Obesity, sedentary behaviors, and diet quality for prevention and early detection of early-onset colorectal neoplasia

项目总结/摘要 早发性结直肠癌（在50岁之前诊断的CRC）发病率的上升，导致了 美国癌症协会（ACS）指南建议平均风险筛查开始在45岁，而不是50岁。 争论的焦点是增加2100万风险很低的成年人的大量成本和资源。 筛选池和“进一步个性化筛选策略”是一个优先事项。确定的贡献者 发病率上升是第一步，但迄今为止，这是一个尚未满足的需求。之前和反映的生活方式因素 早发性CRC的快速增加，包括肥胖、久坐和不良饮食，可能起关键作用。我们 初步数据支持肥胖和久坐行为的重要性， 与65岁以后诊断的CRC相比，从传统的腺瘤-癌序列中处理。 因此，作为筛查的主要目标，对早发性晚期腺瘤的危险因素的研究将有助于 阐明了年轻人结直肠癌发生的见解。不断积累的数据表明， 易位/内毒素血症，引发随后的炎症和免疫反应，并通过 上述生活方式因素，可能是一个新兴的途径。我们假设肥胖， 久坐和饮食质量差通过增加内毒素血症增加早发性晚期腺瘤的风险 和炎症，并有助于早发性CRC的上升。为了验证这些假设，我们将利用 在两个特征良好的前瞻性队列中收集了整个生命过程中的生活方式数据（护士健康研究 II [NHSII]）和南方社区队列研究（SCCS），使用存档的诊断前血液，补充 通过使用微观模拟筛选分析-结肠（MISCAN-结肠）进行决策建模， 告知ACS筛查指南。具体来说，我们将首先前瞻性地研究 中年和早期肥胖、久坐行为、饮食质量和早发性晚期肥胖的风险 腺瘤（Aim 1）。然后，我们将研究诊断前血浆的独立和介导作用， 内毒素血症和炎症的标志物在早发性肿瘤，利用成本效益和可靠的 蛋白质组学平台这种分析还将允许蛋白质-蛋白质相互作用的非靶向发现， 确定新的网络/目标（目标2）。最后，我们将进行荟萃分析，以确定早发性CRC 具体的风险因素，并量化相对风险，并将这些结果整合到MISCAN-Colon中， 生活方式的长期改变对早发性CRC的上升的贡献，并改善模拟 用于支持2018年ACS筛查指南，使用早发CRC特定风险因素/估计（Aim 3）。我们成立的团队，由专注于早发性CRC的早期研究者领导， 流行病学，生物信息学，生物标志物测量和发现，以及决策建模，提供了 无与伦比的专业知识。这项研究将阐明对早发性结直肠癌病因的重要见解 这将是在年轻人中进行最佳/个性化CRC筛查的重要一步。

PROJECT SUMMARY/ABSTRACT The rising incidence in early-onset colorectal cancer (CRC diagnosed before 50), has resulted in updated American Cancer Society (ACS) guideline advising average-risk screening begin at age 45, rather than 50. Debates centered around the substantial cost and resources of adding 21 million adults at very low risk to the screening pool, and “further personalize screening strategies” was a priority. Identifying the contributors of the rising incidence are the first steps but thus far an unmet need. Lifestyle factors that preceded and mirrored the rapid rise of early-onset CRC, including obesity, prolong sitting, and poor diet, may play a critical role. Our preliminary data support the importance of obesity and sedentary behaviors and early-onset CRC are more likely to be processed from traditional adenoma-carcinoma sequence compared to CRC diagnosed after age 65. Therefore, investigation into risk factors for early-onset advanced adenoma, the major targets of screening, will illuminate insights of colorectal carcinogenesis at younger ages. Accumulating data suggest that microbial translocation/endotoxemia, which triggers subsequent inflammation and immune response, and augmented by above-mentioned lifestyle factors, might be an emerging pathway. We hypothesized that obesity, prolonged sitting, and poor diet quality increase risk of early-onset advanced adenoma through increasing endotoxemia and inflammation, and contribute to the rise of early-onset CRC. To test these hypotheses, we will leverage lifestyle data collected throughout life course in two well-characterized prospective cohort (Nurses’ Health Study II [NHSII]) and Southern Community Cohort Study (SCCS) with archived pre-diagnostic blood, complemented by decision modeling using the Microsimulation Screening Analysis‐Colon (MISCAN‐Colon), the model used to inform the ACS screening guideline. Specifically, we will first examine prospectively the associations between mid-adulthood and early-life obesity, sedentary behaviors, and diet quality and risk of early-onset advanced adenoma (Aim 1). We will then investigate into the independent and mediating role of pre-diagnostic plasma markers of endotoxemia and inflammation in early-onset neoplasia, leveraging a cost-efficient and reliable proteomic platform. Such profiling will also allow for untargeted discoveries of protein-protein interactions to identify novel networks/targets (Aim 2). Finally, we will conduct a meta-analysis to identify early-onset CRC specific risk factors and quantify the relative risks, and integrate these findings to the MISCAN-Colon to estimate the contributions of secular changes of lifestyle to the rise of early-onset CRC and to improve the simulations used to support the 2018 ACS screening guideline using early-onset CRC specific risk factors/estimates (Aim 3). Our established team, led by an early stage investigator focused on early-onset CRC, and leaders in epidemiology, bioinformatics, biomarker measurement and discoveries, and decision modeling, offers unparalleled expertise. This investigation will illuminate significant insights into the etiology of early-onset CRC and will be a significant step forward to optimal/personalized CRC screening among younger adults.