Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of p53 function has been implicated in a wide variety of human malignacies. Many studies suggest that in cervical carcinoma p53 function is inactivated either by gene mutation or by complex formation with E6 oncoprotein product of high-risk human papillomavirus (HPV). The aim of this study was to determine the status of HPV infection and p53 gene mutation as well as their correlation in cervical carcinomas. Formalin-fixed paraffin-embedded tissues of 12 cervicitis, 21 cervical intraepithelial neoplasia grade 3 (CIN 3) and 17 squamous cell carcinomas were determined for the presence of HPV using polymerase chain reaction (PCR) amplification and dot blot hybridization. The status of p53 mutations in exons 5-8 was evaluated by polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) and confirmed by direct nucleotide sequencing. HPV infections were detected in all CIN 3 and squamous cell carcinomas (100%). Mutations of p53 were present in 3 of 38 HPV-positive samples: one with an ATG-->TTG transversion (Met-->Leu) in codon 237 of exon 7; and the others with a TGC-->TGG transversion (Cys-->Trp) in codon 242 of exon 7, and a CGT-->CCT transversion (Arg-->Pro) in codon 273 of exon 8, respectively. Our findings show that the frequency of p53 mutation is low in primary cervical carcinoma and that the p53 gene mutation and HPV infection are not mutually exclusive events in the development of cervical cancer. Thus, other genetic events independent of p53 inactivation may also significantly contribute to the carcinogenesis of the uterine cervix.
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PMID:p53 status and human papillomavirus infection in Thai women with cervical carcinoma. 1102 67

Preconceptional exposure of male NIH Swiss mice to chromium(III) chloride resulted in increased incidence of neoplastic and non-neoplastic changes in their progeny, including lung tumors in females [Toxicol. Appl. Pharmacol. 158 (1999) 161-176]. Since mutations in the K-ras protooncogene are frequent, early changes in mouse lung tumors, we investigated possible mutational activation of this gene as a mechanism for preconceptional carcinogenesis by chromium(III). These offspring had lived until natural death at advanced ages (average 816+/-175 days for controls, 904+/-164 for progeny of chromium-treated fathers). Mutations of K-ras, analyzed by single-strand conformation polymorphism and sequencing, were, in codon 12, wild type GGT (glycine), to GAT (aspartic acid); to GTT (valine); and to CGT (arginine); and in codon 61, wild-type CAA (glutamine), to CGA (arginine). K-ras mutation frequencies in lung tumors were very similar in control progeny (4/14) and in progeny of chromium-treated fathers (5/15). Thus, germline mutation or tendency to spontaneous mutation in K-ras does not seem to be part of the mechanism of preconceptional carcinogenesis here. However, an additional interesting observation was that K-ras mutations were much more frequent in lung carcinomas (8/16) than in adenomas (1/13) (P=0.02), for all progeny combined. This was not related to age of the tumor-bearing mice or the size of the tumors. K-ras mutations may contribute to malignant tumor progression during aging, of possible relevance to the putative association of such mutations with poor prognosis of human lung adenocarcinomas.
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PMID:K-ras mutations in mouse lung tumors of extreme age: independent of paternal preconceptional exposure to chromium(III) but significantly more frequent in carcinomas than adenomas. 1115 72

Tumor multicentricity is occasionally observed in esophageal squamous cell carcinoma (SCC). We studied five surgically resected superficial multifocal esophageal SCCs for p53 gene mutation and genetic instability, using DNA extracted from microdissected areas. A total of 38 target areas (TAs) were analyzed in SCC, dysplasia, basal cell hyperplasia (BCH) and normal squamous epithelium. Analysis of the replication error (RER) at 10 microsatellite loci showed microsatellite instability in all TAs, as well as in normal squamous epithelium. p53 gene mutation was identified in 28.9% (11/38 TAs). All cases showed a common missense mutation in exon 8 at codon 273 (CGT-->CAT, Arg-->His), which was DNA contact mutation in the S10 beta strand. In association with microsatellite alterations, 7 of 9 TAs with p53 mutation in exon 8 at codon 273 also showed loss of heterozygosity (LOH) of p53 gene. LOH of p53 gene was detected in 83.8% (31/37 TAs). LOH at D2S123 on 2p16 near MSH2 gene and at D3S1611 on 3p22 near MLH1 gene was detected in 65.4% (17/26) and 71.4% (10/14) TAs, respectively. Frequencies of LOH at p53 and D2S123 were similar in non-cancerous areas and SCCs. LOH of p53 and D2S123 were found in 50% (5/10 TAs) of non-cancerous areas and 60% (9/15 TAs) of SCCs. Our results suggest that genetic instability induces esophageal tumor multicentricity, and that p53 gene contact mutation together with LOH are early events of the multistage carcinogenesis of multifocal primary esophageal SCC.
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PMID:p53 Gene mutation and genetic instability in superficial multifocal esophageal squamous cell carcinoma. 1189 9

Leukemia, a form of haematological malignancy, is a multi-stage disease and a wide range of diverse genes has been speculated to correlate with its initiation and development. Ras has been speculated to be an initiating gene for haematological malignancy, but more investigation will be needed to determine the genes associated with the progression of the disease. 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat leukemia provides a good tool for research into various stages of the disease. The entire coding regions of p53 and ras genes were examined for mutations in the present study. In this experiment, we used fluorescence-labeled polymerase chain reaction single-stranded conformation polymorphism analysis (PCR-SSCP) and direct sequencing to detect mutations of both genes on rat erythroleukemia. Fifteen out of 18 (83.3%) rat leukemias were found to have N-ras codon 61 mutation, consistent with previous results. The result of direct sequencing showed a single base substitution (CAA to CTA), resulting in an amino-acid change from Gln to Leu. No mutations were found in H-ras, K-ras or codon 12 of N-ras. The incidence of p53 gene mutation was 16.6% (3/18) in rat leukemia at late-stage. In the present study, mutation of the p53 gene was detected in three DMBA-induced leukemias as follows: a single-base substitution (CAT to CGT) at codon 177 (exon 5), resulting in an amino-acid change from Arg to Leu, a CGG to CTG/CGG changed at codon 211 (exon 6) resulting in an amino-acid change from His to Arg/His, and a GGG to TGG at codon 242 (exon 6) resulting in an amino-acid change from Gly to Trp, respectively. Thus, mutations of p53 gene do not seem to respond to the carcinogenesis of the DMBA-induced leukemia, in contrast to mutation of the N-ras oncogene, and may possibly be involved in the progress of multi-stage leukemogenesis.
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PMID:Incidence of p53 and ras gene mutations in DMBA-induced rat leukemias. 1238 83

Diesel exhaust (DE) is a major airborne pollutant of urban areas. It contains various polycyclic aromatic hydrocarbons (PAH) and nitrated PAHs. In this study, gpt delta mice were treated with inhalation of 1 or 3 mg m(-3) DE, or a single intratracheal instillation of diesel exhaust particles (DEP) or DEP extract. In the lungs of mice treated with inhalation of 3 mg m(-3) DE for 12 weeks, the mutant frequency (MF) was 3.2-fold higher than that of the control group (1.90 x 10(-5) and 0.59 x 10(-5), respectively). An instillation of DEP and DEP extract resulted in a significant dose-dependent linear increase in MF. In mice treated with 0.5 mg DEP and 0.2 mg DEP extract, the MFs were 3.0- and 2.7-fold higher than that of the control group, respectively. The mutagenic potency (MF mg(-1)) of DEP extract (5.6 x 10(-5)) was double that of DEP (2.7 x 10(-5)), suggesting that the mutagenicity of the latter is derived primarily from compounds in the extract, which itself is responsible for ca. 50% of the weight of DEP. G:C-->A:T transitions were the predominant gpt mutation induced by all three treatments and G:C-->T:A transversions were induced by DEP and DEP extract. Guanine bases centered in nucleotide sequences such as GGA, TGA, CGG, and CGT were the major mutation targets of all three treatments. Thus, our results suggest that the mutagens contained in DEP such as PAH and nitrated PAHs induce mutations and may be responsible for carcinogenesis caused by inhalation of DE.
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PMID:Mutations in the lungs of gpt delta transgenic mice following inhalation of diesel exhaust. 1789 90

Sunlight and ultraviolet-induced mutation of the p53 gene is a frequent, possibly obligate step in skin cancer development, making quantitative measurement of p53 mutation an ideal biomarker for sunlight-induced skin carcinogenesis. To understand how the appearance of p53 mutation relates to skin tumor development, SKH-1 hairless mice were exposed 5 d per week to one of four different doses of simulated solar light (SSL; 0, 6.85, 13.70, 20.55 mJ x CIE/cm(2)) previously characterized for their tumorigenic potential. Allele-specific competitive blocker-PCR (ACB-PCR) was used to measure levels of p53 codon 270 CGT to TGT mutation within DNA isolated from dorsal skin of exposed mice. For each dose, p53 mutant fraction (MF) was measured after 4, 16, and 28 wk of exposure. Significant dose- and time-dependent increases in p53 MF were identified. All p53 MF measurements were integrated by relating the observed p53 MF to the cumulative dose of SSL. The increase in the logarithm of p53 MF was described by the linear function: log(10) MF = alpha + 0.0016 x d, where alpha is the spontaneous log(10) MF after a particular time point and d is the dose of SSL in mJ x CIE/cm(2). The p53 MF induced in nontumor bearing skin by 28 wk of exposure at the high dose of SSL was significantly lower than that found in skin tumors induced by approximately 32 wk of exposure to the same dose of SSL. p53 MF showed a strong negative correlation with tumor latency, suggesting this quantitative biomarker has the potential to predict tumorigenicity.
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PMID:Simulated solar light-induced p53 mutagenesis in SKH-1 mouse skin: a dose-response assessment. 1831 77

The p53 codon 270 CGT to TGT mutation was investigated as a biomarker of sunlight-induced mutagenesis and carcinogenesis. The relationship between tumor development and abundance of this hotspot mutation was analyzed in mouse skin tumors induced by chronic exposure to simulated solar light (SSL). The 24 tumors analyzed had similar growth kinetics, with an average doubling time of approximately 16.4 d. Levels of the p53 codon 270 mutation were quantified in the 24 mouse skin tumors using allele-specific competitive blocker-polymerase chain reaction (ACB-PCR). All tumors contained measurable amounts of the mutation. The p53 codon 270 CGT to TGT mutant fraction (MF) ranged from 2.29 x 10(-3) to 9.42 x 10(-2), with 3.26 x 10(-2) as the median. These p53 MF measurements are lower than expected for an initiating mutation involved in the development of tumors of monoclonal origin. There was no evidence of a correlation between p53 codon 270 MF and either tumor area or an estimate of tumor cell number. Thus, the data do not support the idea that p53 mutation accumulates linearly during tumor development. To investigate how p53 mutation was distributed within tumors, 19 needle biopsies from seven different tumors were analyzed by ACB-PCR. This analysis demonstrated that p53 codon 270 mutation is heterogeneously distributed within tumors. The long-term goal of this research is to combine morphological and p53 MF measurements from tissues corresponding to the various stages of tumor development, in order to derive mathematical models relating the p53 codon 270 mutation to the development of SSL-induced skin tumors.
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PMID:Populations of p53 codon 270 CGT to TGT mutant cells in SKH-1 mouse skin tumors induced by simulated solar light. 1838 87

Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis in the process of tumor growth and metastasis in esophageal adenocarcinoma (EA). Polymorphisms in the VEGF gene have been associated with altered VEGF expression and plasma VEGF levels. We hypothesized that polymorphisms of VEGF may contribute to EA risk. Functional polymorphisms in the VEGF gene (-460C/T, +405C/G and +936C/T) were determined in 308 patients with EA and 546 healthy controls. Logistic regression analysis was employed to assess the associations between genotypes, haplotypes of VEGF and EA risk, adjusting for multiple confounding factors. Compared with the +936CC genotype, the combined +936CT+TT genotypes were significantly associated with increased risk of developing EA, with adjusted odds ratio (OR) = 1.49 [95% confidence interval (CI), 1.05-2.12; P = 0.027]. The -460CT+CC were associated with increased risk of EA in smokers (adjusted OR = 1.57; 95% CI, 1.07-2.30; P = 0.021), whereas the -460CT/CC were associated with decreased risk of EA (adjusted OR = 0.47; 95% CI, 0.25-0.91; P = 0.025) in non-smokers. Compared with non-smokers with the +460TT, smokers with the +460CT+CC had significantly higher risk of EA (adjusted OR = 3.32; 95% CI, 1.56-7.10; P = 0.002). No overall or interacting association with EA risk was found for the +405C/G polymorphism. Haplotype CGT (-460C/+405G/+936T) was significantly associated with higher risk of EA (adjusted OR = 1.70; 95% CI, 1.04-2.73; P = 0.034). These results suggested that cigarette smoking modifies the association between VEGF polymorphisms and EA risk among Caucasians.
Carcinogenesis 2008 Dec
PMID:Genetic polymorphisms of VEGF, interactions with cigarette smoking exposure and esophageal adenocarcinoma risk. 1878 Aug 93

Human papillomavirus (HPV) is considered to be a major etiological factor but is not sufficient for the development of cervical cancer. Other host factors including altered tumor suppressor gene activities might contribute to the carcinogenic process. Fragile Histidine Triad (FHIT) has been shown to play a pivotal role in carcinogenesis. Therefore, we made an attempt to find out point mutation of FHIT gene in HPV mediated cervical cancer in Indian women. 112 cases of cervical carcinoma tissue biopsies and 38 cervical scrapes samples of normal cytology were employed for this study. Herein, we report a novel mutation identified at nucleotide position 655, at codon 98 from CAT --> CGT with ultimate replacement of amino acid Histidine by Arginine in cervical cancer cases. Molecular modeling was performed to predict the effect of this mutation in disease pathology. We predict that this change, His to Arg substitution in substrate-binding domain may generate catalytically inactive protein with loss of tumor suppressor activity.
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PMID:Novel missense mutation in FHIT gene: interpreting the effect in HPV-mediated cervical cancer in Indian women. 1973 Sep 90

This study examined the potential induction of tumor-associated mutations in formaldehyde-exposed rat nasal mucosa using a sensitive method, allele-specific competitive blocker-PCR (ACB-PCR). Levels of p53 codon 271 CGT to CAT and K-Ras codon 12 GGT to GAT mutations were quantified in nasal mucosa of rats exposed to formaldehyde. In addition, nasal mucosa cell proliferation was monitored because regenerative cell proliferation is considered a key event in formaldehyde-induced carcinogenesis. Male F344 rats (6-7 weeks old, 5 rats/group) were exposed to 0, 0.7, 2, 6, 10, and 15 ppm formaldehyde for 13 weeks (6 h/day, 5 days/week). ACB-PCR was used to determine levels of p53 and K-Ras mutations. Although two of five untreated rats had measureable spontaneous p53 mutant fractions (MFs), most nasal mucosa samples had p53 MFs below 10(-5). All K-Ras MF measurements were below 10(-5). No dose-related increases in p53 or K-Ras MF were observed, even though significant increases in bromodeoxyuridine incorporation demonstrated induced cell proliferation in the 10 and 15 ppm formaldehyde-treatment groups. Therefore, induction of tumor-associated p53 mutation likely occurs after several other key events in formaldehyde-induced carcinogenesis.
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PMID:Measurement of tumor-associated mutations in the nasal mucosa of rats exposed to varying doses of formaldehyde. 2034 9


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