Growth Factors and Colon Cancer

生长因子和结肠癌

• 批准号: 6952693
• 负责人: Martha L SLATTERY
• 金额: $ 15.57万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952693
• 关键词: apolipoprotein E; aspirin; calcium; cancer prevention; carcinogenesis; cell growth regulation; cell proliferation; colon neoplasms; disease /disorder prevention /control; gene environment interaction; genetic susceptibility; growth factor; informatics; information systems; insulin; insulin receptor; neoplasm /cancer diagnosis; neoplasm /cancer epidemiology; nutrition aspect of cancer; nutrition related tag; peroxisome proliferator activated receptor; somatotropin; vitamin D; vitamin D receptors

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.

细胞生长和增殖是致癌的核心。 科学证据表明，生长激素和影响这些生长激素的遗传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），生长激素似乎对结直肠癌很重要，受到先前确定的结直肠癌风险因素的影响，如体型和体力活动。 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;已知的肿瘤突变状态的微卫星不稳定性和K-ras突变;和一个结肠直肠癌病例的生殖细胞DNA对约3000例病例和3000名对照进行对照研究，研究影响生长激素以及细胞生长和增殖的遗传变异如何与结直肠癌的发生和随后的生存期相关诊断. 这项研究的重点是遗传和环境的相互作用。 检查的特定基因是沿着胰岛素途径的基因的分子变体，包括IGF 1基因、胰岛素样生长因子结合蛋白-3（IGFBP 3）、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遗传、饮食和生活方式因素相关，与结直肠癌风险改变相关。特别地，我们假设IGF 1、IGFBP 3、IRS-1、IRS-2、PPARgamma、ApoE和VDR的分子变体与饮食如钙、维生素D、糖和血糖指数、阳光照射、体力活动、阿司匹林使用和体型相互作用以改变结直肠癌的风险; IGF 1、IGFBP 3、IRS-1、IRS-2、PPARgamma、ApoE和VDR的分子变体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; IGF 1、IGFBP 3、IRS-1、IRS-2、PPARgamma、ApoE和VDR的分子变体与诊断后的存活率相关。 为了检验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，如可用的。 将确定参与胰岛素和生长因子疾病途径的这些基因的分子变体。 统计分析将使用逻辑回归和生存方法。 这项研究建立在一个独特的现有资源，研究遗传和环境与结直肠癌的关联。 它将提供深入了解结肠癌的病因，因此疾病预防的途径。