• Li-Fraumeni Syndrome: Genetic Mutations, Cancer Risks, and Surveillance Strategies
  • Fatemeh Sadat Shojaeddin,1 Safura Pakizehkar,2,*
    2. Cellular and Molecular Endocrine Research Center (CMERC), Research Institute for Endocrine Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran


  • Introduction: Li-Fraumeni syndrome is an autosomal dominant inherited disease which means that even if the mutation occurs in only 1 of the 2 copies of the TP53 gene, a person will have germline LFS. In cases where a mutation is inherited from parents, this type of mutation is referred to as a germline mutation. In the majority of cases of LFS, an individual will present with one normal and one mutated (altered) copy of the TP53 gene that the presence of a mutated TP53 allele is frequently attributable to inheritance from a parent affected by LFS. Nevertheless, it is estimated that approximately 25% of individuals with LFS lack a family history of the condition and instead exhibit a de novo (new) mutation in the TP53 gene. Inherited mutations of the TP53 gene have been identified as a contributing factor to certain types of cancer. Consequently, LFS is characterized as a cancer-prone syndrome, with an elevated risk for developing a diverse range of childhood and adult malignancies. More than 140 different types of inherited mutations for the TP53 gene have been identified, many of which are located in the DNA binding domain of p53. Somatic pathogenic variants of TP53 have been identified in approximately 50% of all tumors, making it one of the most commonly altered genes in human cancers. The majority of LFS tumours are of the following five cancer types: adrenocortical carcinomas, breast cancer, central nervous system tumors, osteosarcomas and soft-tissue sarcomas. Additionally, LFS is linked to an elevated risk of various other cancers, including leukemia, lymphoma, gastrointestinal cancers, cancers of the head and neck, kidney, larynx, lung, skin (e.g., melanoma), ovary, pancreas, prostate, testis, and thyroid. The lifetime probability of developing cancer in individuals with LFS is ≥70% for males and ≥90% for females. A diagnosis of LFS can be established in a proband who meets all three classic clinical criteria and/or has a heterozygous germline pathogenic variant in TP53. The classic clinical criteria are as follows: A proband with a sarcoma diagnosed before the age of 45 years, a first-degree relative with any cancer diagnosed before the age of 45 years, and a first- or second-degree relative with any cancer diagnosed before the age of 45 years, or a sarcoma diagnosed at any age. Currently, a number of tests are available for individuals with LFS, including predictive testing for at-risk family members, prenatal testing, and preimplantation genetic testing, which may be conducted if a TP53 germline pathogenic variant is present in the family. Accordingly, the recommended surveillance protocols include: A comprehensive physical examination and ultrasound of the abdomen and pelvis should be conducted every three to four months from birth to the age of 18 years. Additionally, an annual neurological examination and whole-body MRI, including a brain MRI, should be performed from the time of diagnosis. For women, a breast MRI should be conducted from the age of 30 to 75 years.
  • Methods: The research methodology entailed an extensive search of the PubMed, Google Scholar, and NCBI databases to identify articles pertinent to Li-Fraumeni syndrome. A comprehensive literature review was conducted to identify studies investigating Li-Fraumeni Syndrome, with a specific focus on genetic mutations, cancer risks, and surveillance strategies. Electronic databases were searched using relevant keywords and studies published between 2023 and 2016 were included. In order to obtain a comprehensive understanding of the subject matter, the review encompassed in vitro studies, and clinical trials.
  • Results: In light of promising preclinical data, the National Cancer Institute (NCI) has initiated a clinical trial investigating metformin as a novel anticancer agent. Preclinical evidence suggests that metformin exerts its anti-tumorigenic effects through multiple mechanisms. Indirectly, metformin reduces systemic insulin levels, whereas directly, it induces energetic stress. Moreover, metformin has been demonstrated to lower cancer incidence by inhibiting mitochondrial metabolism.
  • Conclusion: Li-Fraumeni syndrome (LFS) represents a significant hereditary risk factor for various cancers due to mutations in the TP53 gene. Individuals with Li-Fraumeni syndrome (LFS) are at a significantly increased risk of developing cancer throughout their lifetime, particularly those who are female. It is therefore vital that those diagnosed with LFS are given the opportunity to receive regular surveillance, and any symptoms should be considered promptly. Furthermore, it is crucial that ongoing research, including clinical trials investigating the potential role of metformin in reducing cancer incidence, is supported and encouraged, as this may offer new avenues for prevention and treatment in the future. It is essential that continued awareness and understanding of the syndrome is promoted, as this will ultimately lead to improved outcomes for individuals affected by LFS and their family members.
  • Keywords: Li-Fraumeni syndrome (LFS); TP53 gene; mutation; cancer