TP53 mutations in human cancers: origins, consequences, and clinical use - PubMed (original) (raw)

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TP53 mutations in human cancers: origins, consequences, and clinical use

Magali Olivier et al. Cold Spring Harb Perspect Biol. 2010 Jan.

Abstract

Somatic mutations in the TP53 gene are one of the most frequent alterations in human cancers, and germline mutations are the underlying cause of Li-Fraumeni syndrome, which predisposes to a wide spectrum of early-onset cancers. Most mutations are single-base substitutions distributed throughout the coding sequence. Their diverse types and positions may inform on the nature of mutagenic mechanisms involved in cancer etiology. TP53 mutations are also potential prognostic and predictive markers, as well as targets for pharmacological intervention. All mutations found in human cancers are compiled in the IARC TP53 Database (http://www-p53.iarc.fr/). A human TP53 knockin mouse model (Hupki mouse) provides an experimental model to study mutagenesis in the context of a human TP53 sequence. Here, we summarize current knowledge on TP53 gene variations observed in human cancers and populations, and current clinical applications derived from this knowledge.

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Figures

Figure 1.

Figure 1.

TP53 mutations prevalence in sporadic cancers. The proportion of tumors with somatic TP53 mutations is indicated. Data from IARC TP53 Database (R13, November 2008)(Petitjean et al. 2007b).

Figure 2.

Figure 2.

Type of somatic TP53 mutations in human cancers. (A) Pie charts showing the proportion of the different types of TP53 somatic mutations found in all human cancers. (B) Histogram displaying the position of somatic point mutations in the coding sequence of the TP53 gene. Data from the IARC TP53 Database (R13, November 2008)(Petitjean et al. 2007b).

Figure 3.

Figure 3.

Geographic distribution of germline TP53 mutations. Number of TP53 germline mutation carrier families in each world region. Data from the IARC TP53 Database (R13, November 2008) (Petitjean et al. 2007b).

Figure 4.

Figure 4.

Tumor spectrum in individuals with a germline TP53 mutation. The proportion of specific tumor types among all tumors reported in confirmed TP53 germline mutation carriers is indicated. Data from IARC TP53 Germline Database (R13, November 2008,

http://www-p53.iarc.fr/Germline.html

).

Figure 5.

Figure 5.

Functional impact of somatic TP53 mutations in human cancers. (A) Scatter plots showing the frequency (x-axis) of single amino-acid substitutions in relation to their effect (left panel) or functional impacts on transactivation (right panel), and expected substitution rates (_y_-axis in log). Each point represents a single amino-acid substitution that is shaped and colored according to the mutation effect or functional impact. (B) Pie charts displaying the proportion of all somatic single amino-acid substitutions according to their effect (left panel) or functional impacts on transactivation (right panel). Data from the IARC TP53 Database (R13, November 2008)(Petitjean et al. 2007b).

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