Monica Hollstein

p53 and human cancer: the first ten thousand mutations.

Publisher Summary The p53 protein is a tight, hydrophobic central globule containing the DNA binding domain, flanked by accessible N- and C-terminal regions. This protein is expressed in all cell types but has a rapid turnover and is latent under normal conditions. p53 is mutated in most common human malignancies and behaves as a multifunctional transcription factor involved in the control of cell cycle, programmed cell death, senescence, differentiation and development, transcription, DNA replication, DNA repair, and maintenance of genomic stability. p53 is converted to an active form in response to a number of physical or chemical DNA-damaging agents such as X or gamma irradiation, UV rays, oxidizing agents, cytotoxic drugs, and cancer-causing chemicals. Induction of p53 implies nuclear retention, accumulation of the protein as a result of post-translational stabilization, and allosteric conversion to a form with high sequence-specific DNA-binding capacity. p53 is activated in response to DNA damage, thus acting as a “guardian of the genome” against genotoxic stress. The chapter describes a three-step model of pS3 activation by stress signals. The downstream pS3 signaling is mediated by transcriptional activation of specific genes and by complex formation between p53 and heterologous proteins. The mutations and variations in the p53 gene are due to p53 polymorphisms, somatic mutations, and germline mutations in p53. The chapter also accounts for p53 mutations in sporadic cancers focussing on host-environment interactions. The chapter concludes with the potential clinical applications of the detection of p53 mutations in human tissues.

TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use

Somatic mutations in the TP53 gene are one of the most frequent alterations in human cancers, and germline mutations are the underlying cause of Li-Fraumeni syndrome, which predisposes to a wide spectrum of early-onset cancers. Most mutations are single-base substitutions distributed throughout the coding sequence. Their diverse types and positions may inform on the nature of mutagenic mechanisms involved in cancer etiology. TP53 mutations are also potential prognostic and predictive markers, as well as targets for pharmacological intervention. All mutations found in human cancers are compiled in the IARC TP53 Database (http://www-p53.iarc.fr/). A human TP53 knockin mouse model (Hupki mouse) provides an experimental model to study mutagenesis in the context of a human TP53 sequence. Here, we summarize current knowledge on TP53 gene variations observed in human cancers and populations, and current clinical applications derived from this knowledge.

Naturally occurring carbonyl compounds are mutagens Salmonella tester strain TA104

Strains of Salmonella typhimurium that carry a nonsense mutation at the site of reversion detect a variety of naturally occurring and synthetic carbonyl compounds as direct-acting mutagens. TA104 is reverted efficiently by formaldehyde, alpha, beta-unsaturated aldehydes (enals), and dicarbonyl compounds, such as diacetyl and glutaraldehyde. This strain is much more sensitive to carbonyl mutagenesis than is TA100, a strain previously reported to detect aldehydes as mutagens, or any other characterized strains of Salmonella. Long-chain enals are very toxic to TA104, but addition of a reduced glutathione chase following an incubation period decreases this toxicity, thus enabling the detection of 4-hydroxy-pentenal, a homolog of the lipid peroxidation product, 4-hydroxy-nonenal, as a mutagen. This is the first report of the mutagenicity of a hydroxy-enal, a class of enals produced by lipid peroxidation. Testing conducted with strains that carry the nonsense mutation in different repair backgrounds indicates that the presence of pKM101 and the deletion of the uvrB gene facilitate the detection of enals and dicarbonyls, but not malondialdehyde, as mutagens. Since carbonyl compounds are widely distributed in foods, are generated during cellular metabolism, and are present in body fluids, they may make a significant contribution to the risk of human cancer.

New approaches to understanding p53 gene tumor mutation spectra

The first p53 gene mutation arising in a human tumor was described a decade ago by Baker et al. [S.J. Baker, E.R. Fearon, J.M. Nigro, S.R. Hamilton, A.C. Preisinger, J.M. Jessup, P. van Tuinen, D.H. Ledbetter, D.F. Barker, Y. Nakamura, R. White, B. Vogelstein, Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas, Science 244 (1989) 217-221]. There are now over 10,000 mutations extracted from the published literature in the IARC database of human p53 tumor mutations [P. Hainaut, T. Hernandez, A. Robinson, P. Rodriguez-Tome, T. Flores, M. Hollstein, C.C. Harris, R. Montesano, IARC database of p53 gene mutations in human tumors and cell lines: updated compilation, revised formats and new visualization tools, Nucleic Acids Res. 26 (1998) 205-213; Version R3, January 1999]. A large and diverse collection of tumor mutations in cancer patients provides important information on the nature of environmental factors or biological processes that are important causes of human gene mutation, since xenobiotic mutagens as well as endogenous mechanisms of genetic change produce characteristic types of patterns in target DNA [J.H. Miller, Mutational specificity in bacteria, Annu. Rev. Genet. 17 (1983) 215-238; T. Lindahl, Instability and decay of the primary structure of DNA, Nature 362 (1993) 709-715; S.P. Hussain, C.C. Harris, Molecular epidemiology of human cancer: contribution of mutation spectra studies of tumor suppressor genes, Cancer Res. 58 (1998) 4023-4037; P. Hainaut, M. Hollstein, p53 and human cancer: the first ten thousand mutations, Adv. Cancer Res. 2000]. P53 gene mutations in cancers can be compared to point mutation spectra at the HPRT locus of human lymphocytes from patients or healthy individuals with known exposure histories, and accumulated data indicate that mutation patterns at the two loci share certain general features. Hypotheses regarding specific cancer risk factors can be tested by comparing p53 tumor mutations typical of a defined patient group against mutations generated experimentally in rodents or in prokaryotic and eukaryotic cells in vitro. Refinements of this approach to hypothesis testing are being explored that employ human p53 sequences introduced artificially into experimental organisms used in laboratory mutagenesis assays. P53-specific laboratory models, combined with DNA microchips designed for high through-put mutation screening promise to unmask information currently hidden in the compilation of human tumor p53 mutations.

[29] Detection of oxidative mutagens with a new Salmonella tester strain (TA102)

Publisher Summary Damage to DNA is likely to be a major cause of cancer and other diseases. The Salmonella mutagenicity test, along with other short-term assays, is being used extensively to survey a variety of substances in the environment for mutagenic activity. The test measures back-mutation in several specially constructed mutants of Salmonella. Among the classes of carcinogens that have gone undetected, as mutagens in the Salmonella, assay are chemical oxidants. Oxygen radicals may be the most important class of mutagens contributing to aging and cancer, yet a number of oxidants known to generate reactive oxygen species are not detected as mutagens in the standard Salmonella mutagenicity assay. A new Salmonella tester strain, TA102, has been described recently that detects a variety of oxidants and other agents as mutagens, which are not detected by the standard tester strains. Among the oxidants detected are hydrogen peroxide and other peroxides, X rays, bleomycin, neocarzinostatin, streptonigrin, and other quinones and phenylhydrazinc.

Upper urinary tract urothelial cancers: where it is A:T

Despite a ban on the use of plants of the Aristolochia genus in herbal medicine, as they contain known carcinogens, urothelial carcinoma attributable to the use of this plant seems to be more common than previously thought.

Erratum: Corrigendum: Modelling mutational landscapes of human cancers in vitro

Scientific Reports 4: Article number: 4482; published online: 27 March 2014 updated: 16 January 2017. In this Article, an additional affiliation for Hana Huskova was omitted. The correct affiliations for this Author are listed below: Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer, 69008 Lyon, France.

Abstract 2855: The codon 72 polymorphism of p53 influences the transcription of genes involved in immunity and inflammation

A common polymorphism at codon 72 in the p53 tumor suppressor protein encodes either proline (P72) or arginine (R72). Several groups have reported that in engineered cell lines this polymorphism influences p539s transcriptional, growth arrest, and apoptotic functions. However, the impact of this polymorphism within the context of a living organism has never been examined. In efforts to understand the biological consequences of the p53 codon 72 polymorphism in a living organism, we generated P72 and R72 mice in the background of the Humanized p53 knock-in (Hupki) mouse. In Hupki mice that are extensively back-crossed into a C57Bl/6 background, we find that there are consistent tissue-specific differences in apoptotic function between the P72 and R72 variants. Within the thymus, we find that the P72 variant is associated with increased apoptosis following gamma radiation. Micro-array analysis indicates that a small subset of genes show increased transactivation in thymocytes from P72 mice compared to R72. These genes include caspase 4/11, which mediates the processing of caspase 1. Interestingly, several of these genes are also regulated by NF-kB, and play roles in immunity and inflammation. Mechanistically we show that p53 interacts with the p65 Rel A subunit of NF-kB, and further that the P72 variant of p53 interacts significantly better than R72. These data indicate that the codon 72 polymorphism affects the ability of p53 to interact with NF-kB and to cooperate in the transactivation of genes involved in immunity and inflammation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2855. doi:10.1158/1538-7445.AM2011-2855

Cancer Risk Factors and Prevention

In view of the high cancer mortality figures and the unsatisfactory results of treatment, measures to prevent cancer are urgently needed. Prevention can be achieved both by the avoidance of risk factors (primary prevention) and by early diagnosis or halting the development of the disease (secondary prevention). But of course a prerequisite for targeted prevention is that the main causes of the disease and the mechanism by which it develops are understood. For many forms of cancer this is not the case. The Research Program Cancer Risk Factors and Prevention is investigating selected problems which are regarded as crucial for understanding the development of cancer and which promise to improve cancer prevention.