Lifestyle and Genetic Determinants of IGF-1 as risk fact

超重和身高已被研究为结直肠癌的危险因素，鉴于目前美国肥胖症的流行，这是一项特别重要的任务。然而，风险程度仍然定义不清，生物学机制未知。胰岛素样生长因子（IGF-1）似乎是一个共同的因素，解释了身高和腹部肥胖的生物耦合作为结直肠肿瘤的危险因素，因为它既是身高的决定因素，也是一个候选的肿瘤生长因子，其表达随着高胰岛素血症而增加。我们假设有两种不同的IGF-1相关的结直肠肿瘤进展途径：一种是由生长激素驱动的（大部分是由生长激素驱动的）， 一个是由慢性高胰岛素血症驱动的（强烈的基因-环境）。本研究旨在确定：1）与肥胖和慢性高胰岛素血症相关的生活方式和饮食因素是否与腺瘤和结直肠癌的复发呈正相关; 2）增强IGF-1的产生和生长促进活性的基因中的遗传变异是否与复发性腺瘤和结直肠癌正相关，3）高胰岛素血症的血清生物标志物（瘦素、TNF-α、IL-6、C-反应蛋白、胰岛素）和游离和总IGF-1、IGF-1/IGBP 1比值 与腺瘤复发有关; 4）基因-生活方式和基因-饮食相互作用是否与腺瘤复发和结直肠癌有关，基因-生活方式和基因-饮食相互作用以合作的方式促进高胰岛素/高IGF-1水平。我们将对已知影响IGF-1产生、代谢或活性的基因进行基因分型分析，并检查与IGF-1调节相关的饮食和生活方式因素。通过|结合我们的三项结肠癌预防计划腺瘤复发研究，我们将有足够的能力来确定这些基因和生活方式因素是否与非晚期和晚期腺瘤的风险相关。此外，我们与结肠癌家族登记处的合作将使我们能够评估生活方式和遗传因素（及其相互作用）与结直肠癌结局的关系。这个独特的项目旨在有效地利用现有的数据和生物样本来研究我们的研究假设。

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.