RESUMO
NQO1 is an antioxidant enzyme, important in the detoxification of environmental carcinogens. A single nucleotide polymorphism (C-->T) at position 609 of the NQO1 cDNA has been associated with susceptibility to tumours induced by chemical carcinogens. In our case-control study, we determined the prevalence of the C609T NQO1 polymorphism by PCR-RFLP analysis in Caucasian patients with oesophageal adenocarcinoma (OAC; n=61), cardiac adenocarcinoma (CAC; n=120) or gastric adenocarcinoma (GAC; n=203) vs. a control group that consisted of 252 healthy blood donors. Additionally, NQO1 mRNA expression and NQO1 protein expression were determined by RT-PCR and immunohistochemistry in a subset of cases. The NQO1 C609T genotype distribution was significantly different among controls (C/C, 73.4%; C/T, 25.0%; T/T, 1.6%) as compared to OAC patients (C/C, 49.2%; C/T, 47.5%; T/T, 3.3%; p=0.0004), CAC patients (C/C, 55.8%; C/T, 40.0%; T/T, 4.2%; p=0.0005) and with GAC patients (C/C, 65.5%; C/T; 30.6%, T/T; 3.9%; p=0.0377). The 609T allele overall frequency was 0.141 in controls, 0.270 in OAC patients, 0.241 in CAC patients and 0.192 in GAC patients. Individuals carrying 1 or 2 609T alleles had a 2.85-fold higher risk (95% CI: 1.61-5.07; p=0.0003) for the development of OAC and a 2.18-fold higher risk (95% CI: 1.38-3.44; p=0.0007) for the development of CAC than wild-type gene homozygotes. Immunohistochemical analysis showed NQO1 protein expression in 133 carcinomas, whereas 17 carcinomas were negative. Negativity for NQO1 protein expression correlated strongly with the NQO1 genotype being present in 3.9% of cases with C/C, 13.9% of cases with C/T and 62.5% of cases with T/T genotype (p<0.001). In contrast, NQO1 mRNA expression was detectable irrespective of underlying genotype. In conclusion, determination of the NQO1 genotype may gain importance as a stratification marker in future prevention trials for adenocarcinoma of upper gastrointestinal tract.
Assuntos
Adenocarcinoma/genética , Neoplasias Esofágicas/genética , NAD(P)H Desidrogenase (Quinona)/genética , Mutação Puntual , Polimorfismo Genético , Neoplasias Gástricas/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Refluxo Gastroesofágico/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , RNA Mensageiro/análiseRESUMO
BACKGROUND: The proto-oncogene c-myc is known to be involved in the regulation of proliferation, apoptosis and cell differentiation. MATERIALS AND METHODS: Amplification of c-myc was determined by means of differential PCR in 77 surgically treated stage I or II oesophageal squamous cell carcinomas (SCC) as well as in 43 locally advanced SCC (cT3-4 cN0-1 cM0) treated by radiochemotherapy and facultatively by surgery. The findings were correlated to overall survival and to response to radiochemotherapy. RESULTS: C-myc gene amplification was present in 8 out of 77 surgically treated SCC (10.4%) and in 13 out of 43 multimodally treated SCC (30.2%). Among the surgically treated tumours, the presence of c-myc amplification was correlated with high proliferative activity (p = 0.0399) but not with overall survival. Among the multimodally treated SCC, c-myc amplification tended to be correlated with response to chemotherapy and response to radiochemotherapy (not significant) whereas no impact on overall survival was found. CONCLUSION: Amplification of c-myc is found more frequently in advanced stages of oesophageal SCC than in early stages. C-myc amplification, however, does not influence the overall survival of oesophageal SCC patients treated either by surgery alone or by multimodal therapy.
