Excess body weight and height have been studied as risk factors for colorectal cancer, an especially important undertaking given the current epidemic of obesity in the United States. However, the magnitude of risk remains poorly defined and the biologic mechanism(s) unknown. It seems likely that the insulin-like growth factor (IGF-1) is a common element that explains the biologic coupling of height and abdominal obesity as risk factors in colorectal neoplasia, as it is both a determinant of height and a candidate tumor growth factor whose expression is increased with hyperinsulinemia. We hypothesize that there are two distinct IGF-1-related colorectal neoplasia progression pathways: one driven by growth hormone (largely genetic) and one driven by chronic hyperinsulinemia (strongly gene-environment).
Specific aims have been jdesigned to determine: 1) whether the lifestyle and dietary factors associated with obesity and states of chronic hyperinsulinemia are positively associated with recurrent adenomas and colorectal cancer; 2) whether genetic variation in genes that enhance the production and growth promoting activity of IGF-1 is positively associated with recurrent adenomas and colorectal cancer, 3) whether serum biomarkers of hyperinsulinemia (leptin, TNF-alpha, IL-6, C-reactive protein, insulin) and free and total IGF-1, IGF-1/IGBP1 ratio are associated with adenoma recurrence; and 4) whether gene-lifestyle and gene-diet interactions, acting in a cooperative fashion to promote high insulin/high IGF-1 levels, are associated with recurrent adenomas and colorectal cancer. We will conduct genotyping analyses on genes known to affect IGF-1 production, metabolism, or activity, and examine dietary and lifestyle factors related to the regulation of IGF-1. By |pooling our three adenoma recurrence studies of the Colon Cancer Prevention Program Project, we will have jsufficient power to determine whether these genes and lifestyle factors are associated with risk for both nonadvanced and advanced adenoma. In addition, our collaboration with the Colon Cancer Family Registry will allow us to assess lifestyle and genetic factors (and their interactions) in relation to colorectal cancer outcomes. This unique project is designed to efficiently utilize existing data and biological samples to investigate our study hypotheses.
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