Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database

By A. Petitjean, Ewy A. Mathé, S. Kato, Chikashi Ishioka, Sean V. Tavtigian, Pierre Hainaut, Magali Olivier. Human Mutation, 2007

1,725 citations recorded by the source corpus.

The tumor suppressor gene TP53 is frequently mutated in human cancers. More than 75% of all mutations are missense substitutions that have been extensively analyzed in various yeast and human cell assays. The International Agency for Research on Cancer (IARC) TP53 database (www‐p53.iarc.fr) compiles all genetic variations that have been reported in TP53. Here, we present recent database developments that include new annotations on the functional properties of mutant proteins, and we perform a systematic analysis of the database to determine the functional properties that contribute to the occurrence of mutational “hotspots” in different cancer types and to the phenotype of tumors. This analysis showed that loss of transactivation capacity is a key factor for the selection of missense mutations, and that difference in mutation frequencies is closely related to nucleotide substitution rates along TP53 coding sequence. An interesting new finding is that in patients with an inherited missense mutation, the age at onset of tumors was related to the functional severity of the mutation, mutations with total loss of transactivation activity being associated with earlier cancer onset compared to mutations that retain partial transactivation capacity. Furthermore, 80% of the most common mutants show a capacity to exert dominant‐negative effect (DNE) over wild‐type p53, compared to only 45% of the less frequent mutants studied, suggesting that DNE may play a role in shaping mutation patterns. These results provide new insights into the factors that shape mutation patterns and influence mutation phenotype, which may have clinical interest. Hum Mutat 28(6), 622–629, 2007. Published 2007 Wiley‐Liss, Inc.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/8f6a6110525ac54e22296c21edb7bc21e1dc0d0d

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Citations in the corpus

TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data (2016, methodology): “…on all these aspects of TP53 and published in an unstructured way in peer-reviewed articles have been curated and integrated in the IARC TP53 Database (http://p53.iarc.fr/), providing the scientific community with a unique resource to retrieve and mine this information [Petitjean et al., 2007].”
Genomic Evolution of Breast Cancer Metastasis and Relapse (2017, background): “Gain-of-function mutations in TP53 have been associated with metastasis and drug resistance in cellline and xenograft models (Petitjean et al., 2007; Turner et al., 2017), but in our cohort loss-of-function and gain-of-function mutations were equally enriched in patients with progressive disease…”
Cancer Genome Interpreter annotates the biological and clinical relevance of tumor alterations (2017, background): “First, from manually curated resources [2, 7, 8, 12, 13] and the literature we collected genes that have been experimentally or clinically verified to drive tumorigenesis.”
p53 polymorphisms: cancer implications (2009, neutral): “i1 i2 i3 i4 i5 i6 i7 i8 i9 i10 (41, 10,739) (1, 115) (2, 92) (5, 775) (2, 81) (4, 567) (7, 342) (1, 92) (13, 2,817) (5, 919) Transactivation domains Prolinerich domain DNA-binding domain Tetramerization domain”
TP53 mutations in human cancers: origins, consequences, and clinical use. (2010, methodology): “Data from IARC TP53 Database (R13, November 2008)(Petitjean et al. 2007b).”
COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer (2010, background): “This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly ”
Mutant p53: one name, many proteins. (2012, background): “1A,B; Harris and Hollstein 1993; Cho et al. 1994; Petitjean et al. 2007a).”
Statin use and reduced cancer-related mortality. (2012, neutral): “>100,000 residents 6,186 (33) 96,159 (35) 5,059 (33) 14,895 (33)”
p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure–Function Continuum Concept (2016, background): “Similarly, mutations of the phosphorylatable residues Thr155 and Ser215 located in the DBD are found 99 and 110 times in tumors, respectively [231].”
Predicting the functional impact of protein mutations: application to cancer genomics (2011, methodology): “Therefore we tested the FI score on data obtained from experimental studies of the functional impact of TP53 mutations as collected in the IARC TP53 database (55).”
The Catalogue of Somatic Mutations in Cancer (COSMIC) (2008, background): “These key elements, while fairly obvious, will beneﬁt from further clari-ﬁcation.”