The IARC TP53 database: New online mutation analysis and recommendations to users

Abstract

Mutations in the tumor suppressor gene TP53 are frequent in most human cancers. Comparison of the mutation patterns in different cancers may reveal clues on the natural history of the disease. Over the past 10 years, several databases of TP53 mutations have been developed. The most extensive of these databases is maintained and developed at the International Agency for Research on Cancer. The database compiles all mutations (somatic and inherited), as well as polymorphisms, that have been reported in the published literature since 1989. The IARC TP53 mutation dataset is the largest dataset available on the variations of any human gene. The database is available at www.iarc.fr/P53/. In this paper, we describe recent developments of the database. These developments include restructuring of the database, which is now patient-centered, with more detailed annotations on the patient (carcinogen exposure, virus infection, genetic background). In addition, a new on-line application to retrieve somatic mutation data and analyze mutation patterns is now available. We also discuss limitations on the use of the database and provide recommendations to users.

PRIMA-1MET/APR-246 targets mutant forms of p53 family members p63 and p73

“…The tumor suppressor p53 is expressed at low levels in most cells and tissues but accumulates on cellular stress such as DNA damage, oncogene activation and hypoxia, and triggers cell cycle arrest, senescence and/or apoptosis (for a review, see Vousden and Lu (2002)). Mutations in p53 occur in nearly half of all human tumors (Olivier et al, 2002). p63 and p73 share structural homology with p53, particularly in their DNA-binding domains, with >60% amino acid identity (Kaghad et al, 1997;Schmale and Bamberger, 1997;Osada et al, 1998;Trink et al, 1998;Yang et al, 1998;Zeng et al, 2001).…”

Mutant p53: an oncogenic transcription factor

“…Conversely, p73 and p63 knockout mice exhibit severe developmental defects and do not spontaneously develop tumors (Mills et al, 1999;Yang et al, 1999. Whereas p53 is mutated in almost half of all human cancers (http://.iarc.fr/p53), p73 and p63, despite extensive effort, have been found mutated very rarely in human tumors (Sunahara et al, 1998;Takahashi et al, 1998;Kaelin, 1999;Levrero et al, 2000;Yang and McKeon, 2000;Olivier et al, 2002). Altogether, these findings indicate that among the p53 family members, p53 has been selected as a canonical tumor-suppressor gene whose inactivation certainly gives an advantage to the development and the maintenance of a cancer (Lowe et al, 2004).…”

Reactivation of mutant p53: molecular mechanisms and therapeutic potential

“…This prevents p53-dependent transcription and, hence, p53-mediated tumor suppression. The exceptionally high frequency of p53 mutations in human tumors of diverse types makes p53 unique among genes involved in tumor development (see p53.free.fr and www-p53.iarc.fr; Be´roud and Soussi, 1998;Olivier et al, 2002). Indeed, unbiased sequencing of whole genomes of breast and colon cancers confirmed that p53 is the most commonly mutated gene in these tumors (Sjo¨blom et al, 2006).…”