Growth Factors and Colon Cancer

细胞生长和增殖是癌变的核心。越来越多的科学证据表明，生长激素以及影响这些生长激素的基因变异与结直肠癌有重要关系。此外，胰岛素和胰岛素样生长因子（IGF），似乎对结直肠癌很重要的生长激素，受到先前确定的结直肠癌风险因素（如体型和身体活动）的影响。在这项研究中，我们将使用现有的生活方式和代谢暴露数据；已知肿瘤突变状态微卫星不稳定性和K-ras突变；以及来自大约3000例病例和3000例对照的意外结直肠癌病例对照研究的可用种系DNA，以研究影响生长激素和细胞生长和增殖的遗传变异如何与结直肠癌的发展和诊断后的后续生存相关。这项研究的重点是遗传和环境的相互作用。研究的特定基因是胰岛素通路基因的分子变异，包括IGF1基因、胰岛素样生长因子结合蛋白-3 （IGFBP3）、胰岛素受体底物基因1 （IRS-1）、胰岛素受体底物基因2 (IRS-2)；过氧化物酶体增殖物激活受体γ基因（PPARgamma）、载脂蛋白E基因（ApoE）和维生素D受体基因（VDR）。我们假设这些变异与结直肠癌风险的改变有关，并与遗传、饮食和生活方式因素有关。特别地，我们假设IGF1、IGFBP3、IRS-1、IRS-2、PPARgamma、ApoE和VDR的分子变异与饮食如钙、维生素D、糖和血糖指数相互作用；阳光照射、体力活动、阿司匹林使用和体型可改变结直肠癌的风险；IGF1、IGFBP3、IRS-1、IRS-2、PPARgamma、ApoE和VDR的分子变异与肿瘤中特定类型的突变相关，包括微卫星不稳定性和K-ras突变；IGF1、IGFBP3、IRS-1、IRS-2、PPARgamma、ApoE和VDR的分子变异与诊断后的生存相关。为了验证这些变异与饮食和其他因素相互作用的假设，有必要有一个大的样本量，比如一个可用的。这些参与胰岛素和生长因子疾病途径的基因的分子变异将被确定。统计分析将使用逻辑回归和生存方法。本研究建立在研究结直肠癌的遗传和环境关联的独特现有资源的基础上。它将提供对结肠癌病因的深入了解，从而为疾病预防提供途径。

Cell growth and proliferation are central to carcinogenesis. Scientific evidence that growth hormones, and genetic variants that influence these growth hormones, are importantly related to colorectal cancer is increasing. Furthermore, insulin and insulin-like growth factors (IGF), growth hormones that appear to be important for colorectal cancer, are influenced by previously identified risk factors for colorectal cancer such as body size and physical activity. In this study we will use existing lifestyle and metabolic exposure data; known tumor mutational status of microsatellite instability and K-ras mutations; and available germline DNA from an incident colorectal cancer case-control study of approximately 3000 cases and 3000 controls to study how genetic variants that influence growth hormones and cell growth and proliferation relate to development of colorectal cancer and subsequent survival after diagnosis. The study focuses on genetic and environmental interaction. Specific genes examined are molecular variants of genes along insulin pathway, including the IGF1 gene, insulin- like growth factor binding protein-3 (IGFBP3), the insulin receptor substrate gene 1 (IRS-1), the insulin receptor substrate gene-2 (IRS-2); the peroxisome proliferator-activated receptor gamma gene (PPARgamma), apolipoprotein E gene (ApoE), and the vitamin D receptor gene (VDR). We hypothesize that these variants are associated with altered risk of colorectal cancer in conjunction with genetic, diet, and lifestyle factors. Specially, we hypothesize that molecular variants of IGF1, IGFBP3, IRS-1, IRS-2, PPARgamma, ApoE, and VDR interact with dietary such as calcium, vitamin D, sugar, and glycemic index; sunshine exposure, physical activity, aspirin use, and body size to alter risk of colorectal cancer; that molecular variants of IGF1, IGFBP3, IRS-1, IRS-2, PPARgamma, ApoE, and VDR are associated with specific types of mutations in tumors including microsatellite instability and K-ras mutations; and that molecular variants of IGF1, IGFBP3, IRS-1, IRS-2, PPARgamma, ApoE, and VDR are associated with survival after diagnosis. To test the hypothesis that these variants interact with dietary and other factors, it is necessary to have a large sample size, such as the one available. Molecular variants of these genes that are involved in the insulin and growth factor disease pathway will be determined. Statistical analyses will use logistic regression and survival methods. This study builds on a unique existing resource to study genetic and environmental associations with colorectal cancer. It will provide insight into colon cancer etiology and therefore avenues to disease prevention.