Integrated Epidemiologic Study of Ultra-processed Foods and Colorectal Cancer Survival

项目概要/摘要 结直肠癌（CRC）仍然是美国癌症死亡的主要原因，并且是最常见的癌症之一。 与次优饮食密切相关在各种饮食成分中，超加工食品（UPFs）是 成为CRC越来越重要的风险因素。UPF占美国人日常生活的近60% 卡路里高UPF摄入量可能会增加CRC风险或通过改变代谢物使其预后恶化， 影响血糖或炎症反应或肿瘤微环境，导致癌症进展。食品 加工也可能引入致癌物质，某些UPF成分可能导致体细胞突变。 此外，高UPF摄入量与过量卡路里摄入有关，导致肥胖，这是一种既定的风险 CRC的因素。因此，UPFs可能是CRC进展的重要饮食风险因素，但UPF-CRC 存活率尚未得到充分研究。虽然有证据表明CRC进展与以下因素相关： 尽管通过饮食调节的代谢物的代谢，与UPFs相关的代谢组学谱仍有待表征。 UPFs的成分，如红肉或加工肉类，与烷基化DNA损伤有关， CRC死亡率增加，但UPFs的作用仍不清楚。这些未知数突出表明，迫切需要 了解UPFs和CRC生存之间的关系以及这种关系的分子决定因素 提高CRC的长期生存率。成熟的大型前瞻性队列研究对于 提供严谨的数据来阐明饮食与疾病的关系并推断因果关系。高通量研究进展 代谢组学分析和全外显子组测序（WES）显示出识别敏感生物标志物的巨大潜力 可以更好地预测饮食与疾病的关系。本F99/K 00提案的总体研究目标 通过整合高通量组学和详细的饮食数据， 从大量的男性和女性中收集。F99阶段将重点调查该协会 UPF摄入量与CRC和CRC幸存者中所有原因导致的死亡之间的关系（目标1）; K 00阶段将 通过整合，将重点转移到研究UPF-CRC生存关系的分子相关性 代谢组学分析和肿瘤WES数据，并探索减少UPF的试点干预的可行性 CRC患者的摄入量（目标2）。研究结果将为CRC提供饮食建议 幸存者，加速发现新的生物标志物，为肿瘤护理中的精确营养铺平道路， 并为营养干预改善CRC的长期生存率提供新的见解。下 塔夫茨弗里德曼营养科学与政策学院和哈佛T. H.阐教 公共卫生，候选人将获得严格的研究培训和专业和职业发展 过渡到独立研究职业的技能，重点是研究营养在癌症控制中的作用， 将证据转化为有效的营养干预和临床实践，以提高癌症生存率。

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) remains a leading cause of cancer deaths in the US and is one of the cancers most strongly associated with a suboptimal diet. Within various dietary components, ultra-processed foods (UPFs) are emerging as an increasingly important risk factor for CRC. UPFs make up nearly 60% of Americans’ daily calories. A high UPF intake may increase CRC risk or worsen its prognosis through altered metabolites that may impact glycemic or inflammatory responses, or tumor microenvironment, resulting in cancer progression. Food processing may also introduce carcinogens and certain UPF components can contribute to somatic mutations. Besides, a high UPF intake is associated with excess intake of calories, leading to adiposity, an established risk factor for CRC. Thus, UPFs could be an important dietary risk factor for CRC progression and yet the UPF-CRC survival has not been adequately studied. While evidence suggests that CRC progression is associated with metabolites modulated by diet, the metabolomic profiles associated with UPFs remain to be characterized. Constituents of UPFs such as red or processed meats have been related to alkylating DNA damage and increased CRC mortality, yet the role of UPFs remains unclear. These unknowns highlight the critical need to comprehend the association between UPFs and CRC survival and the molecular determinants of this relationship for improving long-term CRC survivorship. Well-established large prospective cohort studies are crucial to offering rigorous data to elucidate the diet-disease association and infer causality. Advances in high-throughput metabolomic profiling and whole-exome sequencing (WES) show great promise to identify sensitive biomarkers that could better predict the diet-disease relationships. The overarching research goal of this F99/K00 proposal is to investigate the role of UPFs in CRC survival by integrating high throughput -omics and detailed dietary data collected among men and women from large cohorts. The F99 phase will focus on investigating the association between UPF intake and deaths due to CRC and all causes among CRC survivors (Aim 1); the K00 phase will shift the focus to investigating the molecular correlates of UPF-CRC survival relationship by integrating metabolomics profiling and tumor WES data and exploring the feasibility of a pilot intervention to reduce UPF intake among CRC patients (Aim 2). The research findings will inform dietary recommendations for CRC survivors, accelerate the discovery of novel biomarkers to pave the way for precision nutrition in oncology care, and provide new insights into nutrition interventions for improving the long-term survivorship of CRC. Under the mentorship of sponsors at Tufts Friedman School of Nutrition Science and Policy and Harvard T.H. Chan School of Public Health, the candidate will acquire rigorous research training and professional and career development skills for transition to an independent research career focus on studying the role of nutrition in cancer control and translate evidence into effective nutrition interventions and clinical practices to improve cancer survivorship.