Heterogeneity of TP53 Mutations and P53 Protein Residual Function in Cancer: Does It Matter?

Abstract

The human TP53 locus, located on the short arm of chromosome 17, encodes a tumour suppressor protein which functions as a tetrameric transcription factor capable of regulating the expression of a plethora of target genes involved in cell cycle arrest, apoptosis, DNA repair, autophagy, and metabolism regulation. TP53 is the most commonly mutated gene in human cancer cells and TP53 germ-line mutations are responsible for the cancer-prone Li-Fraumeni syndrome. When mutated, the TP53 gene generally presents missense mutations, which can be distributed throughout the coding sequence, although they are found most frequently in the central DNA binding domain of the protein. TP53 mutations represent an important prognostic and predictive marker in cancer. The presence of a TP53 mutation does not necessarily imply a complete P53 inactivation; in fact, mutant P53 proteins are classified based on the effects on P53 protein function. Different models have been used to explore these never-ending facets of TP53 mutations, generating abundant experimental data on their functional impact. Here, we briefly review the studies analysing the consequences of TP53 mutations on P53 protein function and their possible implications for clinical outcome. The focus shall be on Chronic Lymphocytic Leukemia (CLL), which also has generated considerable discussion on the role of TP53 mutations for therapy decisions.

Heterogeneity of the Cancer Cell Line Metabolic Landscape

“…Mutations in TP53 broadly fall into two categories, those directly impacting the DNA binding interface and altering the contact between the protein and DNA (DNA contact mutations), and those altering the wider structure of the protein itself and changing its stability and affinity for binding partners (Conformation mutations) 48,49 . Previous work has highlighted that these two categories of mutations confer differing transcriptional programmes, cellular phenotypes, and interestingly also drug sensitivities 50,51 , we surmised that there may also be metabolic changes associated specifically with each mutation, as well as a conserved set of metabolites that are changed in response to any TP53 mutation. We studied our data for cells with mutations in TP53 that are validated as DNA contact altering, or conformation altering ( Figure 6C ).…”

Expression of Potential Targets for Cell-Based Therapies on Melanoma Cells

“…Further, elevated p53 in tumors expressing mutant p53 may also result in the higher presentation of p53-derived peptides by MHC molecules, making it an ideal target for TCR T cell therapy [ 35 , 36 , 37 ]. However, the large numbers of tumor-associated mutations among the various exons of the p53 tumor suppressor gene reported, make generating a large number of possible mutant p53 vaccines somewhat prohibitive [ 38 ].…”

Antitumor Effects of PRIMA-1 and PRIMA-1Met (APR246) in Hematological Malignancies: Still a Mutant P53-Dependent Affair?

“…More than 80% of CLL cases have genomic aberrations at diagnosis, the most frequent being partial deletions at 13q (~55%), 11q (~15%), 17p (~8%), and gain of chromosome 12 (~15%) [ 32 ]. The incidence of TP53 mutations is approximately 5–7% at diagnosis [ 33 , 34 ], but it rises as the disease progresses, reaching approximately 40% in refractory CLL [ 35 , 36 , 37 , 38 ]. In general, global P53 dysfunctions [i.e., TP53 mutations or (del 17p)] are associated with adverse outcomes due to the development of resistance to chemotherapy and chemo-immunotherapies.…”

“…Very recently, the influence of TP53 mutations on early disease progression has been investigated in CLL [ 51 ]. Since the presence of a TP53 mutation does not necessarily imply a complete P53 inactivation [ 34 ], functional characterization of mutant P53 protein encoded by TP53 mutations was also performed by using the O-CLL1 observational study (clinicaltrial.gov identifier NCT00917540) that recruited a cohort of clinically and molecularly well-characterized Binet stage A patients. The analyzed mutant P53 proteins appeared to be functionally heterogeneous, but such heterogeneity was not associated with differences in TTFT within the group of patients carrying only the TP53 mutation without del(17p).…”