Li–Fraumeni Syndrome: Mutation of TP53 Is a Biomarker of Hereditary Predisposition to Tumor: New Insights and Advances in the Treatment

SIMPLE SUMMARY: Li–Fraumeni Syndrome (LFS) is a rare tumor predisposition syndrome in which the tumor suppressor TP53 gene is mutated in the germ cell population. LFS patients develop a broad spectrum of cancers in their lifetime. The risk to develop these tumors is not decreased by any type of treatment and if the analysis of the TP53 mutational status in the family members was not possible, tumors are often diagnosed in already advanced stages. This review aims to report the evidence for novel mechanisms of tumor onset related to germline TP53 mutations and possible treatments. ABSTRACT: Li–Fraumeni syndrome (LFS) is a rare familial tumor predisposition syndrome with autosomal dominant inheritance, involving germline mutations of the TP53 tumor suppressor gene. The most frequent tumors that arise in patients under the age of 45 are osteosarcomas, soft-tissue sarcomas, breast tumors in young women, leukemias/lymphomas, brain tumors, and tumors of the adrenal cortex. To date, no other gene mutations have been associated with LFS. The diagnosis is usually confirmed by genetic testing for the identification of TP53 mutations; therefore, these mutations are considered the biomarkers associated with the tumor spectrum of LFS. Here, we aim to review novel molecular mechanisms involved in the oncogenic functions of mutant p53 in LFS and to discuss recent new diagnostic and therapeutic approaches exploiting TP53 mutations as biomarkers and druggable targets.