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

描述(申请人提供)：这项拟议研究的目标是评估两种特定途径--炎症和叶酸介导的一碳代谢--中的遗传变异性和生物标记物在一大群女性结直肠癌病因学中的作用。来自流行病学和实验研究的有力证据表明，结直肠癌与炎症和一碳代谢有关，初步研究表明，这两条途径可能是相互联系的。然而，还有许多剩余的问题，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，遗传因素在这些途径中的影响。到目前为止，缺乏对遗传学和相关生物标记物对结直肠癌风险的影响的全面评估，最好是在一项大型前瞻性研究中实现。我们建议在女性健康倡议观察性研究中调查这两条相互关联的与结直肠癌发生相关的途径，该研究对93,000名绝经后妇女进行了平均10.2年的跟踪调查。我们将评估1)与一碳代谢相关的遗传变异性和生物标记物是否与结直肠癌风险相关，以及叶酸强化是否存在不同的关联；2)与前列腺素合成和炎症相关的遗传变异性和生物标记物是否与结直肠癌风险相关；3)遗传因素是否改变与营养的关联或改变对非类固醇抗炎药的反应；以及4)这两条途径之间是否存在相互联系。采用嵌套式病例对照研究，包括1000例结直肠癌发病病例和1500例匹配对照。从基线访问中获得的血液中提取的生物标志物分析包括维生素B12、全反式钴胺II、磷酸吡哆醇(维生素B6)、同型半胱氨酸、血清和红细胞叶酸以及全球淋巴细胞DNA甲基化。炎症的生物标志物包括C反应蛋白和血清淀粉样蛋白A，这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预测风险。基因分型将专注于具有强大功能影响证据的候选多态和单倍型标签SNPs，以全面评估遗传变异性。这项跨学科的协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)加深我们对炎症在结直肠癌发生中的作用的理解；2)增加我们对一碳代谢与结直肠癌发生机制的了解，包括维生素B6和B12的影响，全球DNA甲基化和叶酸强化的影响；以及3)提供关于在基因定义的群体中开发涉及一碳营养物质或非甾体抗炎药的有针对性干预的可能性的有价值的信息。结直肠癌是美国第三种最常见的癌症，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患结直肠癌风险的作用。一个人的营养、抗炎药物的使用和遗传因素可以相互作用，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，以及根据基因特征可能提出的公共卫生建议。

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.