Diet, Activity, and Lifestyle as a Risk Factor for Colorectal Cancer

描述（申请人提供）：结直肠癌的病因有许多饮食和生活方式因素。数据表明，不同肿瘤部位、年龄和性别的病因存在差异，某些暴露会改变其他暴露的影响，这表明在特定环境中各种饮食和生活方式因素的重要性。改变其他危险因素影响的主要因素是阿司匹林和布洛芬类药物的使用。我们之前的数据表明，非甾体抗炎药与多种饮食和生活方式因素相互作用，包括饮食脂肪、BMI、胰岛素相关基因和雌激素。我们假设炎症相关信号通路的遗传变异以及炎症、胰岛素和雌激素聚集的通路（被称为代谢信号通路）最有可能对疾病风险产生影响。我们建议研究两种以前未在结直肠癌中研究过的途径。我们利用先前收集的2780例结直肠癌病例和3025例基于人群的对照数据，以更好地了解炎症、胰岛素和雌激素之间的相互关系。我们研究了炎症相关通路（IL6、IL8、IL10、NFKB、TNF-A、IL4、IL1、ILIRA和IFNG）中已知的功能多态性和候选基因的单倍型，以及位于其他细胞信号通路汇聚的关键节点的基因（SOC1、SOC2、AKT、FRAP1 （mTOR）、TSC1、TSC2、P13K、LKB、AMP、PTEN、S6K）。VEGF, STAT1, STAT6, JNK1，和pSSMAPK)。我们将测试这些基因的遗传多态性和单倍型与结直肠癌之间的关系。我们将评估这些基因与非甾体抗炎药/阿司匹林、雌激素、BMI、膳食脂肪、抗氧化剂和身体活动的相互作用。我们将评估这些多态性/单倍型与特定类型肿瘤突变的关联。我们将利用统计方法来深入了解这些基因如何与特定的疾病途径相关，以及基因如何沿着这些途径相互关联。我们对所有与结直肠癌相关的基因和snp的功能进行了测试，我们将使用允许测试和验证的统计技术验证研究结果。鉴定与结直肠癌相关的多态性或单倍型将促进我们对病因的理解，可能导致特定的健康建议，并可以确定药物治疗的靶点。

DESCRIPTION (provided by applicant): Colorectal cancer has many diet and lifestyle factors that contribute to the etiology. Data suggest that differences in etiology exist by tumor site, age, and sex, and that certain exposures modify the effects of others, indicating the importance of various diet and lifestyle factors in certain environments. Major factors that modify the effects of other risk factors are'use of aspirin and ibuprofen-type drugs. Our previous data have shown that NSAIDs interact with a variety of diet and lifestyle factors, including dietary fat, BMI, insulin- related genes, and estrogen. We hypothesize that genetic variation in an inflammation-related signaling pathway and in a pathway where inflammation, insulin and estrogen converge (designated as a metabolic signaling pathway) will most likely have implications for disease risk. We propose to study two pathways which have not previously been studied with colorectal cancer. We utilize data previously collected on 2780 incident cases of colorectal cancer and 3025 population-based controls to obtain a better understanding of the inter-relationship between inflammation, insulin, and estrogen. We examine known functional polymorphisms and evaluate haplotypes in candidate genes in an inflammation-related pathway (IL6, IL8, IL10, NFKB, TNF-A, IL4, IL1, ILIRA and IFNG) and genes located at key junctions where other cellular signaling pathways converge which we describe as a metabolic signaling pathway (SOC1, SOC2, AKT, FRAP1 (mTOR), TSC1, TSC2, P13K, LKB, AMP, PTEN, S6K.VEGF, STAT1, STAT6, JNK1, and pSSMAPK). We will test associations between genetic polymorphisms and haplotypes of these genes with colorectal cancer. We will evaluate the interaction of these genes with NSAIDs/aspirin, estrogen, BMI, dietary fat, antioxidants, and physical activity. We will evaluate associations of these polymorphisms/haplotypes with specific types of tumor mutations. We will utilize statistical methods to gain insight into how these genes relate to specific disease pathways and how genes inter-relate along these pathways. We include test of functionality for all genes and SNPs identified as being assocatied with CRC and we will validate study findings using statistical techniques that allow for test and validation. Identification of polymorphisms or haplotypes that are relevant to colorectal cancer will advance our understanding of etiology, may lead to specific health recommendations, and can identify targets for drug therapy.