Li-Fraumeni syndrome (LFS) is a rare, hereditary cancer predisposition syndrome characterized by an increased risk of developing a variety of cancer types at an early age. LFS is associated with germline mutations in the TP53 tumor suppressor gene, which plays a crucial role in regulating cell growth and preventing the formation of tumors. The prevalence of LFS is estimated to be 1 case per 3.500-5.500 individuals.
Li-Fraumeni syndrome genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Critical features of Li-Fraumeni Syndrome include:
- Early-Onset Cancers: Individuals with LFS are at an increased risk of developing various cancers at a young age. The most common cancers associated with LFS include soft tissue sarcomas, osteosarcomas, breast cancer, brain tumors, adrenocortical carcinoma, leukemia, and other malignancies.
- Family History: LFS is often characterized by a strong family history of cancer, with multiple family members affected by different types of cancer. Cancers in LFS families tend to occur earlier than expected in the general population.
- TP53 Gene Mutation: LFS is caused by germline mutations in the TP53 gene. These mutations are present in the germ cells (sperm or egg cells) and can be passed on from generation to generation.
- Autosomal Dominant Inheritance: LFS follows an autosomal dominant pattern of inheritance. This means that an individual with a TP53 mutation has a 50% chance of passing the mutation to each of their offspring.
- Second Primary Cancers: Individuals with LFS are at an increased risk of developing multiple primary cancers over their lifetime. The occurrence of a first cancer does not eliminate the risk of developing additional cancers.
- Radiation Sensitivity: People with LFS may be susceptible to the effects of ionizing radiation, which could increase the risk of developing cancers.
- Surveillance and Screening: Given the high risk of cancer, individuals with LFS often undergo regular surveillance and screening to detect tumors at an early, more treatable stage. This may include imaging studies, blood tests, and other screening modalities.
Management of Li-Fraumeni Syndrome involves close monitoring, early detection of cancers, and consideration of risk-reducing strategies. Genetic counseling is crucial for affected individuals and their families to discuss the risks, available screening options, and potential preventive measures.
Due to the complex nature of LFS, individuals identified with TP53 mutations may benefit from a multidisciplinary approach involving geneticists, oncologists, and other healthcare professionals to manage their cancer risks and optimize care.
More Information
More than 1000 mutations in the TP53 gene have been identified in tumors, of which a small proportion are germline mutations associated with Li-Fraumeni syndrome. One of the most prominent germline pathogenic variants of the TP53 gene in LFS is c.1010G>A (p.Arg337His), which is prevalent in southern Brazil, where it is present in 1 in 375 people and is rare in the general population. This variant markedly increases the risk of developing an adrenocortical tumor during childhood. Its penetrance is incomplete, which means that not all people who carry the variant will eventually develop cancer. The c.818G>T mutation (p.Arg273Leu) causes a nonconservative amino acid change with an impact on the secondary structure of the protein, thus on its function.
The c.524G>A variant (p.Arg175His) causes a localized amino acid change in the DNA-binding domain, impacting cell cycle control and transcriptional activation of multiple genes.
Both mutations, c.818G>T and c.524G>A, cause tumor suppressor function loss and oncogenic capacity gain; thus, both are considered a typical “hotspot” in multiple associated tumors. There are other mutations associated with LFS analyzed in this test, although it should be noted that not all known germline mutations in TP53 are analyzed.
Li-Fraumeni syndrome genetic testing analyzes the 65 most frequent pathogenic mutations of the TP53 gene.
The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).
