Colorectal cancer is one of the most common malignancies in the United States and many other countries. Most colorectal cancers arise from adenomatous polyps, pre-malignant lesions that can be removed during an endoscopic procedure to reduce cancer incidence and mortality. Despite considerable research conducted over the past few decades, very few biomarkers have proven useful in assessing individual risk for developing colorectal neoplasia. As part of the renewal for the Tennessee Colorectal Polyp Study (TCPS), we propose to evaluate whether high endogenous production and signaling of prostaglandin E2, a key mediator of COX-2 pathway, may be related to the risk of colorectal adenomas and whether PGE2 -related association may be independent of a low-grade, systematic inflammation, as measured by blood C- reactive protein (CRP). Urinary PGE2 metabolite and blood CRP will be measured in approximately 1000 adenoma patients and polyp-free controls to evaluate the utility of these biomarkers in risk assessment. A two-phase study involving approximately 4600 subjects will be conducted to evaluate polymorphisms in genes affecting PGE2 production (PTGS2, PTGES, 15-PGDH) and signaling (PTGER1-PTGER4) in relation to adenoma risk. Expression levels of genes related to PGE2 production in polyp tissues will be quantified using RT-PCR and correlated with the level of urinary PGE2 metabolite. In addition, we will also investigate risk factors for sessile serrated adenomas (SSA), a group of newly-defined adenomas that may have a different risk profile compared to conventional adenomas. The TCPS is a large, on-going colonoscopy-based epidemiologic study of colorectal adenomas. The resources established in this study will provide exceptional opportunities to test the hypotheses proposed in this application. Results from this study will be valuable for identifying high-risk individuals for cost-effective colorectal screening and chemoprevention.
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