (clinical screening and genetic testing).

The potential for genetic testing (and the implications of the results) should always include discussions with the genetic counselor, doctors, and family.

The following criteria can be used to determine whether genetic testing should be considered:

Classic SLF is diagnosed when a person has all of the following criteria:

1. Sarcoma diagnosed before the age of 45.
2. A relative of the first degree of kinship, i.e. a parent, brother, sister, or child with cancer under the age of 45.
3. A relative of the first or second degree of kinship, i.e. grandmother / grandfather, aunt / uncle, niece / nephew or grandson with cancer under 45 or sarcoma at any age.

Hompret's Criteria for Clinical Diagnosis of Li-Fraumeni Syndrome - a recent set of criteria that have been proposed to identify affected families that go beyond the classic criteria listed above. Diagnosing SLF and performing a gene mutation test TP53 considered for anyone with a personal and family history who meets 1 of the following 3 criteria:

1 Criteria.

• A tumor belonging to the SLF tumor spectrum, up to 46 years of age. This means any of the following diseases: soft tissue sarcoma, osteosarcoma, premenopausal breast tumor, brain tumor, adrenal cortex carcinoma, leukemia or lungs' cancer
• At least 1 member of a first- or second-degree family with a tumor associated with Li-Fraumeni syndrome for except for breast cancer, if the person has a malignant breast tumor before the age of 56 or with multiple tumors.

2 Criteria.

• A person with multiple tumors, with the exception of multiple breast tumors, 2 of which belong to the SLF tumor spectrum, and the first occurred before the age of 46.

3 Criteria.

• A person diagnosed with adrenocortical carcinoma or a tumor of the choroid plexus, i.e. membranes around the brain, regardless of family history.

In addition, patients with anaplastic rhabdomyosarcoma, women with breast cancer under the age of 31, patients with hypodiploid acute lymphoblastic leukemia and SHH subtype medulloblastoma should be examined regardless of the familial anamnesis.

Li-Fraumeni-like syndrome (LFPS) - another similar set of criteria for affected families that do not meet the classical criteria (see higher). There are two suggested definitions of LFPS:

1 LFPS definition, called Birch's definition:

• A person diagnosed with any childhood cancer, sarcoma, brain tumor, or adrenal cortex under the age of 45
• A first- or second-degree relative who has been diagnosed with typical SLF cancer, such as sarcoma, breast carcinoma, brain tumor, adrenal cortex tumor, or leukemia, in any age
• Relatives of the first or second degree of kinship with a diagnosis of cancer before the age of 60.

2 LFPS definition, called Iles definition:

• 2 first- or second-degree relatives diagnosed with typical SLF cancer such as sarcoma, breast carcinoma, brain carcinoma, adrenal cortex tumor, or leukemia, at any age.

- Other risk factors specific to breast cancer to consider:

A woman who has a history of breast cancer at a younger age and does not have an identifiable mutation in genes 1 or 2 for breast cancer called BRCA1 or BRCA2, may have a mutation TP53.

A woman who is diagnosed with breast carcinoma before age 30 and does not have a BRCA mutation is estimated to have a mutation TP53 from 4% to 8%.

Women with breast cancer diagnosed between the ages of 30 and 39 may also have a slight increased risk of mutation TP53.

In younger women with breast carcinoma, the mutation TP53 may also occur with any of the following: a family history of malignant neoplasms, especially those associated with SLF, a personal history of a breast tumor that is positive for estrogen, progesterone, and HER2 / neu markers, also known as "triple positive" breast cancer, and a personal history of additional cancer associated with the syndrome Li-Fraumeni.

Standard treatments

There is currently no standard treatment for Li-Fraumeni syndrome. With a few exceptions, oncology in patients with SLF is treated in the same way as oncology in other patients, but research continues on how best to manage these types of malignant neoplasms implicated in SLF.

Studies have shown that patients with SLF appear to have an increased risk of radiation-induced cancer, so the use of radiation therapy should be approached with caution. For this reason, you should limit computed tomography (CT) scans and other diagnostic methods associated with ionizing radiation. However, radiation therapy should not be avoided if the benefits outweigh the risks.

Because people living with SLF are prone to developing a number of different types of cancer, people should make sure they include simple preventive measures such as sun protection and quitting tobacco products.

Patients with Li-Fraumeni syndrome are prone to anxiety, depression and clinically significant disorders. Psychological monitoring is important, as is support.

Forecast

There is no difference in treatment for SLF cancer and other malignant tumors that occur sporadically. Advances in cancer treatment in children have increased the long-term survival rate of most children. Common complications in survivors include secondary primary malignancies, which most often occur within 6–12 years after the first tumor.

A second cancer can arise from a genetic predisposition such as constitutional mutations TP53. The risk of a second cancer increases with age when the first cancer is diagnosed. The risk of a second tumor increases with exposure to radiation, so people should avoid or minimize exposure to diagnostic and therapeutic radiation whenever possible. They have a predisposition to the development of subsequent primary tumors (especially sarcomas) in the previous radiation fields.

The cumulative probability that a person affected by SLF will develop a second cancer is close to 60% 30 years after developing the first cancer.

Complications

People with Li-Fraumeni syndrome can become resistant to chemotherapy. The risk of other primary types of carcinoma is increased if germ line mutation occurs. There is evidence that a genetic mutation TP53 may cause a person to be hypersensitive to ionizing radiation. People with mutations TP53 germline exposure should be avoided or minimized as much as possible.