Multidisciplinary Study of Folate Intake and Colorectal Cancer

叶酸摄入量与结直肠癌的多学科研究

• 批准号: 10302525
• 负责人: Xuehong Zhang
• 金额: $ 27.62万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-10 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302525
• 关键词: Address; Animals; Cancer Etiology; Carbon; Cessation of life; Chemopreventive Agent; Cohort Studies; Colorectal Cancer; Consensus; Copy Number Polymorphism; DNA; DNA Damage; DNA Methylation; DNA Repair; DNA Sequence Alteration; DNA biosynthesis; Data; Databases; Development; Diagnosis; Diet; Dietary Intervention; Etiology; Exhibits; Folic Acid; Folic Acid Deficiency; Follow-Up Studies; Fortified Food; Fruit; Future; Genomics; Goals; Health Professional; Human; Incidence; Intake; Knowledge; Lead; Link; Malignant Neoplasms; Measures; Molecular; Morbidity - disease rate; Mutation; Normal Cell; Nurses' Health Study; Participant; Patients; Pattern; Play; Population Study; Prospective cohort study; Public Health; Reporting; Research; Research Personnel; Risk Estimate; Role; Source; Testing; Tetrahydrofolates; United States; Vegetables; base; cancer chemoprevention; cancer diagnosis; cancer prevention; cancer subtypes; cancer survival; carcinogenesis; colon cancer patients; colon carcinogenesis; colorectal cancer prevention; colorectal cancer risk; design; dietary chemoprevention; dietary guidelines; exome; exome sequencing; innovation; insight; intervention program; molecular subtypes; mortality; mortality risk; multidisciplinary; nutritional genomics; patient population; population based; potential biomarker; prevent; tumor; tumorigenesis

Project Summary / Abstract Colorectal cancer (CRC) remains one of the leading cause of cancer-related deaths in the United States. Long-term diet plays an important role in cancer prevention, as it can take decades for normal cells to become a malignant tumor, but the role of folate in CRC development and progression is unclear. Folate functions as an essential one-carbon donor for DNA synthesis and methylation and is involved in DNA damage repair during carcinogenesis, but human and animal studies report mixed findings on folate and CRC risk. Specifically, researchers have not reached consensus on 1) how short- and long-term folate intakes are associated with colorectal carcinogenesis; 2) potential underlying mechanisms, and 3) the degree to which such associations may differ by major sources of folate intake (e.g., vegetables, fruits, fortified foods, or supplements). Furthermore, the relationship between folate intake and survival among CRC patients remains to be elucidated, and no one has investigated folate intake with CRC risk and survival by integrating whole- exome sequencing (WES) data into population-based cohort studies. The objective of this proposal is to rigorously address these knowledge gaps on folate intake and CRC development and progression by leveraging existing data with an innovative approach that integrates WES of tumor and normal DNA pairs from 1,146 CRC patients in three large prospective cohort studies—the Nurses’ Health Study (NHS), the NHS II, and the Health Professionals Follow-up Study. Our central hypotheses are 1) Higher intake of folate before CRC diagnosis can prevent DNA mutations during cancer development, and 2) Higher post-diagnosis intake of folate is associated with CRC mortality for tumors with such DNA changes. We will test these hypotheses in two specific aims: 1) Evaluate folate’s chemopreventive role by timing and sources in relation to exome-wide DNA change patterns in CRC; and 2) Assess DNA change patterns as potential biomarkers indicating the survival benefit associated with post-diagnosis higher intake of folate in CRC patients. Our data of well- validated assessments of diets measured every 4 years for > 30 years is particularly valuable for examining long-term folate intake with genomic features of defective DNA damage repair in CRC. We will assess genomic features of DNA damage based on copy number, variation burden, and mutational signatures utilizing WES data. This research is innovative in defining molecular subtyping of CRC based on DNA change patterns that will refine risk estimates for specific CRC subtypes and provide more evidence for the relationship between folate intake and specific subtypes. The contribution is significant because these expected discoveries would facilitate design of dietary guidelines on timing and sources of folate intake for CRC prevention, support innovative dietary intervention programs among patients with CRC diagnosis, and lay the groundwork for nutrigenomics studies that further elucidate the role of diet in carcinogenesis.

项目概要/摘要 结直肠癌（CRC）仍然是美国癌症相关死亡的主要原因之一。 长期饮食在癌症预防中起着重要作用，因为正常细胞可能需要几十年的时间才能变成 一种恶性肿瘤，但叶酸在结直肠癌发生和进展中的作用尚不清楚。叶酸的功能为 DNA 合成和甲基化的重要单碳供体，参与 DNA 损伤修复 但人类和动物研究报告的叶酸和结直肠癌风险的结果不一。 具体来说，研究人员尚未就以下问题达成共识：1) 短期和长期叶酸摄入量如何 与结直肠癌发生有关； 2) 潜在的潜在机制，以及 3) 程度 这种关联可能因叶酸摄入的主要来源（例如蔬菜、水果、强化食品或 补充）。此外，叶酸摄入量与 CRC 患者生存率之间的关系仍然存在 有待阐明，并且没有人通过整合整体研究叶酸摄入量与结直肠癌风险和生存的关系。 外显子组测序 (WES) 数据纳入基于人群的队列研究。该提案的目的是 严格解决叶酸摄入和结直肠癌发生和进展方面的知识差距 通过创新方法利用现有数据，该方法将肿瘤和正常 DNA 对的 WES 相结合 三项大型前瞻性队列研究（护士健康研究 (NHS)、NHS II、 和卫生专业人员后续研究。我们的中心假设是 1) 之前摄入更多的叶酸 CRC 诊断可以预防癌症发展过程中的 DNA 突变，并且 2) 诊断后摄入更多 叶酸与具有此类 DNA 变化的肿瘤的 CRC 死亡率相关。我们将测试这些假设 两个具体目标：1) 通过与全外显子组相关的时间和来源评估叶酸的化学预防作用 CRC 中的 DNA 变化模式； 2) 评估 DNA 变化模式作为潜在的生物标志物，表明 CRC 患者的生存获益与诊断后较高的叶酸摄入量相关。我们的数据很好- 超过 30 年每 4 年测量一次的饮食经过验证的评估对于检查特别有价值 长期叶酸摄入与结直肠癌 DNA 损伤修复缺陷的基因组特征。我们将评估 基于拷贝数、变异负担和突变特征的 DNA 损伤的基因组特征 WES 数据。这项研究在基于 DNA 变化模式定义 CRC 分子亚型方面具有创新性 这将完善特定 CRC 亚型的风险估计并为这种关系提供更多证据 叶酸摄入量和特定亚型之间。这一贡献是重大的，因为这些预期 这些发现将有助于设计有关结直肠癌叶酸摄入时间和来源的膳食指南 预防，支持 CRC 诊断患者的创新饮食干预计划，并奠定 为进一步阐明饮食在致癌作用中的作用的营养基因组学研究奠定了基础。