RESUMEN
Epidemiological studies of underground miners suggested that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P = 0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (odds ratio = 1.69, P = 8.2 × 10(-5)) and greater survival in SCC cases (hazard ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggest that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners.
Asunto(s)
Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Minería , Neoplasias Inducidas por Radiación/genética , Enfermedades Profesionales/genética , Sirtuina 1/genética , Uranio/envenenamiento , Alelos , Carcinoma de Células Escamosas/etiología , Estudios de Casos y Controles , Colorado , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Neoplasias Pulmonares/etiología , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias Inducidas por Radiación/etiología , Enfermedades Profesionales/etiología , Exposición Profesional/efectos adversos , Polimorfismo de Nucleótido Simple , Radón/envenenamientoRESUMEN
One promising approach for early detection of lung cancer is by monitoring gene promoter hypermethylation events in sputum. Epidemiologic studies suggest that dietary fruits and vegetables and the micronutrients they contain may reduce risk of lung cancer. In this study, we evaluated whether diet and multivitamin use influenced the prevalence of gene promoter methylation in cells exfoliated from the aerodigestive tract of current and former smokers. Members (N = 1,101) of the Lovelace Smokers Cohort completed the Harvard Food Frequency Questionnaire and provided a sputum sample that was assessed for promoter methylation of eight genes commonly silenced in lung cancer and associated with risk for this disease. Methylation status was categorized as low (fewer than two genes methylated) or high (two or more genes methylated). Logistic regression models were used to identify associations between methylation status and 21 dietary variables hypothesized to affect the acquisition of gene methylation. Significant protection against methylation was observed for leafy green vegetables [odds ratio (OR) = 0.83 per 12 monthly servings; 95% confidence interval (95% CI), 0.74-0.93] and folate (OR, 0.84 per 750 microg/d; 95% CI, 0.72-0.99). Protection against gene methylation was also seen with current use of multivitamins (OR, 0.57; 95% CI, 0.40-0.83). This is the first cohort-based study to identify dietary factors associated with reduced promoter methylation in cells exfoliated from the airway epithelium of smokers. Novel interventions to prevent lung cancer should be developed based on the ability of diet and dietary supplements to affect reprogramming of the epigenome.