Bacterial correlates of colorectal cancer subgroups and survival

结直肠癌亚组和生存的细菌相关性

• 批准号: 10228664
• 负责人: AMANDA IRENE PHIPPS
• 金额: $ 64.57万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/10228664
• 关键词: 16S ribosomal RNA sequencing; Address; Anatomy; Antibiotics; 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; Human; Individual; KRAS2 gene; Knowledge; Length; Lesion; Location; Malignant Neoplasms; Mediating; Methylation; Microbe; Mismatch Repair; Mismatch Repair Deficiency; Molecular; Mutate; Mutation; Natural History; Normal tissue morphology; Pathway interactions; Patients; Pattern; Phenotype; Play; Population; Population Study; Probiotics; Prognosis; 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; phenotypic biomarker; premalignant; prognostic significance; rRNA Genes; sound; surveillance strategy; tissue archive; treatment strategy; tumor; tumor microbiome

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.

项目总结/摘要 人类肠道是数百种细菌的复杂生态系统的家园。除了在以下方面的关键作用之外， 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识到， 影响健康的许多其他方面--有时是不利的。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 结直肠癌（CRC）的进展。在这些细菌中，具核梭杆菌的富集具有 最常见于CRC。然而，肠道细菌群落结构的其他方面和 平衡可以合理地促进CRC的自然史。更好地了解 CRC上的肠道细菌群落可以为CRC预防，早期发现， 和治疗。然而，要达成这样的理解，就需要考虑到《儿童权利公约》是一个 异质性疾病：基于肿瘤属性的CRC亚组（例如，解剖部位，DNA缺陷 错配修复）与不同的病因学途径和不同的预后有关。因此 驱动这些CRC亚组自然病程的因素可能是不同的。客观 本研究的目的是确定CRC中细菌富集模式和群落结构的差异 在病因学和预后意义的肿瘤亚组之间，并评估这些差异的影响 CRC生存率。在目标1中，我们将完善目前对F的作用的理解。CRC中的核质， 确定F.肿瘤亚组间的细胞核富集， 临床病理学的（例如，诊断时的阶段）和分子属性（例如，BRAF突变状态，锯齿样 亚型）。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 细菌分类群平衡的差异（2a），以及（2b）内细菌多样性的差异， （2c）肿瘤亚组之间。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CRC存活。为了实现这些目标，我们将利用 普吉湾结直肠癌队列（PSCCC）：一项基于人群的研究， 正在进行生存随访的侵袭性CRC，流行病学数据可用， 已经测定了肿瘤属性。通过这个项目，我们将进行有针对性的候选人（即，F. 核特异性的）和全局的（即，16 S rRNA基因测序）测定来表征肠道细菌 来自1，250例CRC病例的结直肠肿瘤和匹配的正常结肠组织中， PSCCC。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亚组以及与CRC的关系 生存通过这项研究获得的见解最终可以为更有针对性的CRC监测策略提供信息 并促进抗生素或益生菌CRC疗法和化学预防剂的发展。