Multidisciplinary Study of Folate Intake and Colorectal Cancer

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才能变成 一种恶性肿瘤，但叶酸在CRC发展和进展中的作用尚不清楚。叶酸的功能是 一种DNA合成和甲基化的重要单碳供体，参与DNA损伤修复 在致癌过程中，叶酸和CRC的风险是不一致的，但人类和动物研究报告了叶酸和CRC风险的混合结果。 具体来说，研究人员还没有达成共识1）如何短期和长期叶酸摄入量是 与结直肠癌发生相关; 2）潜在的潜在机制，以及3） 这种关联可能因叶酸摄入的主要来源而不同（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 还没有人研究叶酸摄入与CRC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。这项建议的目的是 严格解决叶酸摄入量和CRC发展和进展方面的知识差距， 利用现有的数据与创新的方法，整合WES的肿瘤和正常的DNA对， 三项大型前瞻性队列研究中的1，146名CRC患者-护士健康研究（NHS），NHS II， 和卫生专业人员随访研究。我们的中心假设是：1）在服用叶酸之前， CRC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 叶酸与具有这种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）通过与外显子组范围相关的时间和来源来评估叶酸的化学预防作用。 CRC中的DNA变化模式;和2）评估DNA变化模式作为指示CRC的潜在生物标志物。 CRC患者诊断后叶酸摄入量增加对生存的益处我们的数据- 每4年测量一次饮食的有效评估，持续> 30年， 长期叶酸摄入与CRC中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 这将改善特定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的关系贡献是巨大的，因为这些预期 这些发现将有助于设计CRC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 为营养基因组学研究奠定基础，进一步阐明饮食在致癌作用中的作用。

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.