Li-Fraumeni Syndrome: Current Perspectives on Molecular Pathogenesis, Surveillance Strategies, Clinical Management...

Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant hereditary cancer predisposition syndrome caused by germline mutations in the TP53 tumor suppressor gene, conferring a markedly increased lifetime risk of multiple early-onset malignancies. Pediatric patients are particularly susceptible to developing soft tissue sarcomas, osteosarcomas, adrenocortical carcinomas, central nervous system tumors, and hematologic malignancies, necessitating early recognition and lifelong surveillance. Over the past decade, substantial advances in the understanding of TP53 biology have deepened insight into the molecular mechanisms underlying tumor development and informed the evolution of comprehensive surveillance strategies. This literature review summarizes the current understanding of the molecular pathogenesis of LFS, reviews the pediatric cancer spectrum, and compares contemporary surveillance recommendations, including the Toronto protocol, European Reference Network (ERN) GENTURIS guidelines, and recent American Association for Cancer Research (AACR) recommendations. We further discuss current clinical management, challenges associated with lifelong surveillance, and emerging therapeutic approaches, including mutant p53 reactivation, synthetic lethality strategies, and pharmacologic cancer prevention with agents such as metformin. Although no targeted therapy has been approved specifically for individuals with LFS, advances in precision medicine and ongoing clinical trials continue to expand the potential for preventive and therapeutic options. Continued international collaboration, prospective clinical research, and integration of molecular discoveries into clinical practice will be essential to optimize surveillance protocols, develop effective targeted interventions, and improve long-term outcomes for children and families affected by Li-Fraumeni Syndrome.