Identification of Microbiome Based Markers to Improve Colorectal Cancer Detection

鉴定基于微生物组的标记物以改善结直肠癌检测

基本信息

批准号：
10082437
负责人：
MACK T. RUFFIN
金额：
$ 31.93万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-15 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10082437
关键词：
Address Adult Age Aliquot American Animals Bacteria Biological Biological Assay Biological Markers Blinded Body mass index Characteristics Chronic Clinical Clinical Data Clinical Trials Collaborations Collection Colon Carcinoma Colonic Adenoma Colonic Diseases Colonoscopy Colorectal Colorectal Cancer Complement DNA Data Databases Detection Development Diagnosis Early Detection Research Network Early Diagnosis Early treatment Elements Etiology Feces Gastrointestinal tract structure Gender Genes Genetic Variation Goals Health Hemoglobin Hemoglobin concentration result High grade dysplasia Histopathology Human Human body Individual Intake Large Intestine Carcinoma Lead Lesion Link Machine Learning Mass Screening Materials Testing Measures Meat Mediating Methods Michigan Mission Modeling Neoplasms New England Non-Steroidal Anti-Inflammatory Agents Participant Patient-Focused Outcomes Patients Performance Population Predictive Value Preparation Process Prospective Studies Proxy Public Health Publishing Research Research Personnel Research Support Resected Residual state Risk Sampling Sensitivity and Specificity Somatic Cell Source Specificity Target Populations Technology Testing Time Tissues Training Universities Validation Villous Work adenoma base biobank biomarker validation cancer diagnosis cohort colon cancer screening colon carcinogenesis colorectal cancer screening compliance behavior cost density design fecal microbiome gut microbiome gut microbiota improved innovation insight interest member microbial microbiome microbiome composition microbiota mortality patient subsets predictive modeling rRNA Genes random forest screening stool sample systemic inflammatory response validation studies

项目摘要

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.

项目概要每 20 名美国人中就有 1 人患有结直肠癌 (CRC)，一旦确诊，超过三分之一的人将罹患结直肠癌活不过5年。尽管可以进行筛查，但仍需进行粪便检测，例如粪便免疫化学检测 (FIT) 真阳性率在 64-68% 之间，假阳性率在 5-10% 之间。而且，其他方法（例如结肠镜检查）具有侵入性且昂贵，并且患者依从率较低。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 CRC 相关生物标志物的创新来源：肠道微生物组。这些细菌栖息在胃肠道中，在之前的研究中基本上被忽视了。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进 CRC 的检测并了解导致 CRC 增加的生物学变化背后的机制发生结直肠癌的风险。该提案的目的是评估基于微生物组的粪便的使用 CRC 的生物标志物。中心假设是结肠腺瘤和结肠癌的发展部分取决于由肠道微生物组介导，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，促进结直肠癌的发展。通过最近与大学的合作密歇根州早期检测研究网络五大湖新英格兰临床验证成员研究表明，完整粪便中细菌种群的丰度可以显着提高检测CRC的能力。当前的提案旨在证明结合基于微生物组的基于标准粪便的分析将改善 CRC 的检测。提出了三个具体目标：(i) 量化 FIT 和微生物组组合模型的敏感性和特异性，以提高敏感性和特异性检测 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检测 SRN 的样本，以及 (iii) 测量患者特征和模型之间的关联表现。拟议的研究将产生重大贡献，因为这是第一次一组经过验证的 CRC 生物标志物，基于微生物组，接近预测值结肠镜检查只需一小部分费用。拟议的研究因其范围、目标而具有创新性人口和将微生物组组成与物理样本联系起来的能力，获取患者临床数据，以及整合来自平行生物标志物验证研究的数据的潜在机会，这些研究使用了相同的样品。成功完成这些目标将为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。