Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular epidemiology is increasingly being applied in studies of cancer risks derived from exposure to environmental carcinogens of both endogenous and exogenous origins. Analytical methods have been developed that are capable of detecting and quantifying levels of covalent adducts of several important classes of carcinogens with cellular DNA and blood proteins. Methods of sufficient sensitivity and specificity to detect ambient levels of exposure are in current use. These are being used in studies related to tobacco use (polycyclic aromatic hydrocarbons, aromatic amines, tobacco-specific nitrosamines); dietary exposures (aflatoxins, N-nitrosamines, heterocyclic amines); medicinal exposures (cisplatin, alkylating agents, 8-methoxypsoralen, ultraviolet photoproducts); occupational exposures (aromatic amines, polycyclic aromatic hydrocarbons, oxides of ethylene and styrene, and vinyl chloride); and oxidative damage (8-hydroxyguanine, thymine glycol). Methodologic improvements together with their expanded use in feasibility studies continue to produce results that support the validity of this approach for detecting and quantifying exposure to carcinogens. Genetic markers are also being used to detect early biological responses in efforts to link carcinogen exposure to initiating events in the carcinogenesis process. These include, in addition to traditional cytogenetic markers (e.g., chromosomal aberrations, sister chromatid exchange, micronuclei), other alterations in chromosomal structure such as restriction fragment length polymorphisms, loss of heterozygosity, and translocation markers. Specific genetic changes have recently been identified as critical molecular events in the initiation and development of many cancers. Important among these are activation of oncogenes, especially those of the ras family, and inactivation of tumor-suppressor genes (e.g., p53 and Rb) by point mutations and/or chromosomal deletions and other structural changes. Although some of these changes are known to occur in chemically induced tumors of experimental animals, the possible role of chemical carcinogens in the induction of genetic abnormalities in human cancers has yet to be determined. Continuing investigations employing the methods of molecular epidemiology promise to provide further evidence concerning these relationships. Future investigations employing newly developed molecular biological methods, in particular those based on polymerase chain reaction amplification of DNA, to identify alterations in DNA and chromosomal structure, combined with methods for characterizing exposure to carcinogens and early effects, have great potential for further elucidating the role of genotoxic agents in the etiology of human cancers and also for the development of strategies for their prevention.
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PMID:Molecular epidemiology in cancer risk assessment and prevention: recent progress and avenues for future research. 148 46

Angiosarcomas of the liver are rare, malignant cancers composed of neoplastic blood vessels. Human hapatic angiosarcomas have been associated with liver cirrhosis or exposure to vinyl chloride, Thorotrast or arsenic. A recent analysis of six hepatic angiosarcomas associated with vinal chloride exposure found three mutations and all were A:T --> T:A transversions, which are otherwise uncommon in human cancers. To test the specificity of this mutation spectrum, we analyzed 21 hepatic angiosarcomas not associated with vinyl chloride exposure. Four cases were exposed to Thorotrast, none had a history of arsenic exposure and the rest were sporadic. Exons 5-8 of the p53 gene were amplified by polymerase chain reaction, and the products were sequenced directly. Two G:C --> A:T transitions were found in two tumors: TGCstop in codon 136. Neither mutation was associated with Thorotrast exposure. These data indicate that p53 mutations are uncommon in sporadic hepatic angiosarcomas (2/21, 9%), and the mutational profile is consistent with endogenous mechanisms. Both features support the evidence linking vinyl chloride exposure to hepatic angiosarcomas containing an increased frequency of p53 mutations with a mutational spectrum (i.e. A:T --> T:A transversions) characteristic of chloroethylene oxide, a carcinogenic metabolite of vinyl chloride.
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PMID:p53 mutations in primary hepatic angiosarcomas not associated with vinyl chloride exposure. 758 14

Mutations in the p53 tumor suppressor gene are commonly found in the major human cancers and the mutational spectrum in some cancer types is consistent with the genotoxic effects of the associated environmental risk factors. Thus far there is little information on p53 mutations in cancers of factory workers with a history of carcinogen exposure in the workplace. Occupational exposure to vinyl chloride causes liver angiosarcomas (ASL) and also increases the risk of several other cancers. Loss of p53 function in osteo- and fibrosarcomas can occur by two different mechanisms, p53 mutation and amplification of the MDM2 gene. We examined tumors from five vinyl chloride-exposed patients, four with ASL and one with hepatocellular carcinoma (HCC), for evidence of MDM2 proto-oncogene amplification or p53 mutation in exons 5-8. Amplification of MDM2 was not found, but in two of the angiosarcomas an A:T to T:A missense mutation was detected. p53 sequence analysis of vinyl chloride associated cancers may provide valuable information on the relationship between carcinogen exposure and DNA damage in cancer-related genes.
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PMID:p53 mutations at A:T base pairs in angiosarcomas of vinyl chloride-exposed factory workers. 829 34

The tumor suppressor gene p53 has been identified as the most frequent target of genetic alterations in human cancers. Vinyl chloride, a known human carcinogen that induces the rare sentinel neoplasm angiosarcoma of the liver, has been associated with specific A-->T transversions at the first base of codons 249 and 255 of the p53 gene. These mutations result in an Arg-->Trp amino acid substitution at residue 249 and an Ile-->Phe amino acid substitution at residue 255 in a highly conserved region in the DNA-binding core domain of the p53 protein. To determine the effects of these substitutions on the three-dimensional structure of the p53 protein, we have performed molecular dynamics calculations on this core domain of the wild-type and the Trp-249 and Phe-255 mutants to compute the average structures of each of the three forms. Comparisons of the computed average structures show that both mutants differ substantially from the wild-type structure in certain common, discrete regions. One of these regions (residues 204-217) contains the epitope for the monoclonal antibody PAb240, which is concealed in the wild-type structure but accessible in both mutant structures. In order to confirm this conformational shift, tumor tissue and serum from vinyl chloride-exposed individuals with angiosarcomas of the liver were examined by immunohistochemistry and enzyme-linked immunosorbent assay. Individuals with tumors that contained the p53 mutations were found to have detectable mutant p53 protein in their tumor tissue and serum, whereas individuals with tumors without mutations and normal controls did not.
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PMID:Conformational effects in the p53 protein of mutations induced during chemical carcinogenesis: molecular dynamic and immunologic analyses. 881 13

One of the challenges in environmental health is to attribute a certain health effect to a specific environmental exposure and to establish a cause-effect relationship. Molecular epidemiology offers a new approach to addressing these challenges. Mutations in the tumor suppressor gene p53 can shed light on past environmental exposure, and carcinogenic agents and doses can be distinguished on the basis of mutational spectra and frequency. Mutations in p53 have successfully been used to establish links between dietary aflatoxin exposure and liver cancer, exposure to ultraviolet light and skin cancer, smoking and cancers of the lung and bladder, and vinyl chloride exposure and liver cancer. In lung cancer, carcinogens from tobacco smoke have been shown to form adducts with DNA. The location of these adducts correlates with those positions in the p53 gene that are mutated in lung cancer, confirming a direct etiologic link between exposure and disease. Recent investigations have also explored the use of p53 as a susceptibility marker for cancer. Furthermore, studies in genetic toxicology have taken advantage of animals transgenic for p53 to screen for carcinogens in vivo. In this review, we summarize recent developments in p53 biomarker research and illustrate applications to environmental health.
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PMID:Molecular epidemiology in environmental health: the potential of tumor suppressor gene p53 as a biomarker. 911 84

The production of mutations in cellular tumor suppressor genes such as p53 is involved in the development of many human cancers. These mutations result in the expression of mutant forms of the encoded p53 protein which can potentially serve as a biomarker for this carcinogenic process. Workers exposed to vinyl chloride who are at risk for the development of the sentinel neoplasm angiosarcoma of the liver represent a model population for the study of such a mutant p53 biomarker, since vinyl chloride is known to cause specific p53 mutations in persons with angiosarcoma of the liver. To determine the relation between vinyl chloride exposure and this p53 biomarker, the authors examined serum samples collected between 1987 and 1992 from a cohort of 225 French vinyl chloride workers and 111 unexposed controls (matched according to age, sex, race, smoking, and alcohol drinking) for the presence of mutant p53 protein, using an enzyme-linked immunosorbent assay. Stratification of the exposed workers by quartile of vinyl chloride exposure (in estimated ppm-years) yielded a statistically significant trend of increasing odds ratios for p53 biomarker seropositivity with increasing exposure. These results suggest that this serum biomarker for mutant p53 protein is related to vinyl chloride exposure and may be an early indicator of carcinogenic risk in exposed individuals.
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PMID:Molecular epidemiology of p53 protein mutations in workers exposed to vinyl chloride. 948 5

Ethenobases are exocyclic adducts formed with DNA by some environmental carcinogens such as vinyl chloride or urethane. In the last few years, they have received a renewed interest due to the development of sensitive techniques of analysis that made it possible to measure their formation in vivo. This minireview summarizes the information gained recently from the work of several laboratories, including ours. Increased levels of DNA etheno adducts have been measured in target tissues from rodents exposed to vinyl chloride or urethane. Hepatic tumours caused by exposure to vinyl chloride in humans and in rats and lung tumours induced by urethane in mice exhibit base pair substitution mutations in the ras and p53 genes which seem to be exposure-specific and consistent with the promutagenic properties of ethenobases. Background levels of etheno adducts have been detected in DNA from non-exposed humans or animals, pointing to an alternative, endogenous pathway of formation. This background may be affected by dietary factors. It could arise from the reaction of trans-4-hydroxy-2-nonenal (or its epoxide 2,3-epoxy-4-hydroxynonanal), a lipid peroxidation product, with nucleic acid bases. Elevated levels of etheno adducts are found in hepatic DNA from humans and rodents with genetic predisposition to oxidative stress and lipid peroxidation in the liver, and with an associated increased risk of liver cancer. These data suggest that DNA ethenobases could serve as new biomarkers of oxidative stress/lipid peroxidation.
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PMID:Formation of DNA etheno adducts in rodents and humans and their role in carcinogenesis. 970 7

We have analysed liver angiosarcomas from individuals having been occupationally exposed to vinyl chloride (VC) to identify, in cancer-related genes, lesions which could be VC-specific. Two genetic alterations have been identified: the first one is a GGC --> GAT (Gly --> Asp, Asp13p21) mutation at codon 13 in the Ki-ras gene, found in five out of six tumors. The second one is an AT --> TA transversion in the p53 gene resulting in missense mutations at different codons and was found in three out of six tumors. By analysing both the tumors and sera from the same patients, we have shown that the Asp13p21 and mutant p53 proteins could be detected reliably in the serum. We thereafter analysed 225 serum samples, selected from a cohort of about 900 VC-exposed workers, for the presence of the two mutant proteins and p53 antibodies. A statistical analysis supports a strong dose-response relationship between the serum markers positivity and the VC-exposure. A follow-up of this cohort should now allow us to assert the predictive value of these markers.
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PMID:Critical genes as early warning signs: example of vinyl chloride. 1002 20

The events leading to cancer are complex and interactive. Alteration of cancer genes, such as the tumor suppressor gene p53, plays a central role in this process. Analysis of the frequency, type and site of mutations in important cancer-related genes may provide clues to the identification of etiological factors and sources of exposure. In this chapter we have selected a few examples of environmental human carcinogens and have attempted to use the knowledge of their mechanisms of mutagenesis, as derived from in vitro cell systems, as a key to understanding the complexity of p53 mutation spectra in tumors arising at the putative target organ. The analysis will focus on environmental exposure to UV radiation. The examples of tobacco smoke, dietary aflatoxin and vinyl chloride will be also briefly discussed.
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PMID:Mutation spectra resulting from carcinogenic exposure: from model systems to cancer-related genes. 1002 95

Chloroacetaldehyde (CAA) reacts with DNA bases, forming hydroxyethano derivatives of different stability, which are subsequently converted into etheno (epsilon) adducts: epsilon A, epsilon C, epsilon G. DNA polymerase fingerprint analysis was used to study the distribution of CAA-induced modifications in the p53 sequence. A plasmid bearing cDNA containing the human p53 gene was reacted in vitro with CAA, then dehydrated for conversion of hydroxyethano into etheno adducts, and primer extension by T7 DNA polymerase in the presence of four dNTPs was performed. The DNA repair enzymes methylpurine-DNA glycosylase and Escherichia coli exonuclease III were used to convert epsilon A residues in the template into DNA strand breaks, which enabled precise localization of the epsilon A residues within the p53 gene. Hydroxyethano derivatives of adenine and cytosine in a template blocked T7 DNA polymerase and caused premature chain termination opposite adenine or one base before cytosine. After dehydration, both epsilon A and epsilon C were much more easily by-passed by T7 DNA polymerase. Formation of epsilon G was identified as 'stop bands' one base before guanine residues. Modification of cytosine and guanine was additionally recognized by weakening or disappearance of non-specific stops on an undamaged template, probably due to steric hindrance by the tertiary DNA structure for polymerase. Etheno adduction of cytosine and guanine relaxed the compact DNA structure and enabled DNA polymerase to by-pass. In exons 5-8 of p53, 143 out of 500 sites appeared to be damaged by CAA, with four particularly densely modified regions between codons 135-147, 218-222, 234-255 and 284-292. The pattern of modification followed the pattern of p53 mutations found in vinyl chloride-associated liver angiosarcomas in humans and rats, but only in regions that showed 100% homology with the human sequence. The factors that influence DNA damage and induction of mutations in the p53 gene by CAA and vinyl chloride are discussed.
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PMID:Localization of chloroacetaldehyde-induced DNA damage in human p53 gene by DNA polymerase fingerprint analysis. 1062 28


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