This proposal is built upon an ongoing population-based case-control study on marijuana use and the risk of lung and UAT cancers funded by NIH. The objectives are to better understand the molecular mechanisms for the risk of lung cancer. We propose that the development of lung cancer is an interactive process involving previous environmental exposures such as active and passive tobacco smoking, marijuana smoking; intrinsic host susceptibility such as polymorphisms and methylations of the GST P1 and polymorphisms of the TP53 gene and genetic instability including TP53 and mutations and p16 methylations an and other alterations. The study will be based on 600 cases and 600 controls interviewed by the parent study. Among those, we project 420 lung cancer patients with have their tumor tissue available for the analysis and 488 case and 488 controls will have their buccal cell samples for this proposed study, according to our pilot study. Epidemiological factors will be obtained by face-to-face interview. Our study is designed Our study is designed to fulfill these specific aims. (1) We will assay polymorphisms and hypermethylations of GST P1 in 488 cases and 488 controls, to evaluate will have their buccal cell samples for this proposed study, according to our pilot study. Epidemiological factors will be obtained by face-to-face interview. Our study is designed to fulfill these specific aims. (1) We will assay polymorphisms and hypermethylations of GST P1 in 488 cases and 488 controls, to evaluate the effects of those alterations on the risk of lung cancer, and explore gene-environment interaction between GSTP1 and environmental exposures. Other metabolic genes involved in PAH metabolism such as GSTM1 and P450A1 will be assayed. (2) We will measure polymorphisms of TP53 gene in 488 cases and 488 controls and examine the effects of polymorphisms of TP53 gene by a case-control study. We will measure TP53 mutations by PCR-SSCP and sequencing to test the hypothesis that cases with lung cancer with and without p53 mutations are etiologically distinctive groups with regard to major risk factors such as active and passive tobacco smoking, occupational exposure, etc. (3) We will measure p16 methylations and other alterations including mutations, homozygous deletions, and microsatellite instability, and correlate these alterations with tobacco smoking and occupational exposures. The result of this study may provide insight into lung carcinogenesis. It may assist us to identify high-risk individuals for intervention and may have translational potential to screening, early detection and prognostic prediction.
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