TP53 mutations in human cancers: origins, consequences, and clinical use.
Journal: 2010/September - Cold Spring Harbor perspectives in biology
ISSN: 1943-0264
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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Cold Spring Harb Perspect Biol 2(1): a001008

TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use

Group of Molecular Carcinogenesis, International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 08 France
LIGHT Laboratories, University of Leeds, United Kingdom
Correspondence:rf.crai@tuaniah

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.

Abstract

Genetic variations in the tumor suppressor gene TP53 (OMIM #191117) contribute to human cancers in different ways. First, somatic mutations are frequent in most cancers (Hollstein et al. 1991). The antiproliferative role of p53 protein in response to various stresses and during physiological processes such as senescence makes it a primary target for inactivation in cancer (Levine 1997). The main modes of TP53 inactivation are single-base substitution and loss of alleles, with inactivation by viral or cellular proteins playing a major role in specific cancers (Tommasino et al. 2003). Second, inheritance of a TP53 mutation causes predisposition to early-onset cancers including breast carcinomas, sarcomas, brain tumors, and adrenal cortical carcinomas, defining the Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) syndromes (Li et al. 1988; Olivier et al. 2003). Third, TP53 is highly polymorphic in coding and noncoding regions and some of these polymorphisms have been shown to increase cancer susceptibility and to modify cancer phenotypes in TP53 mutation carriers (Whibley et al. 2009).

Whereas tumor suppressors are commonly inactivated by frameshift or nonsense mutations, most TP53 mutations are missense and cause single amino-acid changes at many different positions. Mutations are thus diverse in their type, sequence context, position, and structural impact, making it possible to identify mutation patterns in relation with cancer type and etiology. The occurrence of special mutation patterns may inform on the nature of the mutagens that have caused them, making TP53 an interesting gene to analyze in the realm of molecular epidemiology.

Data on mutation prevalence in human cancer can be conveniently accessed through the IARC TP53 database (http://www-p53.iarc.fr/), a resource that compiles all TP53 gene variations reported in human cancers with annotations on tumor phenotype, patient characteristics, and structural and functional impact of mutations (Petitjean et al. 2007b). Recently, it has become possible to confront these observations with experimental data generated in a novel mouse model, the HupKi mouse, that contains a human TP53 sequence at the mouse TP53 locus and recapitulates the effects of environmental mutagens in a human sequence context (Luo et al. 2001). In this article, we review the current knowledge on the origin, causes, and consequences of TP53 variations and mutations in cancer and we discuss their significance as biomarkers in epidemiology and in the clinics.

Complete list available at http://www-p53.iarc.fr/PolymorphismView.asp.

Missense polymorphisms are highlighted (amino-acid substitution and codon into brackets).

*Somatic mutations reported in the IARC TP53 Database (R13, November 2008).

Footnotes

Editors: Arnold J. Levine and David Lane

Additional Perspectives on The p53 Family available at www.cshperspectives.org

Footnotes

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