Li–Fraumeni syndrome is an extremely rare autosomal dominant hereditary disorder. Named after Frederick Pei Li and Joseph F. Fraumeni, Jr., the American physicians who first recognized and described the syndrome, Li–Fraumeni syndrome greatly increases susceptibility to cancer. This syndrome is also known as the Sarcoma, breast, leukaemia and adrenal gland (SBLA) syndrome, this definition is based on historical and classical criteria family and is based on the observation of a sarcoma in a patient aged less than 45 years of first-degree consanguineous to a person who has had cancer (of any type) before age 45 , second-degree consanguineous or a person who has had a tumor or a sarcoma before 45 years.
The syndrome is linked to germline mutations of the TP53 tumor suppressor gene, which normally helps control cell growth. The mutations can be inherited or can arise de novo early in embryogenesis or in one of the parent's germ cells.
The TP53 gene is responsible for initiating DNA repair mechanisms and/or apoptosis upon detection of DNA damage. P53 is a dominant negative mutation, so the mutant protein can inactivate the normal protein, meaning the mutant protein is dominant. Because of this, Li–Fraumeni syndrome, with one of the two p53 copies already mutated, predisposes a person to cancer development. Persons with Li–Fraumeni syndrome have an approximately 25-fold increased risk of developing a malignant tumor by age 50 than the population average, and are at risk for a wide range of malignancies, with particularly high occurrences of breast cancer, brain tumors, acute leukemia, soft tissue sarcomas, bone sarcomas, and adrenal cortical carcinoma.
Li–Fraumeni syndrome is characterised by:
• several kinds of cancer are involved;
• cancer often appears at a young age;
• cancer often appears several times throughout the life of an affected person.
Li-Fraumeni syndrome (LFS) is associated with high risks of a diverse spectrum of childhood- and adult-onset malignancies.The tumors most closely associated with LFS are: soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumors, and adrenocortical carcinoma(ACC), and leukemias. In addition, a variety of other cancers may occur: Gastrointestinal cancers, Genitourinary cancers, Leukemias and lymphomas, Lung cancers, Neuroblastomas and other childhood cancers, Skin cancers, Thyroid cancers. Age-specific cancer risks have been calculated.
Epidemiology
This syndrome is considered rare with ~400 individuals from 64 families reported in the literature Its true incidence is unknown.
The frequency of new (de novo) TP53 mutations is estimated to be at least 7% and may be as high as 20%.
The risk of developing a tumor in an individual carrying a mutation in the TP53 gene is 15% at 15 years, 50% at 30 years and 90% at 60 years.
The cancer risks in LFS demonstrate significant gender differences. For women with LFS, the lifetime risk of cancer is nearly 100% and for men with LFS, the lifetime risk of cancer is about 73%. This gender difference in cancer risk is primarily the result of the high incidence of breast cancer among women with LFS.
There is a high risk of a second radiation-induced cancer. Genetic counseling is delicate because of the broad spectrum of tumors and their appearance at all ages, especially during childhood. They are not effective specific surveillance measures, except for breast cancer in women after age 20.
Table: Tumor-Specific Cancer Risks in Families with LFS Who Have Germline TP53 mutations
| Tumor Type | Relative Risk (95% CI) |
| Bone | 107 (49-203) |
| Connective Tissue | 61 (33-102) |
| Brain | 35 (19-60) |
| Pancreas | 7.3 (2-19) |
| Breast | 6.4 (4.3-9.3) |
| Colon | 2.8 (1-6) |
| Liver | 1.8 (2.1-64) |
Pathology
• LFS1: The TP53 (in humans, the TP53 gene is located on the short arm of chromosome 17,17p13.1), Tumor protein p53, also known as p53, cellular tumor antigen p53, phosphoprotein p53 tumor suppressor gene p53, normally assists in the control of cell division and growth through action on the normal cell cycle. TP53 assists in repair or destruction of "bad" DNA before it can enter the normal cell cycle, thus preventing abnormal and/or cancerous growth of cells. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Mutations of TP53 prevent this normal function and allow damaged cells to divide and grow in an uncontrolled, unchecked manner forming tumors (cancers). TP53 mutations have been primarily implicated in Li–Fraumeni.
p53 becomes activated in response to myriad stressors, including but not limited to DNA damage (induced by either UV, IR, or chemical agents such as hydrogen peroxide), oxidative stress, osmotic shock, ribonucleotide depletion, and deregulated oncogene expression; the TP53 gene can also be damaged in cells by mutagens (chemicals, radiation, or viruses).
• LFS2: A variant of Li–Fraumeni does not have a mutation in TP53 but instead has mutation of the CHEK2 (or CHK2) gene. CHK2 is also a tumor suppressor gene. CHK2 regulates the action of p53. CHK2, a protein kinase, is activated by ATM which detects DNA damage, and in this way DNA damage information can be conveyed to p53 to indirectly arrest the cell cycle at that point for DNA repair to be able to take place or to cause apoptosis (programmed cell death). In response to DNA damage and replication blocks, cells prevent cell cycle progression through the control of critical cell cycle regulators.
• A third locus has been mapped to the long arm of chromosome 1 (1q23) but no gene has yet been identified.
Most of these mutations in p53 are located in DNA binding domain of the protein and have a dominant-negative effect over alternate wild type alleles.
Diagnosis
Li–Fraumeni syndrome is diagnosed if the following three criteria are met:
1. the patient has been diagnosed with a sarcoma at a young age (below 45),
2. a first-degree relative has been diagnosed with any cancer at a young age (below 45),
3. and another first-degree or a second-degree relative has been diagnosed with any cancer at a young age (below 45) or with a sarcoma at any age.
Management
Evaluation for cancer in an individual diagnosed with Li-Fraumeni syndrome (LFS) should be based on personal medical histories and to some extent, the specific pattern of cancer in the family. Testing can include comprehensive physical examination, neurologic examination, blood counts, imaging studies, endoscopies, and/or biopsies.
Genetic counseling and genetic testing are used to confirm that somebody has this gene mutation. Once such a person is identified, early and regular screenings for cancer are recommended for him or her as people with Li–Fraumeni are likely to develop another primary malignancy at a future time (57% within 30 years of diagnosis).
The genetic tests available for Li-Fraumeni syndrome are
• Gene: TP53
• Related cancer types: Breast cancer, soft tissue sarcoma, osteosarcoma (bone cancer), leukemia, brain tumors, adrenocortical carcinoma (cancer of the adrenal glands), and other cancers
Chompret criteria
The Chompret criteria for screening are
A proband who has:
• tumor belonging to the LFS tumor spectrum - soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumor, adrenocortical carcinoma, leukemia or lung bronchoalveolar cancer - before age 46 years;
and at least one of the following
• at least one first or second degree relative with an LFS tumour (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumours
• a proband with multiple tumours (except multiple breast tumours), two of which belong to the LFS tumour spectrum and the first of which occurred before age 46 years
• a proband who is diagnosed with adrenocortical carcinoma or choroid plexus tumour, irrespective of family history
Treatment of manifestations
Routine oncologic management is recommended for malignancies in individuals with LFS, with the exception of breast cancer, in which mastectomy rather than lumpectomy is recommended in order to reduce the risks of a second primary breast tumor and avoid radiation therapy. Concerns about increased risk for radiation-induced second primary tumors has led to more cautious use of therapeutic radiation in general, but most experts recommend that treatment efficacy be prioritized above concerns about late effects after careful analysis of risks and benefits.
Prevention of primary manifestations
Prophylactic mastectomy to reduce the risk for breast cancer is an option for women with a germline TP53 mutation. Recent recommendations for colonoscopy may be considered surveillance as well as primary prevention of colorectal cancer. Counseling for avoidance of sun exposure, tobacco use, and exposure to other known or suspected carcinogens is encouraged.
Prevention of secondary complications
Persons with a TP53 mutation are cautioned to avoid radiation therapy whenever possible in order to limit the risk for secondary radiation-induced malignancies. However, when radiation is considered medically necessary to improve the chance of survival from a given malignancy, it may be used at the discretion of the treating physician and patient. The concern regarding radiation carcinogenesis is based on older data. There is interest in examining risks associated with more modern techniques, which may be less carcinogenic.
Data on possible sensitivity to the carcinogenic effects of modern chemotherapy regimens are considerably more limited. In rare cases, individuals with germline TP53 mutations have developed myelodysplastic syndrome and/or acute myeloid leukemia after treatment with radiation or chemotherapy for a prior tumor.
Surveillance
There are no definitive prospective data on the optimal methods for and efficacy of tumor surveillance for children or adults with a germline TP53 mutation. Currently, it is recommended that: (1) children and adults undergo comprehensive annual physical examination; (2) children and adults be encouraged see a physician promptly for evaluation of lingering symptoms and illnesses; (3) women undergo breast cancer monitoring, with annual breast MRI and twice annual clinical breast examination beginning at age 20-25 years. The use of mammograms has been controversial because of radiation exposure and limited sensitivity. When included, annual mammograms should alternate with breast MRI, with one modality every six months; (4) adults consider routine screening for colorectal cancer with colonoscopy every 2-3 years beginning no later than age 25 years; (5) individuals consider organ-targeted surveillance based on the pattern of cancer observed in their family. Intensified surveillance with whole-body MRI protocols for adults and children who carry a germline TP53 mutation are being evaluated in investigational settings.
Agents/circumstances to avoid
There is some evidence that TP53 mutations confer an increased sensitivity to ionizing radiation. Thus, individuals with germline TP53 mutations should avoid or minimize exposure to diagnostic and therapeutic radiation whenever possible. Radiation-induced second malignancies have been reported among individuals with germline TP53 mutations. Detailed studies to more formally assess this risk are in development.
Individuals with LFS are also encouraged to avoid or minimize exposures to known or suspected carcinogens, including sun exposure, tobacco use, occupational exposures, and excessive alcohol use, because the effects of carcinogenic exposures and germline TP53 mutations may be cumulative. For example, individuals with a germline TP53 mutation who smoke cigarettes have been shown to be at significantly increased risk of developing lung cancer than individuals with a germline TP53 mutation who do not smoke.
Evaluation of relatives at risk
It is appropriate to offer genetic counseling and testing to all relatives who are at risk of having a familial TP53 mutation.
Pregnancy Management
Women with LFS who are pregnant should bring any potential symptoms of cancer to the attention of their physicians. Women with LFS who are pregnant can continue to have clinical breast exams and/or breast imaging studies if indicated.
There are no special recommendations for screening a fetus identified as having a germlineTP53 mutation. Once the infant is born, he or she can be evaluated for signs of cancer.
Prenatal testing is possible for families with LFS. The familial TP53 mutation must be identified before prenatal testing can be performed. Prenatal diagnosis for pregnancies at 50% risk for LFS is possible by analyzing DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation.
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