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

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.

Keywords: Li–Fraumeni syndrome (LFS); TP53; biomarker; cancer predisposition; germline mutation.

Figure 1

Protein domains of p53. Human p53 protein has 393 aminoacidic residues and is composed of a transactivation domain (TAD), proline-rich domain (PRD), DNA-binding domain (DBD), tetramerization or oligomerization domain (OD), and a C-terminal regulatory domain (RD).

Figure 2

Mechanisms of action of wild-type and mutant p53 protein in response to different stresses. (A) In response to diverse types of cellular stress signals, the wild-type p53 protein is induced to activate different pathways by its recruitment onto specific DNA consensus sequences of target gene promoters. (B) On the other side, mutant p53 forms oncogenic complexes with other transcription factors, usually not bound by wild-type p53, resulting in the aberrant activation of genes that promote GOF activities. Notably, when TP53 mutations occur in one of the alleles, mutant p53 co-exists with wtp53 acting as a dominant negative (DN) factor in the heterodimer complexes, until the loss of the wild-type allele by loss-of-heterozygozity (LOH).

Figure 3

(A) A lolliplot showing six mutant p53 germline variants in Li–Fraumeni syndrome with their frequency of mutation. (B) Pareto diagram representing the frequency of occurrence of six mutant p53 hotspots in the LFS cancers. The orange bars represent the tumors with a higher percentage of TP53 mutations according to the Pareto analysis.