RESUMEN
Lung cancer is the most common malignancy in the Western world, and the main risk factor is tobacco smoking. Polymorphisms in metabolic genes may modulate the risk associated with environmental factors. The glutathione S-transferase theta 1 gene (GSTT1) is a particularly attractive candidate for lung cancer susceptibility because of its involvement in the metabolism of polycyclic aromatic hydrocarbons found in tobacco smoke and of other chemicals, pesticides, and industrial solvents. The frequency of the GSTT1 null genotype is lower among Caucasians (10-20%) than among Asians (50-60%). The authors present a meta- and a pooled analysis of case-control, genotype-based studies that examined the association between GSTT1 and lung cancer (34 studies, 7,629 cases and 10,087 controls for the meta-analysis; 34 studies, 7,044 cases and 10,000 controls for the pooled analysis). No association was observed between GSTT1 deletion and lung cancer for Caucasians (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.87, 1.12); for Asians, a positive association was found (OR = 1.28, 95% CI: 1.10, 1.49). In the pooled analysis, the odds ratios were not significant for either Asians (OR = 0.97, 95% CI: 0.83, 1.13) or Caucasians (OR = 1.09, 95% CI: 0.99, 1.21). No significant interaction was observed between GSTT1 and smoking on lung cancer, whereas GSTT1 appeared to modulate occupational-related lung cancer.
Asunto(s)
Glutatión Transferasa/genética , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Pueblo Asiatico/estadística & datos numéricos , Estudios de Casos y Controles , Interpretación Estadística de Datos , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Glutatión Transferasa/fisiología , Humanos , Neoplasias Pulmonares/etnología , Polimorfismo Genético , Factores de Riesgo , Fumar/efectos adversos , Población Blanca/estadística & datos numéricosRESUMEN
In order to detect the contribution of cytochrome P450 1A1 (CYP1A1), aryl hydrocarbon receptor (AhR), glutathione S-transferases M1 (GSTM1), P1 (GSTP1), and T1 (GSTT1) genes in breast cancer, genetic analysis was performed, as well as transcriptional analysis in sporadic primary tumours and corresponding adjacent normal tissues from the same patient. CYP1A1 3'-untranslated region (3'-UTR) termed as m1 (MspI) polymorphism and the null(-) deletions of both GSTM1 and GSTT1 genes were examined in genomic DNA from blood samples of 207 female breast cancer patients and 171 age and sex matched controls. The frequencies of the m1 genotype of the CYP1A1 gene in cases and controls were 0.13 and 0.15, while the frequencies of homozygotes with GSTM1(-) were 0.52, in each, and for homozygotes with GSTT1(-) were 0.14 and 0.10, respectively. Statistical analysis of these genotypes in combinations did not reveal any significant difference between the breast cancer population and the control group. Expression of mRNA levels of CYP1A1, GSTM1, GSTP1, GSTT1 and AhR genes in 31 breast cancer patients, revealed inter-individual variation in an independent manner to patient age, genotype, or tumour stage. Eighty-seven percent of the tumour specimens tested were deregulated, compared to their normal counterparts, in at least one locus. Up-regulation of CYP1A1 was observed only when one of the GSTM1 or GSTP1 was down-regulated while the other remained constant. Genotyping analysis did not show any correlation to breast cancer risk. However, RT-PCR analysis provided evidence that CYP1A1, AhR, GSTM1, GSTP1 and GSTT1 genes are frequently deregulated in breast cancer and could be used as molecular biomarkers for better clinical management of such patients, with respect to chemotherapy.