TP53 Gene

The TP53 gene (TP53 is the acronym for Tumor Protein 53), is a tumor suppressor gene. In humans, the TP53 gene is located on the short arm of chromosome 17 (17p13.1). The gene spans 20 kb, with a non-coding exon 1 and a very long first intron of 10 kb. TP53 orthologs have been identified in most mammals for which complete genome data are available.

The gene encodes the tumor suppressor protein p53, which contains transcription activation, DNA binding and oligomerization domains. P53 responds to various cellular stresses to regulate the expression of target genes, thereby causing cell cycle arrest, apoptosis, senescence, DNA repair or changes in metabolism.

Mutations in the TP53 gene are associated with a variety of human tumor types, including Li-Fraumeni syndrome (very rare) and osteogenic sarcoma. Furthermore, mutations are described in associations with myelodysplastic syndrome. There they are considered to be a rather unfavourable prognostic sign. An important paralog of this gene is TP73.

Alternative splicing of the TP53 gene (see mutations below) and the use of alternative promoters result in multiple transcript variants and isoforms. Tp53 mutations are found in all maligenic tumor types. They contribute to the complex network of molecular events that lead to tumor formation. Loss of a tumor suppressor usually occurs through major deleterious events, such as frameshift mutations or premature stop codons. There is no single hotspot in the DNA binding domain, but the majority of mutations occur at amino acid positions 175, 245, 248, 273, and 282 (Olivier et al. 2010).

For the encoded protein to perform its biological function, four p53 polypeptides must form a tetramer that functions as a transcription factor. Therefore, even an inactivating mutation in one of the four polypeptides can result in a dominant-negative phenotype of varying degrees.

Keimban-associated TP53 mutations are the hallmark of Li-Fraumeni syndrome, an autosomal dominantly inherited tumor predisposition syndrome in which children and adolescents already develop multiple tumors, particularly of the adrenal gland, soft tissues, bone, and mammary gland. It was further found that many variants (both germline and somatic) have a prognostic impact on patient outcome.

1. Barbosa K et al.(2019) The role of TP53 in acute myeloid leukemia: challenges and opportunities. Genes Chromosomes Cancer 58:875-888.
2. Jiao XD et al. (2018) The prognostic value of TP53 and its correlation with EGFR mutation in advanced non-small cell lung cancer, an analysis based on cBioPortal data base. Lung Cancer123:70-75.

3. Nieuwenburg SA et al (2020) Cumulative risk of skin cancer in patients with Li-Fraumeni syndrome. Fam Cancer 19:347-351.

4. Petry V et al (2020) Radiotherapy-induced malignancies in breast cancer patients with TP53 pathogenic germline variants (Li-Fraumeni syndrome). Fam Cancer 19:47-53.

5. Valdez JM et al. (2017) Li-Fraumenisyndrome: aparadigmfor theun derstanding of hereditary cancer predisposition. Br JHaematol 176:539-552.