Gene-environment interaction is a seminal concept in the molecular epidemiology of human cancer. Our case-control (using hospital- and population-based controls) studies focus on lung cancer, a tobacco-related cancer. Exposure to second-hand tobacco smoke has many detrimental health effects, one of which is an increased lung cancer risk, and children may be more susceptible to the health hazards of second-hand smoke. Furthermore, alterations in the genetic background of innate immunity genes may further increase their susceptibility to lung cancer. Therefore, we hypothesized that never smokers, with specific mammose-binding lectin (MBL2) haplotypes predictive of high serum MBL levels, who are exposed to childhood second-hand smoke, may be more susceptible to developing lung cancer. We utilized the NCI-Maryland Lung Cancer Case-Control Study to investigate the association between childhood second-hand smoke and lung cancer risk. We found that the lung cancer among never smokers and among participants was associated with exposure to second-hand smoke during childhood. The MBL2 HYPA haplotype (high MBL secretor phenotype) was associated with lung cancer risk among those exposed to childhood second-hand smoke. These results were validated with an independent case-control study of never smokers from the Mayo Clinic. Cell cycle checkpoints play critical roles in the maintenance of genomic integrity and inactivation of checkpoint genes, and are frequently perturbed in most cancers. In a case-control study of 299 non-small cell lung cancer cases and 550 controls in Maryland, we investigated the association between gamma-radiation-induced G2/M arrest in cultured blood lymphocytes and lung cancer risk, and examined genotype-phenotype correlations between genetic polymorphisms of 20 genes involved in DNA repair and cell cycle control and gamma-radiation-induced G2/M arrest. The study was specifically designed to examine race and gender differences in risk factors. Our data indicated that a less efficient DNA damage-induced G2/M checkpoint was associated with an increased risk of lung cancer in African American women with an adjusted odds ration (OR) of 2/63 (95% CI= 1.01 - 7.26);there were no statistically significant associations for Caucasians or African American men. When the African American women were categorized into quartiles, a significant reverse trend of decreased G2/M checkpoint function and increased lung cancer risk was present, with lowest-vs-highest quartile OR of 13.72 (95% CI = 2.30 - 81.92, P trend less than 0.01). Genotype-phenotype correlation analysis indicated the polymorphisms in ATM, CDC25C, CDKN1A, BRCA2, ERCC6, TP53, and TP53BP1 genes were significantly associated with the gamma-radiation-induced G2/M arrest phenotype. This study provides evidence that a less efficient G2/M checkpoint is significantly associated with lung cancer risk in African American women. The data also suggested that the function of the G2/M checkpoint is modulated by genetic polymorphisms in genes involved in DNA repair and cell cycle control. This is the first study to observe an association between functional polymorphisms in an innate immune system gene and lung cancer survival.
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