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

“The tumor suppressor gene TP53 (OMIM ]191117) encodes a transcription factor that responds to several forms of cellular stress and exerts multiple, antiproliferative functions [Vogelstein et al., 2000].”

“Inherited TP53 mutations predispose to a wide spectrum of early-onset cancers and are associated with Li-Fraumeni and Li-Fraumeni-like syndrome (LFS and LFL, respectively) [Malkin et al., 1990].”

“In lung cancers, V157F, R158L, R248L, and R273L hotspots are due to G4T transversions that have been shown to be caused by the presence of benzo(a)-pyrene diol epoxide (BPDE) adducts on guanines at these codons [Denissenko et al., 1996].”

“Studies in mouse models of LFS have reported evidence of GOF for R175H and R273H mutants [Lang et al., 2004; Olive et al., 2004].”

“It contains annotations related to the clinical and pathological characteristics of tumors, as well as the demographics and carcinogen exposure of patients [Olivier et al., 2002].”

“Studies in mouse models of LFS have reported evidence of GOF for R175H and R273H mutants [Lang et al., 2004; Olive et al., 2004].”

“Somatic TP53 gene alterations are frequent in most human cancers [Hainaut and Hollstein, 2000], ranging from 5 to 80% depending on the type, stage, and etiology of tumors.”

“…2007 WILEY-LISS, INC. and a single study has performed a systematic analysis of the activity of all possible missense mutations produced by singlenucleotide substitution in the entire sequence of TP53 (2,314 mutations) on eight different p53-RE in yeast cells [Kato et al., 2003].”

“However, in a recent study on a large series of patients with breast cancer, we found that TP53 mutations were an independent factor of poor prognosis [Olivier et al., 2006], but that TA did not accurately predict differences in survival among patients with TP53 mutations.”

“Other less frequent cancers include leukemias, stomach cancer, colorectal cancer [Birch et al., 2001].”

“fr]) based on interspecies sequence conservation [Mathe et al., 2006].”

“The first systematic study was performed in yeast, and measured the ability of 35 mutants to inhibit the TA of wildtype p53 on its consensus response-element [Brachmann et al., 1996].”

“Since then, data has been produced on more than 200 mutants and it appears that DNE is promoter- and cell-typedependent [Dearth et al., 2007].”

“The most frequent cancers associated with TP53 mutations are breast cancer (BC), bone and soft tissue sarcomas (BoneS and STS), brain tumors (BT), and adrenocortical carcinomas (ADR) [Olivier et al., 2003; Wong et al., 2006].”

“However, in LFS families, LOH has been shown to occur in about half of the tumors [Varley et al., 1997].”

“…(40% for Gadd45 and 85% for P53R2), R213Q has been shown to retain TA on MDM2 and growth suppressive activity in human cells [Hsiao et al., 1994; Pan and Haines, 2000], and R283H to retain apoptotic activity in Saos-2 cells and TA on WAF1 in yeast assays [Maurici et al., 2001; Smith et al., 1999].”

“…substitution rates for each possible single-nucleotide substitution in the coding sequence of p53 have been calculated using a TP53 cDNA sequence (Homo sapiens|gi:35213) and dinucleotide substitution rates derived from human-mouse aligned sequence of chromosomes 21 and 10 [Lunter and Hein, 2004].”

“…(40% for Gadd45 and 85% for P53R2), R213Q has been shown to retain TA on MDM2 and growth suppressive activity in human cells [Hsiao et al., 1994; Pan and Haines, 2000], and R283H to retain apoptotic activity in Saos-2 cells and TA on WAF1 in yeast assays [Maurici et al., 2001; Smith et al., 1999].”

“…(40% for Gadd45 and 85% for P53R2), R213Q has been shown to retain TA on MDM2 and growth suppressive activity in human cells [Hsiao et al., 1994; Pan and Haines, 2000], and R283H to retain apoptotic activity in Saos-2 cells and TA on WAF1 in yeast assays [Maurici et al., 2001; Smith et al.,…”

“Loss of function mutations in TP53 are very common in cancer and are a somatic marker of elevated mutation rate [50].”

“For the human tumor suppressor protein TP53, a set of 2,314 single point mutants and corresponding biological activity levels were obtained from the IARC TP53 database [33].”

“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 cited. the curators…”

“Data from IARC TP53 Database (R13, November 2008)(Petitjean et al. 2007b).”