A Molecular Epidemiological Study On The Association Of Polymorphisms In DNA Double-strand Break Repair Gene XRCC4 And Environmental Factors With The Risk Of Lung Cancer

[Objectives]To explore the main risk factors of lung cancer and study the independent and interaction effects of polymorphisms in DNA double-strand break repair gene XRCC4 and environmental factors to the development of lung cancer. The study is expected to provide the scientific basis for the prevention of lung cancer.[Methods]1. A case-control study was designed with 781 lung cancer patients and 1 control for each patient. Patients with histologically confirmed lung cancer were recruited in 3 main hospitals (The first affiliated hospital of Fujian medical university, Union hospital and Fuzhou general hospital) in Fuzhou from December 2006 to January 2010. Controls were selected from the visitors of participating hospital and designated communities, matched to the cases on age(±3)and gender. Eligible subjects were personally interviewed using a questionnaire.5 ml blood sample was collected from each patient; Saliva was collected from control by The Oragene DNA self-collection Kit and saliva samples were preserved in room-temperature. Buccal cell samples provided by other controls were preserved in 4℃. The genomic DNA was extracted from all samples.2. PCR-RFLP and TaqMan(?) probes were applied to determine the genotype of selected subjects.3. The construction of XRCC4 promoters with different genotype of rs6869366 was finished by using PCR combined the technology of site-directed mutagenesis. The effects of DNA mutation on promoters' activity were evaluated by dual-luciferase(?) reporter assay system.4. Epidata 3.1 was used to set data bank and SPSS 15.0 for statistical analysis. PHASE 2.1 software and HAPLO.STAT were used to estimate haplotype frequencies and LDA software for the analysis of linkage disequilibrium. [Results]1. The risk factors of lung cancer included:polluted factory near the living place, insufficient ventilation, kitchen fumes, use grain bin, smoke over 30 pack-year, Second-hand smoke (at home and workplace), the history of pulmonary operation, irritant smell after decoration, use of pesticide and introversive character. The protective factors of lung cancer included:frequent intake of fruits(>3times/week), light tea drinking, moderate labor intensity and frequent exercise(10 years ago).2. The analysis of XRCC4 polymorphisms with susceptibility to lung cancer suggested that the G/G or G/T genotype of rs6869366 presented significant risk of developing lung cancer. But no association between the SNP rs3734091, rs1056503 and lung caner were observed.3. The linkage disequilibrium between rs6869366 and rs3734091 were obser ved.Haplotype frequencies analysis showed that Hap3-GC(OR=1.933,95%CI=1.1 94-3.329) were associated with a significantly elevated risk of lung cancer,com pared with Hapl-TC. Dihaplotype analysis suggested that the individualswith T C/GC dihaplotype have a 1.922-fold(95%CI=1.170-3.393) excess risk of lung cancer, compared with individuals with TC/TC dihaplotype.[Conclusion]1. The environmental pollution, active and passive smoking, the exposure to pesticide and unhealthy life style were identified as the risk factors of lung c ancer.2. The polymorphisms of XRCC4 are associated with the susceptibility of lung cancer.