Growth Factors and Colon Cancer

生长因子和结肠癌

• 批准号: 7122040
• 负责人: Martha L SLATTERY
• 金额: $ 62.53万
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7122040
• 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作用的核心。 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大肠癌重要有关。此外，胰岛素和胰岛素样生长因子（IGF），似乎对大肠癌很重要的生长激素受到了先前确定的结直肠癌的危险因素的影响，例如身体大小和体育活动。 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；微卫星不稳定性和K-RAS突变的已知肿瘤突变状态；以及大约3000例病例和3000例对照的事件结直肠癌病例对照研究中可用的种系DNA，以研究如何影响生长激素和细胞生长的遗传变异与结肠癌的发展以及诊断后随后的生存有关。 该研究的重点是遗传和环境相互作用。 所检查的特定基因是沿胰岛素途径的基因的分子变异，包括IGF1基因，胰岛素类似生长因子结合蛋白-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的受体伽马基因（Ppargamma），载脂蛋白E基因（APOE）和维生素D受体基因（VDR）。 我们假设这些变体与结肠癌的风险改变有关，以及遗传，饮食和生活方式因素。特别是，我们假设IGF1，IGFBP3，IRS-1，IRS-2，PPARGAMMA，APOE和VDR的分子变异与饮食相互作用，例如钙，维生素D，糖和血糖指数；阳光暴露，体育锻炼，阿司匹林使用和体型，以改变结直肠癌的风险； IGF1，IGFBP3，IRS-1，IRS-2，PPARGAMMA，APOE和VDR的分子变体与包括微卫星不稳定性和K-RAS突变在内的肿瘤中特定类型的突变有关；以及IGF1，IGFBP3，IRS-1，IRS-2，PPARGAMMA，APOE和VDR的分子变异与诊断后的生存有关。 为了检验这些变体与饮食和其他因素相互作用的假设，有必要具有较大的样本量，例如可用的样本量。 这些基因的分子变异将确定胰岛素和生长因子疾病途径的分子变异。 统计分析将使用逻辑回归和生存方法。 这项研究以独特的现有资源为基础，以研究与结直肠癌的遗传和环境关联。 它将提供有关结肠癌病因的洞察力，从而提供预防疾病的途径。