A Prospective Study of Colorectal Cancer: One-Carbon Metabolism and Inflammation

结直肠癌的前瞻性研究：一碳代谢和炎症

• 批准号: 7368014
• 负责人: CORNELIA M ULRICH
• 金额: $ 64.18万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-09 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7368014
• 关键词: Address; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Area; Biological Assay; Biological Markers; Blood; C-reactive protein; Cancer Etiology; Carbon; Case-Control Studies; Cessation of life; Characteristics; Colorectal; Colorectal Cancer; DNA Methylation; DNMT3B gene; Data Quality; Diet; Dinoprostone; Drug usage; Enzymes; Epidemiology; Erythrocytes; Folate; Folic Acid; Food Interactions; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Haplotypes; Holo Transcobalamin II; Homocysteine; Homocystine; Individual; Inflammation; Inflammatory; Inherited; Intake; Intervention; Investigation; Joints; Knowledge; Learning; Lesion; Link; Lymphocyte; MTHFR gene; Malignant Neoplasms; Measures; Mediating; Metabolism; Methionine; Methylenetetrahydrofolate reductase (NADPH); Nested Case-Control Study; Nutrient; Nutritional; Nutritional status; Observational Study; PTGS2 gene; Pathway interactions; Persons; Pharmaceutical Preparations; Postmenopause; Premalignant; Process; Production; Prospective Studies; Prostaglandins; Proteins; Public Health; Recommendation; Research; Research Design; Risk; Role; Serum; Serum amyloid A protein; Source; Time; United States; Validation; Visit; Vitamin B 12; Vitamin B6; Vitamins; Woman; Women' s Health; base; cancer risk; carcinogenesis; cohort; cost; cyclooxygenase 2; cytokine; follow-up; fortification; in vivo; men; nucleotide metabolism; nutrition; prevent; prospective; research study; response

DESCRIPTION (provided by applicant): The goal of the proposed study is to evaluate the role of genetic variability and biomarkers in two specific pathways - inflammation and folate-mediated one-carbon metabolism - in colorectal cancer etiology within a large cohort of women. Strong evidence from epidemiology and experimental studies implicates inflammation and one-carbon metabolism in colorectal cancer, and preliminary studies show that these two pathways may be interconnected. However, there are many remaining questions, particularly regarding the impact of genetic factors in these pathways in the presence of differences in nutritional status or NSAID use. To date, a comprehensive assessment of the impact of genetics and relevant biomarkers on colorectal cancer risk is lacking, and can best be achieved within a large prospective study. We propose to investigate these two interrelated pathways of demonstrated relevance to colorectal carcinogenesis within the Women's Health Initiative Observational Study, a prospective cohort of >93,000 postmenopausal women who will have been followed for an average of 10.2 years. We will evaluate whether 1) genetic variability and biomarkers relevant to one-carbon metabolism are associated with colorectal cancer risk, and whether associations differ by folic-acid fortification; 2) genetic variability and biomarkers relevant to prostaglandin synthesis and inflammation are associated with colorectal cancer risk; 3) whether genetic factors modify associations with nutrients or modify the response to NSAIDs; and 4) whether there are interconnections between the two pathways. A nested case-control study is proposed, which includes 1000 incident colorectal cancer cases and 1500 matched controls. Biomarker assays derived from blood obtained at the baseline visit include vitamin B12, holo-transcobalamin II, pyridoxalphosphate (vitamin B6), homocysteine, serum and RBC folate, and global lymphocyte DNA methylation. Biomarkers of inflammation include C-reactive protein and serum amyloid A. These will be measured at two time points, allowing us to evaluate whether a rise in these inflammatory markers is predictive of risk. Genotyping will focus both on candidate polymorphisms with strong evidence for functional impact and haplotype tagSNPs, for a comprehensive assessment of genetic variability. This interdisciplinary collaborative study will be both comprehensive and cost-effective, utilizing a high- quality data source. Results will: 1) further our understanding of the role of inflammation in colorectal carcinogenesis; 2) increase our knowledge about the mechanisms linking one-carbon metabolism to colorectal carcinogenesis, including about the influence of vitamins B6 and B12, and global DNA methylation and the impact of folic-acid fortification; and 3) provide valuable information regarding the possibility of developing targeted interventions involving one-carbon nutrients or NSAIDs among genetically defined groups. Colorectal cancer is the third most common cancer in the United States and the second most common cause of cancer death among both men and women. This study will investigate the role of diet and inflammation on women's risk of colorectal cancer. A person's nutrition, use of anti-inflammatory drugs, and inherited genetic factors can interact to determine an individual's risk of colorectal cancer. Through this research, we will learn more about how to prevent colorectal cancer and about possible public health recommendations based on genetic characteristics.

描述（由申请人提供）：拟议研究的目标是评估遗传变异和生物标志物在一大群女性结直肠癌病因学中的两种特定途径（炎症和叶酸介导的一碳代谢）中的作用。流行病学和实验研究的有力证据表明炎症和一碳代谢与结直肠癌有关，初步研究表明这两种途径可能是相互关联的。然而，仍然存在许多问题，特别是在营养状况或非甾体抗炎药使用存在差异的情况下，遗传因素对这些途径的影响。迄今为止，还缺乏对遗传学和相关生物标志物对结直肠癌风险影响的全面评估，最好通过大型前瞻性研究来实现。我们建议在女性健康倡议观察研究中调查这两种与结直肠癌发生相关的相互关联的途径，该研究是一个由超过 93,000 名绝经后女性组成的前瞻性队列，平均随访时间为 10.2 年。我们将评估：1）与一碳代谢相关的遗传变异和生物标志物是否与结直肠癌风险相关，以及这种关联是否因叶酸强化而有所不同； 2）与前列腺素合成和炎症相关的遗传变异和生物标志物与结直肠癌风险相关； 3）遗传因素是否会改变与营养素的关联或改变对非甾体抗炎药的反应； 4) 两条路径之间是否存在互连。提出了一项巢式病例对照研究，其中包括 1000 例结直肠癌病例和 1500 例匹配对照。基线访视时获得的血液生物标志物检测包括维生素 B12、全转钴胺素 II、磷酸吡哆醛（维生素 B6）、同型半胱氨酸、血清和红细胞叶酸以及整体淋巴细胞 DNA 甲基化。炎症生物标志物包括 C 反应蛋白和血清淀粉样蛋白 A。这些将在两个时间点进行测量，使我们能够评估这些炎症标志物的上升是否可以预测风险。基因分型将重点关注具有功能影响有力证据的候选多态性和单倍型标签SNP，以全面评估遗传变异性。这项跨学科合作研究将利用高质量的数据源，既全面又具有成本效益。结果将：1）进一步了解炎症在结直肠癌发生中的作用； 2) 增加我们对一碳代谢与结直肠癌发生之间联系的机制的了解，包括维生素 B6 和 B12 的影响、整体 DNA 甲基化以及叶酸强化的影响； 3) 提供有关在基因定义的群体中制定涉及一碳营养素或非甾体抗炎药的有针对性的干预措施的可能性的宝贵信息。结直肠癌是美国第三大常见癌症，也是男性和女性癌症死亡的第二大常见原因。这项研究将调查饮食和炎症对女性结直肠癌风险的影响。一个人的营养、抗炎药物的使用和遗传因素可以相互作用来决定一个人患结直肠癌的风险。通过这项研究，我们将更多地了解如何预防结直肠癌以及基于遗传特征的可能的公共卫生建议。