Colorectal cancer is the second leading cause of cancer death in the United States, and colorectaladenomas are well-established precursors to these cancers. Without preventive actions, approximately 6%of Americans will develop this malignancy during their lifetime. We propose to examine 3 inter-relatedpathogenic pathways for colorectal carcinogenesis: the vitamin D axis, inflammation, and insulin/insulin-likegrowth factor signaling. We will also assess the influence of DNA methylation aberrations on growth factorsignaling. Many of the proposed modifiable factors for colorectal neoplasia (low intakes of Vitamins D,calcium and folate, and high intakes of alcohol, obesity, inactivity, and non-use of aspirin) may operatethrough these pathways. We will examine prospectively and extensively how these modifiable factors mayinfluence colorectal neoplasia risk operating through these pathways. We will utilize data from the HealthProfessionals Follow-up Study (HPFS) and Nurses' Health Study (NHS), two large ongoing prospectivestudies of men and women, respectively. Participants for the analysis of cancers will be drawn from theHPFS whereas participants for the analysis of adenomas will be drawn from both cohorts. We will studyrelevant exposures utilizing (1) multiple questionnaires accumulated over 20 years to assess the influence oflong-term exposures including diet, (2) nutrient and hormonal biomarkers, and (3) genetic factors relevant tothe pathways of interest. These exposures and genetic factors will be examined in relation to variousendpoints including (1) colorectal cancer incidence, (2) colorectal adenoma incidence, (3) specific molecularalterations in colorectal cancer (including K-ras mutation, VEGF expression, microvessel density, loss ofexpression of p21 and p27, and overexpression of phospho-Akt, FASN, and COX-2), and (4) survival fromcolorectal cancer following a curative resection of colorectal cancer. By better understanding underlyingmechanisms, dose-response relations, inter-relations among factors acting in similar pathways, variation inresponse due to genetic susceptibility, and specificity in associationsto specific tumor markers, we cansolidify and refine recommendations aimed at reducing the incidence and mortality from this largelypreventable cancer.
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