Multidisciplinary Study of Folate Intake and Colorectal Cancer

项目摘要/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。 长期饮食在预防癌症中起着重要作用，因为正常细胞可能需要几十年的时间才能变成 叶酸是一种恶性肿瘤，但叶酸在结直肠癌发生发展中的作用尚不清楚。叶酸的作用是 DNA合成和甲基化所必需的一碳供体，参与DNA损伤修复 在致癌过程中，但人类和动物研究报告了关于叶酸和CRC风险的混合结果。 具体地说，研究人员还没有就1)叶酸的短期和长期摄入量达成共识 与结直肠癌的发生有关；2)潜在的潜在机制；3)在多大程度上 这种联系可能因叶酸摄取的主要来源(例如，蔬菜、水果、强化食品或 补充剂)。此外，叶酸摄入量与结直肠癌患者存活率之间的关系仍然存在。 需要阐明的是，还没有人通过整合完整的- 外显子组测序(WES)数据纳入基于人群的队列研究。这项建议的目的是 严格解决这些关于叶酸摄入和结直肠癌发生和进展的知识空白 通过一种创新的方法利用现有数据，该方法集成了来自 三项大型前瞻性队列研究中的1,146名结直肠癌患者-护士健康研究(NHS)，NHS II， 和健康专业人员的后续研究。我们的中心假设是：1)之前较高的叶酸摄入量 结直肠癌诊断可以防止癌症发展过程中的DNA突变，以及2)诊断后更高的摄入量 对于有这种DNA变化的肿瘤，叶酸与CRC死亡率有关。我们将在以下方面测试这些假设 两个具体目标：1)根据外膜的时间和来源评价叶酸的化学预防作用 DNA变化模式；2)评估DNA变化模式作为潜在的生物标记物。 结直肠癌患者诊断后较高叶酸摄入量对生存期的影响。我们的油井数据- 对每4年测量一次、持续30年的饮食的有效评估对于检查 长期叶酸摄入与结直肠癌患者DNA损伤修复缺陷的基因组特征。我们将评估 基于拷贝数、变异负荷和突变特征的DNA损伤的基因组特征 WES数据。本研究在根据DNA变化模式确定结直肠癌分子亚型方面具有创新性 这将改进特定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的关系。贡献是巨大的，因为这些人预计 这些发现将有助于设计关于结直肠癌叶酸摄入时间和来源的饮食指南 预防，支持结直肠癌诊断患者的创新饮食干预计划，并为 为进一步阐明饮食在癌症发生中的作用的营养基因组学研究奠定基础。

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.