Bacterial correlates of colorectal cancer subgroups and survival

结直肠癌亚组和生存的细菌相关性

基本信息

批准号：
9768994
负责人：
AMANDA IRENE PHIPPS
金额：
$ 60.94万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768994
关键词：
16S ribosomal RNA sequencing Address Anatomy Antibiotics Archives Ascending colon Automobile Driving BRAF gene Bacteria Biological Biological Assay Cancer Control Cancer Etiology Cancer Prognosis Carcinoma Cecum Characteristics Chemopreventive Agent Clinical Colon Colorectal Colorectal Cancer Colorectal Neoplasms Communities Complex CpG Islands DNA Data Development Diagnosis Disease Early Diagnosis Ecosystem Epidemiology Epigenetic Process Equilibrium Etiology Evaluation Exhibits Fusobacterium nucleatum Future Genes Health Heterogeneity Home environment Human Individual KRAS2 gene Knowledge Length Lesion Location Malignant Neoplasms Mediating Methylation Microbe Mismatch Repair Molecular Mutate Mutation Natural History Normal tissue morphology Pathway interactions Patients Pattern Phenotype Play Population Population Study Premalignant Probiotics Rectum Resources Risk Factors Role Site Smoking Somatic Mutation Specimen Stage at Diagnosis Structure Subgroup Testing Tissues Translating Tumor Markers Virulence adenoma bacterial community base beta diversity cancer initiation cancer survival cohort colorectal cancer prevention colorectal cancer progression colorectal cancer risk colorectal cancer treatment epidemiologic data follow-up gut bacteria gut microbiota immune function immune health improved insight molecular subtypes mutational status outcome forecast phenotypic biomarker prognostic significance rRNA Genes sound surveillance strategy treatment strategy tumor tumor microbiome

项目摘要

PROJECT SUMMARY / ABSTRACT The human gut is home to a complex ecosystem of hundreds of bacterial species. Beyond its critical role in facilitating and promoting healthy digestive and immune function, that ecosystem is increasingly recognized to impact many other aspects of health – sometimes adversely. In particular, recent evidence has suggested that specific gut bacteria, or imbalances in gut bacterial populations, could play a role in the initiation and progression of colorectal cancer (CRC). Among such bacteria, enrichment of Fusobacterium nucleatum has been most commonly implicated in CRC. However, other aspects of the gut bacterial community structure and balance could plausibly contribute to the natural history of CRC. Improved understanding as to the impact of the gut bacterial community on CRC could generate new opportunities for CRC prevention, early detection, and treatment. Attaining such understanding, however, requires consideration for the fact that CRC is a heterogeneous disease: CRC subgroups based on tumor attributes (e.g., anatomic site, deficient DNA mismatch repair) have been associated with distinct etiologic pathways and differing prognosis. Therefore, the factors driving the natural history of these CRC subgroups could plausibly be expected to differ. The objective of this study is to identify differences in patterns of bacterial enrichment and community structure in CRC across tumor subgroups of etiologic and prognostic significance, and to assess the impact of those differences on CRC survival. In Aim 1, we will refine current understanding as to the role of F. nucleatum in CRC by identifying differences in the distribution of F. nucleatum enrichment across tumor subgroups defined by clinicopathologic (e.g., stage at diagnosis) and molecular attributes (e.g., BRAF-mutation status, serrated-like subtype). In Aim 2, we will expand our evaluation of the gut bacterial community to consider broader differences in the balance of bacterial taxa (2a), as well as differences in bacterial diversity within (2b) and between (2c) tumor subgroups. Lastly, in Aim 3, we will evaluate the relationship between aspects of gut bacterial community structure and CRC survival. In pursuit of these Aims, we will leverage the resources of the Puget Sound Colorectal Cancer Cohort (PSCCC): a population-based study of individuals with incident invasive CRC for whom follow-up for survival is ongoing, epidemiologic data are available, and numerous tumor attributes have been assayed. Through this project, we will conduct targeted candidate (i.e., F. nucleatum-specific) and global (i.e., 16S rRNA gene sequencing) assays to characterize the gut bacterial community in colorectal tumors and matched normal colon tissues from 1,250 CRC cases participating in the PSCCC. Adding these data to the PSCCC will provide an important opportunity to comprehensively investigate the relationship of the gut bacterial ecosystem to CRC subgroups of etiologic significance, and to CRC survival. Insights gained through this study could ultimately inform more targeted CRC surveillance strategies and motivate the development of antibiotic or probiotic CRC therapies and chemopreventive agents.

项目概要/摘要人类肠道是一个由数百种细菌组成的复杂生态系统的家园，其在其他方面发挥着重要作用。促进和促进健康的消化和免疫功能，该生态系统越来越被认为可以影响健康的许多其他方面——有时特别是，最近的证据表明。特定的肠道细菌或肠道细菌种群的不平衡可能在启动和在这些细菌中，具核梭杆菌的富集与结直肠癌（CRC）的进展有关。然而，肠道细菌群落结构和其他方面也与结直肠癌有关。平衡可能有助于增进对 CRC 影响的了解。结直肠癌肠道细菌群落可以为结直肠癌预防、早期发现、然而，要获得这样的理解，需要考虑 CRC 是一种疾病这一事实。异质性疾病：基于肿瘤属性（例如解剖部位、DNA 缺陷）的 CRC 亚组错配修复）与不同的病因途径和不同的预后相关。驱动这些 CRC 亚组自然史的因素可能会有所不同。本研究的目的是确定结直肠癌中细菌富集模式和群落结构的差异跨具有病因学和预后意义的肿瘤亚组，并评估这些差异的影响在目标 1 中，我们将通过以下方式完善目前对具核梭杆菌在 CRC 中的作用的理解。识别 F. nucleatum 富集在肿瘤亚组中的分布差异，定义为临床病理学（例如诊断阶段）和分子属性（例如 BRAF 突变状态、锯齿状在目标 2 中，我们将扩大对肠道细菌群落的评估，以考虑更广泛的情况。细菌分类群平衡的差异 (2a)，以及 (2b) 和 (2b) 内细菌多样性的差异 (2c) 肿瘤亚组之间的关系最后，在目标 3 中，我们将评估肠道各方面之间的关系。细菌群落结构和结直肠癌生存为了实现这些目标，我们将利用资源。普吉特海湾结直肠癌队列 (PSCCC)：一项针对事件个体的人群研究正在进行生存随访的侵袭性结直肠癌，流行病学数据可用，并且有大量通过这个项目，我们将进行靶向候选（即 F. 核杆菌特异性）和全局（即 16S rRNA 基因测序）测定来表征肠道细菌参与该研究的 1,250 例 CRC 病例中结直肠肿瘤和匹配的正常结肠组织中的社区将这些数据添加到 PSCCC 将为全面调查提供重要机会。肠道细菌生态系统与具有病因学意义的 CRC 亚群以及 CRC 的关系通过这项研究获得的见解最终可以为更有针对性的 CRC 监测策略提供参考。并推动抗生素或益生菌结直肠癌疗法和化学预防药物的开发。