Li-Fraumeni syndrome and genetics
Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition condition linked primarily to mutations in the TP53 gene, which acts as a critical tumor suppressor. Individuals with LFS face a substantially increased risk of developing various types of cancer at a young age, including sarcomas, breast cancer, brain tumors, and adrenocortical cancer, with lifetime risks estimated at 85-90% for women and 70% for men. The syndrome can lead to multiple primary cancers appearing throughout a person's life, sometimes even in childhood.
Diagnosis of LFS typically involves evaluating family cancer histories and genetic sequencing to confirm the presence of TP53 mutations, which can be inherited in an autosomal dominant manner. There are also associations with mutations in the CHEK2 gene, although the exact implications of these mutations are less understood. While there is no unique treatment for LFS itself, individuals diagnosed with cancers associated with the syndrome undergo standard cancer therapies, with additional considerations to minimize radiation exposure due to increased risks of secondary malignancies. Regular cancer screening and vigilant monitoring of symptoms are recommended for individuals and their families, as early detection can be crucial for improving outcomes.
Li-Fraumeni syndrome and genetics
ALSO KNOWN AS:TP53; LFS; classic Li-Fraumeni syndrome; Li-Fraumeni-like syndrome
DEFINITION Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome. While many cancers can occur in LFS, typical cancers are of early age onset and include sarcoma, breast, brain, and adrenocortical. Melanoma, pancreatic cancer, and colon cancer may also be seen. LFS also holds an increased risk for multiple primary cancers.
Risk Factors
Persons at risk for LFS are identified through patterns of cancers and ages of onset in family members. More than half of persons with LFS have a mutation in the TP53 gene. While LFS is not gender-specific, there is a greater lifetime risk of cancer for women because of the risk for female breast cancer. LFS cancers can occur in childhood.
Etiology and Genetics
LFS is a rare syndrome that usually involves the inheritance of a mutation of the TP53 gene located on chromosome 17. A tumor-suppressor gene, the TP53 gene is referred to as the “guardian of the genome.” The protein that it encodes can initiate cell death, can stop cell division, and can activate DNA repair. When mutated, the defective protein product allows abnormal cells to proliferate.
Mutations in the TP53 gene are commonly seen in acquired tumors, being present in nearly half of all tumors. The germ-line mutations in the TP53 gene leading to LFS, however, are rare, even though hundreds of distinct germ-line TP53 mutations associated with LFS have been described.
The described germ-line mutations in the TP53 gene are transmitted by autosomal dominant inheritance. The mutation may be passed from either the maternal or paternal lineage, with a fifty percent chance of transmission with each offspring. Since only one abnormal copy is transmitted, offspring are born with one functioning TP53 gene. The functioning tumor-suppressor gene prevents cancer formation. However, when the functioning gene becomes mutated, tumor suppression is lost, and a number of cancers can arise.
In addition to TP53, there are also germ-line mutations in CHEK2 that may be associated with LFS. The CHEK2 gene is on chromosome 22 and codes for a protein that acts as a tumor suppressor. The protein interacts with several proteins, including the protein derived from the TP53 gene. Inheritance of CHEK2 mutations is similar to TP53. However, the cancer risks of CHEK2 mutations may differ from those of TP53 mutations, and it is not clearly known if CHEK2 mutations actually cause LFS.
Symptoms
LFS is an inherited predisposition to cancer. Thus, there is no disease present at birth, and sometimes no associated disease ever occurs among mutation carriers. Those who do develop cancer will develop symptoms respective of the cancer type—that is, the various cancers present with symptoms that are not unique to LFS.
Screening and Diagnosis
Screening for LFS is done through assessment of family cancer history, with genetic sequencing performed to confirm the diagnosis. There are multiple criteria based on family history for defining LFS, including the classic LFS and Li-Fraumeni-like syndrome (LFL). Classic LFS is defined by having a proband with a sarcoma diagnosed before forty-five years of age and a first-degree relative with any cancer under forty-five years of age and a first- or second-degree relative with any cancer under forty-five years of age or a sarcoma at any age.
Families with LFL are defined as a proband with any childhood cancer or sarcoma, brain tumor, or adrenocortical tumor diagnosed before forty-five years of age, and a first- or second-degree relative with a typical LFS cancer at any age, and a first- or second-degree relative with any cancer under the age of sixty years. Additional criteria for LFS and LFL exist. Some emphasize even younger age probands, very-early-onset breast cancer, and/or adrenocortical cancer.
Treatment and Therapy
For individuals with LFS who are affected with cancer, treatment and therapy will be similar to the clinical management of the respective cancer—that is, there is no special cancer treatment based on having inherited a genetic mutation associated with LFS. However, persons with LFS should consider limiting radiation exposure, as radiation-induced second malignancies have been seen among persons with TP53 mutations.
Prevention and Outcomes
LFS is highly penetrant, with overall lifetime cancer risks of eighty-five to ninety percent for women and seventy percent for men. When cancers do occur, they tend to have younger ages of onset. Most cancers in LFS occur before age fifty. A number of the cancers occur in childhood, and the female breast cancer associated with LFS may occur in adolescence.
In general, cancer prevention among LFS families includes targeted surveillance based on the individual family history. However, many of the cancers associated with the LFS have limited early detection. For breast cancer, mastectomy or annual mammogram and breast MRI beginning at age twenty to twenty-five with clinical breast examination every six months in addition to monthly self breast examination may be indicated. Additional management for all associated cancers includes heightened suspicion of patient complaints even if of a vague nature such as headache, bone pain, or abdominal discomfort.
For persons with LFS, and possible testing of other family members may be indicated to guide cancer prevention and improve outcomes. In 2024, researchers working at the Anderson Cancer Center at the University of Texas in Houston developed a new risk prevention model expected to help genetic counselors better predict the chances LFS patients will develop cancer.
Bibliography
Nam H. Nguyen et al. "Validating Risk Prediction Models for Multiple Primaries and Competing Cancer Outcomes in Families with Li-Fraumeni Syndrome Using Clinically Ascertained Data." Journal of Clinical Oncology, vol. 42, no. 18, pp. 2186-2195, 3 April 2024, doi.org/10.1200/JCO.23.01926. Accessed 9 Sept. 2024.
Offit, Kenneth. Clinical Cancer Genetics. New York: Wiley-Liss, 1998. A clinically oriented text of cancer genetic syndromes.
Schottenfeld, David, and Joseph F. Fraumeni, Jr. Cancer Epidemiology and Prevention. 2d ed. New York: Oxford University Press, 1996. A comprehensive text on cancer.
Vogel, Victor G. Management of Patients at High Risk for Breast Cancer. Malden, Mass.: Blackwell Science, 2001. A valuable text.