TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes
TLDR
It is shown that intrinsic mutagenicity rates, loss of transactivation activities, and to a lesser extent, dominant-negative activities are the main driving forces that determine TP53 mutation patterns and influence tumor phenotype.Abstract:
A large amount of data is available on the functional impact of missense mutations in TP53 and on mutation patterns in many different cancers. New data on mutant p53 protein function, cancer phenotype and prognosis have recently been integrated in the International Agency for Research on Cancer TP53 database (http://www-p53.iarc.fr/). Based on these data, we summarize here current knowledge on the respective roles of mutagenesis and biological selection of mutations with specific functional characteristic in shaping the patterns and phenotypes of mutations observed in human cancers. The main conclusion is that intrinsic mutagenicity rates, loss of transactivation activities, and to a lesser extent, dominant-negative activities are the main driving forces that determine TP53 mutation patterns and influence tumor phenotype. In contrast, current experimental data on the acquisition of oncogenic activities (gain of function) by p53 mutants are too scarce and heterogenous to assess whether this property has an impact on tumor development and outcome. In the case of inherited TP53 mutations causing Li-Fraumeni and related syndromes, the age at onset of some tumor types is in direct relation with the degree of loss of transactivation capacity of missense mutations. Finally, studies on large case series demonstrate that TP53 mutations are independent markers of bad prognosis in breast and several other cancers, and that the exact type and position of the mutation influences disease outcome. Further studies are needed to determine how TP53 haplotypes or loss of alleles interact with mutations to modulate their impact on cancer development and prognosis.read more
Citations
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Blinded by the Light: The Growing Complexity of p53
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TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use
TL;DR: Current knowledge on TP53 gene variations observed in human cancers and populations, and current clinical applications derived from this knowledge are summarized.
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Mutant p53 in Cancer: New Functions and Therapeutic Opportunities
TL;DR: There is growing evidence that these mutant p53s have both lost wild-type p53 tumor suppressor activity and gained functions that help to contribute to malignant progression.
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When mutants gain new powers: news from the mutant p53 field
Ran Brosh,Varda Rotter +1 more
TL;DR: Recent studies on mutant p53 regulation, gain-of-function mechanisms, transcriptional effects and prognostic association are reviewed, with a focus on the clinical implications of these findings.
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