Identification of Microbiome Based Markers to Improve Colorectal Cancer Detection

项目摘要 每20个美国人中就有一个患上结直肠癌（CRC），一旦确诊，超过三分之一的人将 五年都活不下来。虽然筛查是可用的，粪便化验，如粪便免疫化学试验（FIT） 真阳性率在64-68%之间，假阳性率在5- 10%之间。此外，委员会认为， 诸如结肠镜检查的其它方法是侵入性的且昂贵的，并且具有低的患者依从率。 显然需要改进的非侵入性方法来筛选个体或随后的结肠镜检查。 目前的提案描述了使用CRC相关生物标志物的创新来源：肠道微生物组。 这种细菌的集合栖息在胃肠道中，并且在以前的研究中在很大程度上被忽视。 人类CRC的病因学和检测。这项研究的长期目标是开发生物标志物， 改善CRC的检测，并了解增加CRC的生物学变化背后的机制。 发展CRC的风险。该提案的目的是评估基于微生物组的粪便微生物的使用。 CRC的生物标志物。中心假设是结肠腺瘤和癌的发展部分是 这些变化是由肠道微生物组介导的，并且微生物组的变化可用于识别健康变化。 动物研究表明，微生物组的变化可导致慢性局部和全身性疾病。 炎症，促进CRC的发展。通过最近与大学的合作， 早期检测研究网络五大湖新英格兰临床验证的密歇根州成员 结果表明，完整粪便中细菌种群的丰度可以显着提高 检测CRC的能力。目前的提案旨在证明，结合基于微生物组的 使用标准的基于粪便的分析将改善CRC检测。提出了三个具体目标： 量化组合FIT和微生物组模型的灵敏度和特异性，以提高灵敏度， 检测SRN的特异性，（ii）评估残留FIT材料作为整个粪便替代物的能力 样本检测SRN，以及（iii）测量患者特征和模型之间的关联 性能这项拟议中的研究将产生重大贡献，因为将首次有 一组经验证的CRC生物标志物，其基于接近CRC预测值的微生物组。 结肠镜检查的费用。本研究的创新之处在于其研究范围、研究对象、研究方法和研究方法 人口和将微生物组组成与物理样品联系起来的能力，对患者临床数据的访问， 和潜在的机会，以纳入来自平行生物标志物验证研究的数据， 同样的样品。这些目标的成功完成将在检测 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.