A Prospective Study of Diet and Colorectal Neoplasia

饮食与结直肠肿瘤的前瞻性研究

基本信息

批准号：
8130985
负责人：
CHARLES S FUCHS
金额：
$ 95.73万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8130985
关键词：
25-hydroxyvitamin D Alcohol consumption American Anti-Inflammatory Agents Anti-inflammatory Arachidonate 5-Lipoxygenase Aspirin Attenuated Biological Markers C-Peptide C-reactive protein CYP2C9 gene Calcium Cancer Etiology Carbon Cessation of life Colorectal Colorectal Adenoma Colorectal Cancer Colorectal Neoplasms DNA Methylation Data Diabetes Mellitus Diagnosis Diet Dietary Practices Dietary intake Dose Epigenetic Process Excision FASN gene Family history of Fatty acid glycerol esters Fatty-acid synthase Folate Follow-Up Studies GC gene Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Growth Factor Health Professional Hormonal Hyperinsulinism Incidence Inflammation Inflammatory Insulin Insulin-Like Growth Factor Binding Protein 3 Insulin-Like Growth Factor I Insulin-Like Growth Factor II Insulin-Like Growth-Factor-Binding Proteins Intake Interleukin-6 Malignant Neoplasms Measures Meat Metabolism Methylation Molecular Mutate Mutation Non-Steroidal Anti-Inflammatory Agents Nurses&apos Health Study Nutrient Obesity Ornithine Decarboxylase PTGS1 gene PTGS2 gene Participant Pathway interactions Peroxisome Proliferator-Activated Receptors Plasma Polyunsaturated Fatty Acids Prevention strategy Preventive Prospective Studies Prostacyclin synthase Questionnaires RXR Recommendation Recording of previous events Research Personnel Risk Risk Factors Signal Transduction Somatomedins Specificity Thromboxanes Tumor Markers United States VDR gene Variant Vascular Endothelial Growth Factors Vitamin D Weight Gain Woman adenoma adiponectin calcium intake cancer risk carcinogenesis cohort cyclooxygenase 1 density energy balance fruits and vegetables improved indexing inflammatory marker interest men modifiable risk mortality overexpression programs response tumor

项目摘要

Colorectal cancer is the second leading cause of cancer death in the United States, and colorectal adenomas are well-established precursors to these cancers. Without preventive actions, approximately 6% of Americans will develop this malignancy during their lifetime. We propose to examine 3 inter-related pathogenic pathways for colorectal carcinogenesis: the vitamin D axis, inflammation, and insulin/insulin-like growth factor signaling. We will also assess the influence of DNA methylation aberrations on growth factor signaling. Many of the proposed modifiable factors for colorectal neoplasia (low intakes of Vitamins D, calcium and folate, and high intakes of alcohol, obesity, inactivity, and non-use of aspirin) may operate through these pathways. We will examine prospectively and extensively how these modifiable factors may influence colorectal neoplasia risk operating through these pathways. We will utilize data from the Health Professionals Follow-up Study (HPFS) and Nurses' Health Study (NHS), two large ongoing prospective studies of men and women, respectively. Participants for the analysis of cancers will be drawn from the HPFS whereas participants for the analysis of adenomas will be drawn from both cohorts. We will study relevant exposures utilizing (1) multiple questionnaires accumulated over 20 years to assess the influence of long-term exposures including diet, (2) nutrient and hormonal biomarkers, and (3) genetic factors relevant to the pathways of interest. These exposures and genetic factors will be examined in relation to various endpoints including (1) colorectal cancer incidence, (2) colorectal adenoma incidence, (3) specific molecular alterations in colorectal cancer (including K-ras mutation, VEGF expression, microvessel density, loss of expression of p21 and p27, and overexpression of phospho-Akt, FASN, and COX-2), and (4) survival from colorectal cancer following a curative resection of colorectal cancer. By better understanding underlying mechanisms, dose-response relations, inter-relations among factors acting in similar pathways, variation in response due to genetic susceptibility, and specificity in associationsto specific tumor markers, we can solidify and refine recommendations aimed at reducing the incidence and mortality from this largely preventable cancer.

结直肠癌是美国癌症死亡的第二大原因，大肠癌腺瘤是这些癌症的完善前体。没有预防措施，大约有6％美国人将在他们的一生中发展这种恶性肿瘤。我们建议检查3个相关的结直肠癌的致病途径：维生素D轴，炎症和胰岛素/胰岛素样生长因子信号传导。我们还将评估DNA甲基化畸变对生长因子的影响信号。许多提出的关于大肠肿瘤的可修改因素（维生素D的低摄入量，钙和叶酸，饮酒，肥胖，不活跃和不使用阿司匹林的摄入量可能会起作用）通过这些途径。我们将向前瞻性和广泛地检查这些可修改因素如何影响结直肠肿瘤的风险通过这些途径运行。我们将利用健康数据专业人士后续研究（HPFS）和护士健康研究（NHS），两项大型持续的前瞻性分别研究男人和女人。将从 HPFS，而分析腺瘤的参与者将从两个队列中提取。我们将学习使用（1）在20年内积累的多个问卷来评估的影响，以评估长期暴露包括饮食，（2）营养和荷尔蒙生物标志物，以及（3）与遗传因素有关感兴趣的途径。这些暴露和遗传因素将相对于各种终点包括（1）结直肠癌的发生率，（2）结直肠腺瘤的发病率，（3）特定分子结直肠癌的改变（包括K-RAS突变，VEGF表达，微扰动密度，丧失 p21和p27的表达，以及磷酸化，FASN和COX-2）的过表达，以及（4）结肠癌切除后结直肠癌。通过更好地理解潜在的机理，剂量反应关系，作用在相似途径的因素之间的相互关系，变化的变化由于遗传敏感性和缔合特定肿瘤标记的特异性而引起的响应，我们可以巩固和完善的建议，旨在降低此次的发病率和死亡率可预防的癌症。