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

项目摘要/摘要 早发性结直肠癌(50岁以前确诊的结直肠癌)发病率的上升导致了 美国癌症协会(ACS)建议中等风险筛查的指南从45岁开始，而不是50岁。 争论集中在增加2100万非常低风险的成年人的巨大成本和资源上 筛查池，以及“进一步个性化筛查策略”是优先事项。确定项目的贡献者 发病率上升是第一步，但到目前为止还没有得到满足。生活方式因素先于并反映了 早发性结直肠癌的迅速增加，包括肥胖、久坐和饮食不良，可能起到关键作用。我们的 初步数据支持肥胖和久坐行为的重要性，早发性结直肠癌的可能性更大 与65岁后确诊的结直肠癌相比，按传统的腺瘤-癌序列进行处理。 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调查将 阐明年轻时结直肠癌发生的洞察力。越来越多的数据表明，微生物 移位/内毒素血症，触发随后的炎症和免疫反应，并通过 上述生活方式因素，可能是一条新兴的途径。我们假设肥胖症，延长 久坐和饮食质量差通过增加内毒素血症增加患早发性晚期腺瘤的风险 和炎症，并导致早发性结直肠癌的增加。为了检验这些假设，我们将利用 在两个特征良好的前瞻性队列中收集的整个生命过程的生活方式数据(护士健康研究 II[NHSII])和南方社区队列研究(SCCS)，以及存档的诊断前血液，补充 通过使用微模拟筛选分析-冒号(MISCAN-COLON)进行决策建模，该模型用于 告知急性冠脉综合征筛查指南。具体地说，我们将首先前瞻性地研究 成年中期和早期肥胖、久坐行为和饮食质量与早发性晚期心脏病的风险 腺瘤(目标1)。然后我们将研究诊断前血浆的独立和中介作用。 早发性肿瘤的内毒素血症和炎症标志物，利用具有成本效益和可靠性的 蛋白质组平台。这样的分析还将允许对蛋白质-蛋白质相互作用的无目标发现 确定新的网络/目标(目标2)。最后，我们将进行Meta分析，以确定早发性CRC 具体的风险因素和量化的相对风险，并将这些发现整合到MISCAN-COLON中进行估计 生活方式的长期变化对早发性结直肠癌发病的贡献及模拟研究的改进 用于支持使用早发性CRC特定风险因素/估计(AIM)的2018年ACS筛查指南 3)。我们现有的团队由一名专注于早发性结直肠癌的早期研究人员领导，并在 流行病学、生物信息学、生物标记物测量和发现，以及决策建模，提供 无与伦比的专业知识。这项研究将有助于深入了解早发性结直肠癌的病因。 这将是在年轻人中进行最佳/个性化结直肠癌筛查的重要一步。

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.