RESUMO
Extremely high rates of squamous cell carcinoma of the esophagus (SCCE) are observed in Iran, reflecting unknown, genetic and/or epidemiological risk factors. Among genetic alterations in SCCE, TP53 mutations are the most frequent, vary among populations, and may provide clues on etiological mechanisms. We have analysed mutations in TP53 (exons 5-8) in 98 SCCE from Iran by temporal temperature gel electrophoresis and direct sequencing. We found 58 mutations in 49 patients (50%), with a high prevalence of C to T transitions at CpG dinucleotides (29.3%). The TP53 mutation pattern in Iran was significantly different from that observed in SCCEs from high incidence areas of China and Western Europe (P=0.007). Moreover, the prevalence of mutations at A : T base pairs (transitions and transversions) was higher in men than in women (38.7% vs 11.1%, P=0.033). COX-2 overexpression was detected in 69% of the cases evaluated (24/35), without significant association with TP53 mutation. Accumulation of nitrotyrosine, a marker of protein damage by excess levels of nitric oxide, was observed in tumor cells in six of 18 [corrected] cases analysed. These results are consistent with the hypothesis that several factors are involved in TP53 mutagenesis in Iran. These factors include a baseline of chronic inflammatory stress, which may have a multiplicative impact on the sensitivity of esophageal cells to exogenous factors of risk.
Assuntos
Carcinoma de Células Escamosas/genética , DNA de Neoplasias/genética , Neoplasias Esofágicas/genética , Genes p53 , Mutação , Tirosina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/etiologia , China/epidemiologia , Doença Crônica , Códon/genética , Códon sem Sentido , Ilhas de CpG , Ciclo-Oxigenase 2 , Análise Mutacional de DNA , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/etiologia , Esofagite/complicações , Europa (Continente)/epidemiologia , Éxons/genética , Feminino , Mutação da Fase de Leitura , Humanos , Incidência , Irã (Geográfico)/epidemiologia , Isoenzimas/análise , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Óxido Nítrico/biossíntese , Mutação Puntual , Prostaglandina-Endoperóxido Sintases/análise , Fatores de Risco , Análise de Sequência de DNA , Tirosina/análiseRESUMO
Two hundred liters of drinking water of the city of Tehran were collected as tap water in a glass container and passed through a XAD-2 resin column at a flow rate of 60-100 ml/minute. The adsorbed materials were eluted with acetone, dried and dissolved in 2 ml dimethylsulfoxide (DMSO). Doses up to 10 microliters did not elevate sister chromatid exchanges (SCE) in CHO fibroblasts, while 20 microliters caused a significant increase in SCE. However, this dose did not show any chromosomal aberration (CA) in V79 fibroblasts. Doses up to 50 microliters of the extract did not increase his+ spontaneous revertant colonies in Salmonella typhimurium tester strain TA98, TA100 and TA102 in the absence of S9 metabolizing mixture, neither induced DNA alkaline labile sites in V79 fibroblasts.
