Impact of mutant p53 functional properties onTP53mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database

Abstract

Communicated by David GoldgarThe 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

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

“…To test for T cell responses against driver gene mutations of GI tumors we assembled a panel of long peptides comprising the most frequent KRAS 49-51 and TP53 52 hotspot mutations found in CRC and pancreatic cancer. We also included the BRAF V600E mutation 53 , which is a frequent driver mutation in melanoma but is also found to a lower percentage (10.7%) in GI tumors 51 .…”

“…The most relevant mutations in TP53, KRAS and BRAF genes for colorectal and pancreatic cancer were chosen using the IARC TP53 Database (version R17, November 2013) 52 and COSMIC database for somatic mutations in cancer (from the Sanger Institute, COSMIC v69 Release) 51 , respectively. Peptides were produced by the DKFZ core facility for peptide synthesis.…”

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

“…Somatic TP53 mutations occur in about 40,6% of head and neck cancers [36]. Contrary, mutations of TP53 were not found in any of 19 cases of ONB, but about the half of all cases showed p53 overexpression [37].…”

Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

“…17 The SNP309G may also give higher sensitivity to MDM2 antagonists such as Nutlin-3a. 18 The reported frequencies of these polymorphisms vary (eg, 23%-67% for P72, 19 with 58% in Norwegians, 20 and 8%-58% for SNP309G, with 55% in Norwegians 21 ). Here, we investigate whether these normal variants and somatic aberrations of TP53 or MDM2 in tumor material may affect disease outcome, and also how they may relate to Nutlin-3a responses in vitro.…”