TP53 is probably the most extensively studied tumour-suppressor gene, and patients with TP53 mutations are known to have a poor outcome. However, inconsistencies in the analysis of TP53 status, and failure to realize that different mutations behave in different ways, prevent us from effectively applying our vast knowledge of this protein in clinical practice. What simple steps can be taken to ensure that patients benefit from our understanding of TP53?

In 1994 we described a list of approximately 2500 point mutations in the p53 gene of human tumors and cell lines which we had compiled from the published literature and made available electronically through the file server at the EMBL Data Library. This database, updated twice a year, now contains records on 4496 published mutations (July 1995 release) and can be obtained from the EMBL Outstation-the European Bioinformatics Institute (EBI) through the network or on CD-ROM. This report describes the criteria for inclusion of data in this database, a description of the current format and a brief discussion of the current relevance of p53 mutation analysis to clinical and biological questions.

Highlights d TP53 mutation effects analyzed by five data platforms in 32 cancers/10,225 patients d More than 91% of cancers with TP53 mutations show loss of both functional TP53 alleles d TP53 mutation affects genomic stability, global RNA, miRNA, and protein expression d Mutant p53 RNA expression signature helps prognostic predictions in 11 cancer types

More than 50% of human tumors carry TP53 gene mutations and in consequence more than 45,000 somatic and germline mutations have been gathered in the UMD TP53 database (http://p53.fr). Analyses of these mutations have been invaluable for bettering our knowledge on the structure-function relationships within the TP53 protein and the high degree of heterogeneity of the various TP53 mutants in human cancer. In this review, we discuss how with the release of the sequences of thousands of tumor genomes issued from high-throughput sequencing, the description of novel TP53 mutants is now reaching a plateau indicating that we are close to the full set of mutants that target the elusive tumor-suppressive activity of this protein. We performed an extensive and thorough analysis of the TP53 mutation database, focusing particularly on specific sets of mutations that were overlooked in the past because of their low frequencies, for example, synonymous mutations, splice mutations, or mutations-targeting residues subject to posttranslational modifications. We also discuss the evolution of the statistical methods used to differentiate TP53 passenger mutations and artifactual data from true mutations, a process vital to the release of an accurate TP53 mutation database that will in turn be an invaluable tool for both clinicians and researchers.

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Analysis of TP53 mutations from a large cohort of CRC patients has identified tumor site, type of mutation, and adjuvant treatment as important factors in determining the prognostic significance of this genetic alteration.

p53 mutations are found in 50% of human cancers. Molecular epidemiology has shown strong correlations between the spectrum of p53 mutations and exposure to exogenous carcinogens. This spectrum is influenced quantitatively and qualitatively by various upstream genetic filters that modulate carcinogen activation, detoxification, and/or DNA repair. In this review, we will discuss how other factors such as tissue specificity, SNP of genes associated with the p53 pathway, other genetic alterations, or p53 mutant heterogeneity can act as a second set of downstream filters that also have a profound impact on the spectrum of p53 mutations.

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