Spontaneous and inherited TP53 genetic alterations

Abstract

The p53 protein is a transcription factor that prevents tumors from developing. In spontaneous and inherited cancers there are many different missense mutations in the DNA binding domain of the TP53 gene that contributes to tumor formation. These mutations produce a wide distribution in the transcriptional capabilities of the mutant p53 proteins with over four logs differences in the efficiencies of forming cancers in many diverse tissue types. These inherited and spontaneous TP53 mutations produce proteins that interact with both genetic and epigenetic cellular modifiers of p53 function and their inherited polymorphisms to produce a large number of diverse phenotypes in individual patients. This manuscript reviews these variables and discusses how the combinations of TP53 genetic alterations interact with genetic polymorphisms, epigenetic alterations, and environmental factors to begin predicting and modifying patient outcomes and provide a better understanding for new therapeutic opportunities.

Fig. 1. Tumor tissue types, ages of onset, and excess risk of cancers.

Li Fraumeni patients inherit a mutant TP53 allele that acts at an early age of onset (six months to 20 years) indicating that the mutant p53 protein functions as an initial or truncal mutation promoting benign cell replication and clonal expansion and producing a high excess risk for cancer. TP53 mutations that give rise to cancers later in life more likely function as a later mutation in an ordered series of mutant genes that drive cancerous growth. By 50–70 years of life, cancers arise with low excess risk and the mutant p53 protein acts in the benign to malignant transformation as the last gene in the ordered series of cancer forming mutations [9, 10, 27].

Fig. 2. A linear representation of the p53 protein with five domains.

The XAF-1 protein binds within the proline-rich domain (see Fig. 2) and the great majority of missense mutations that contribute to cancers reside in the DNA binding domain. The eight spontaneous mutations and two environmental mutations form the ten most common TP53 mutations (33% of cancers), which have very little or no transcriptional activity. More than 350 additional TP53 missense mutations have a weak transcriptional activity, a much lower frequency of occurrence in producing cancers over a four log distribution, and cause 67% of cancers. The hypothesis that pro-apoptotic XAF-1 binding to a weak transcriptional p53 protein promotes apoptosis so that the weak allele fails to form cancer. An XAF-1 gene transcriptionally silenced by epigenetic marks or a polymorphism that inactivates the protein would then permit weak, minor TP53 alleles to produce cancer [37].

Fig. 3. P53: an informed stress responder.

The p53 and MDM-2 proteins form a module in the cell where p53 transcribes the MDM-2 gene and the MDM-2 protein promotes the degradation of the p53 protein. Stress signals, in this case, DNA damage is sensed by the ATM protein which phosphorylates a CHEK-2 mediator which in turn phosphorylate serine -15 in the p53 protein, and other sites in p53 and MDM-2, that disrupts the MDM-2-P53 protein complex. This increases p53 protein levels and along with other epigenetic modifications of p53 and MDM-2 the p53 transcription factor makes an informed choice between cell cycle arrest, DNA repair, and return to homeostasis or programed cell death by one of five possible methods [10].

Fig. 4. The functions of the XAF-1 protein in promoting p53 mediated apoptosis.

1. The XAF-1 protein binds to the p53 protein in the proline domain and dissociates MDM-2 from p53, stabilizing p53. 2. The XAF-1 protein binds to the ubiquitin ligase SIAH-2, which inhibits its functions, increasing the levels and activity of HIPK-2, which in turn phosphorylates p53-serine 46, which promotes the transcription of a pro-apoptotic p53 pathway. 3. The XAF-1 protein also binds to ZNF-313, a ubiquitin ligase that promotes the degradation of the p21 protein (cell cycle arrest). This is also is a pro-apoptotic activity [46].