Tumor protein p53 (TP53) testing and Li-Fraumeni syndrome : current status of clinical applications and future directions

Abstract

Prevalent as an acquired abnormality in cancer, the role of tumor protein p53 (TP53) as a germline mutation continues to evolve. The clinical impact of a germline TP53 mutation is often dramatic and affects the full life course, with a propensity to develop rare tumors in childhood and multiple common cancers of unexpectedly early onset in adulthood. In this article, we review the clinical relevance of germline mutations in the TP53 tumor suppressor gene to current healthcare practice, including the optimal ways to identify patients with Li-Fraumeni syndrome (LFS), to recognize the core cancers associated with LFS, and to develop strategies for early detection of LFS-associated tumors. Several TP53-targeted approaches to improve outcomes in LFS patients are also reviewed. A case report is used to highlight special TP53 testing dilemmas and unique challenges associated with genetic testing decisions in the current age of rapidly advancing genomic technologies.

Fig. 1

A graphic representation of the TP53 gene (boxes) and protein (cylinders), adapted from the IARC TP53 database.^[21] The TP53 gene contains 11 exons represented by the numbered boxes. The exons 2-4 (yellow) encode for the two Transactivation domains (I, II) of the protein (amino acids 1 through 42 and 43-62). Exons 5-8 (blue) encode for the DNA binding portion of the protein (amino acids 102-292). Exons 9 and 10 (green) encode for the Oligomerisation (amino acids 323-356) and Regulatory (amino acids 363-393) domains. The approximate location of the initiation codon (ATG) is denoted.

Fig. 2

Summary of the most frequent TP53 germline mutations by codon, reproduced from the International Agency for research on Cancer (IARC) TP53 database.^[21] Each vertical line represents the codon location of a TP53 germline mutation. The codon location for the most frequently reported mutations (based on percentage of base substitutions) are located at the top of the vertical line. For instance, the Brazilian founder mutation, at codon position 337, is the most frequently reported mutation.

Fig. 3

Pedigree for the family described in the case example