While lung cancer is the most common fatal cancer in most populations of the world, the mechanisms by which tobacco smoke or other carcinogens cause lung cancer and the genetic factors that might enhance susceptibility are only partly understood. Several lines of evidence suggest, however, that inflammation may be a potential key pathway in lung carcinogenesis. Some of the most novel and promising findings from the Initial Vanderbilt Lung SPORE (P50 CA090949) were the demonstration of the potential utility of urinary metabolites of prostaglandin E2 (PGE2), a key mediator of the COX-2 pathway, as an inflammation biomarker and the detection of polymorphisms in the prostacyclin synthase (PTGIS) gene in assessing individual risk for lung cancer. We propose in this application to follow up these promising clues in a prospective study by examining the relations of the urinary PGE2 metabolite PGE-M and the prostacyclin (PGI2) metabolite PGI-M with the risk of lung cancer. Over the past ten years, we have established tremendous resources in two NCI-funded cohort studies, the US Southern Community Cohort Study (SCCS) (R01 CA092447) and the Chinese Shanghai Women's Health Study (SWHS) (R01 CA70867). In this application, we will take advantage of these valuable resources and propose a large nested case-control study to investigate: 1) the association of lung cancer risk and the urinary prostaglandin E2 metabolite (PGE-M) and urinary prostacyclin metabolite (PGI-M);and 2) the association of lung cancer risk with genetic polymorphisms of the genes involved in prostaglandin synthesis (PTGS2, PTGS1, PTGES, and PTGIS) and metabolism (15-PGDH). We will also investigate the association of lung cancer risk with plasma C-reactive protein (CRP), a sensitive marker of systemic inflammation, and the urinary leukotriences E4. Only a few cohort studies have collected both blood and urine samples at baseline to comprehensively measure relevant biomarkers. Therefore, the SCCS and SWHS, with their wealth of survey data and biospecimens, represent a unique opportunity to prospectively investigate the hypotheses proposed in this application. The proposed study is highly innovative and extremely cost-efficient. The study has great potentials to generate valuable biomarker information useful for identifying persons at high risk and amenable for screening for the detection of these cancers at an early, more curable stage.
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