Identification of Microbiome Based Markers to Improve Colorectal Cancer Detection

项目摘要 每20名美国人中就有一人罹患结直肠癌，一旦确诊，超过三分之一的人会患上结直肠癌 活不过5年。虽然可以进行筛查，但粪便检测，如粪便免疫化学试验(FIT) 真阳性率-68%，假阳性率5%-10%。此外， 其他方法，如结肠镜检查，具有侵入性，费用昂贵，患者依从率低。 显然需要改进的非侵入性方法来筛查个体或随后的结肠镜检查。 目前的提案描述了使用一种与结直肠癌相关的生物标志物的创新来源：肠道微生物组。 这种细菌聚集在胃肠道中，在以前的研究中基本上被忽略了。 人类结直肠癌的病因和检测。这项研究的长期目标是开发生物标记物 改进对CRC的检测，并了解增加的生物变化背后的机制 发展CRC的风险。这项提案的目的是评估基于微生物组的粪便的使用 结直肠癌的生物标志物。中心假设是结肠腺瘤和结肠癌的发生在一定程度上 肠道微生物群的变化可以用来确定健康方面的变化。 来自动物的研究表明，微生物组的变化可以导致慢性局部和全身 炎症，促进结直肠癌的发展。通过最近与密歇根大学的合作 密歇根州大湖区早期检测研究网络成员新英格兰临床验证 中心的研究表明，完整粪便中细菌种群的丰度可以显著提高 检测CRC的能力。目前的提案试图证明，将基于微生物组的 使用标准的基于粪便的分析将改进CRC检测。提出了三个具体目标：(一) 量化FIT和微生物组组合模型的敏感性和特异性，以提高敏感性和 检测SRN的特异性，(Ii)评估残留配对材料作为整个粪便代用品的能力 样本用于检测SRN，以及(Iii)测量患者特征和模型之间的关联 性能。拟议的研究将产生重大贡献，因为将首次 一组经过验证的结直肠癌生物标记物，基于接近 结肠镜检查的费用只是成本的一小部分。所提出的研究具有创新性，因为它的范围、目标 群体和将微生物组组成与物理样本联系起来的能力，对患者临床数据的访问， 以及纳入来自平行生物标记物验证研究的数据的潜在机会 同样的样本。这些目标的成功完成将在检测到 结肠腺瘤有一个非常真实的机会来开发一组强大的微生物生物标志物 补充现有技术。

Project Summary One of every 20 Americans develops colorectal cancer (CRC) and, once diagnosed, more than one-third will not survive 5 years. Although screening is available, stool assays such as fecal immunochemical test (FIT) have true positive rates ranging between 64-68% and false positive rate ranging between 5-10%. Moreover, other approaches such as colonoscopy are invasive and expensive and have low rates of patient adherence. There is clearly a need for improved non-invasive methods to screen individuals or subsequent colonoscopy. The current proposal describes using an innovative source of CRC-related biomarkers: the gut microbiome. This collection of bacteria inhabits the gastrointestinal tract and has largely been ignored in previous studies of the etiology and detection of CRC in humans. The long-term goal of this research is to develop biomarkers that improve the detection of CRC and to understand the mechanisms behind the biological changes that increase the risk of developing CRC. The objective of this proposal is to assess the use of microbiome-based fecal biomarkers of CRC. The central hypothesis is that development of colonic adenomas and carcinomas is in part mediated by the gut microbiome and that changes to the microbiome can be used to identify changes in health. Animal studies from have demonstrated that changes in the microbiome can lead to chronic local and systemic inflammation, which promotes the development of CRC. Through a recent collaboration with the University of Michigan members of the Early Detection Research Network Great Lakes New England Clinical Validation Center it was shown that the abundance of bacterial populations within intact feces could significantly improve the ability to detect CRC. The current proposal seeks to demonstrate that combining microbiome-based analyses with standard stool-based analyses will improve CRC detection. Three specific aims are proposed: (i) quantify the sensitivity and specificity of a combined FIT and microbiome model to improve the sensitivity and specificity of detecting SRN, (ii) assess the ability of residual FIT material to serve as a proxy for a whole fecal sample in detecting SRN, and (iii) measure the association between patient characteristics and model performance. The proposed research will yield a significant contribution because for the first time there will be a validated set of biomarkers for CRC that are based on the microbiome that approach the predictive value of colonoscopies for a fraction of the cost. The proposed research is innovative because of its scope, target population and ability to link microbiome composition with a physical sample, access to patient clinical data, and potential opportunities to incorporate data from parallel biomarker validation studies that have used the same samples. Successful completion of these aims will yield a significant translational step in the detection of colonic adenoma with a very real opportunity to develop a robust panel of microbial biomarkers that complement existing technologies.