RESUMO
In an attempt to correlate the TP53 mutation pattern of squamous cell carcinomas of the esophagus (ESCC) and life style factors of patients from the high risk area Rio Grande do Sul, Brazil, 135 ESCC were analyzed, after prescreening by p53 immunohistochemistry, by SSCP and DNA sequencing of TP53, exon 5-9. Forty-nine somatic TP53 mutations (and 1 case with p53 polymorphism) were identified as missense (n = 39), frameshift (n = 6), silent (n = 1), amber (n = 1) or intron border mutations (n = 2) that cause splicing aberrations. They were preferentially found in exon 5 (36.7%) and exon 8 (32.7%). Several mutations were located in the mutation hot spot codons 248, 273 and 282, mainly at CpG sites. Transition mutations were observed in 53.1% (among them 50% G > A), transversion mutations in 34.7% (among them 47.1% G > T) and frameshifts in 12.2%, the latter 2 mainly in smokers and alcohol drinkers. Transitions were more prevalent in females than in males (p < 0.05). TP53 mutations, mainly transversions, were more frequently found in heavy smokers (p = 0.03), with the same tendency after chronic alcohol consumption. Comparison with the worldwide IARC database disclosed differences in the TP53 mutation pattern of the Brazilian tumors, with a higher accumulation of TP53 mutations in exon 8 and a higher prevalence of transition mutations. Mutations at the reported hot spot codon 176 were missing. Although difficult because of the documented coexposure to various life style risk factors in most patients of this series, the hypothesis is proposed that besides smoking and alcohol drinking the commonly consumed hot mate tea in this high risk area for ESCC is responsible for this different pattern of TP53 mutations because of chronic hyperthermic irritation and inflammation in the esophagus with an endogenous formation of radicals or carcinogenic factors that lead to a higher prevalence of transition mutations.
Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Genes p53 , Estilo de Vida , Mutação , Adulto , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Carcinoma de Células Escamosas/etiologia , Neoplasias Esofágicas/etiologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Nitrosaminas/toxicidade , Fatores de Risco , Fumar/efeitos adversos , Proteína Supressora de Tumor p53/análiseRESUMO
A proliferaçäo celular é um fator importante para a maior suscetibilidade a transformaçäo maligna da célula. Altas taxas de proliferaçäo de hapatócitos podem ser obtidas através de hepatectomia parcial. Com o uso de hidroxiuréia, uma populaçäo celular em proliferaçäo pode ser bloqueada na transiçäo da fase G1 para a fase de síntese. Este artifício permite obter altas taxas de sincronizaçäo celular em fígado de rato após hepatectomia e possibilita experiências com cancerígenos em fases específicas do ciclo celular. Com a finalidade de verificar o surgimento de tumores e de lesöes pré-neoplásicas no fígado de ratos submetidos a exposiçäo repetida de cancerígeno em uma mesma fase do ciclo celular, ratos Wistar foram submetidos a hepatectomia parcial e sincronizaçäo celular com hidroxiuréia. Dietilnitrosamina foi injetada por via intraperitonial na fase G1, quatro horas após a hepatectomia, e uma hora após a perfusäo continuada de dez horas com hidroxiuréia, na fase de síntese de DNA. Houve predomínio significante do surgimento de lesöes pré-neoplásicas e de tumores nos animais injetados com o cancerígeno na fase de síntese.