Bacterial correlates of colorectal cancer subgroups and survival

项目摘要/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。除了它在以下方面的关键作用 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，或肠道细菌种群的失衡，可能在肠道细菌的启动和转移中发挥作用 结直肠癌的进展(CRC)。在这类细菌中，核梭杆菌的浓缩具有 最常与儿童权利委员会有牵连。然而，肠道细菌群落结构的其他方面和 平衡似乎可以为儿童权利公约的自然历史做出贡献。提高对以下问题的认识 结直肠癌上的肠道细菌群落可能为结直肠癌的预防、早期发现、 和治疗。然而，要达到这种理解，就需要考虑这样一个事实，即《儿童权利公约》是 异质性疾病：基于肿瘤属性(例如，解剖部位、DNA缺陷)的CRC亚型 错配修复)与不同的致病途径和不同的预后有关。因此， 驱动这些CRC亚群自然历史的因素似乎可以被认为是不同的。目标是 这项研究的目的是确定结直肠癌细菌丰富模式和群落结构的差异。 跨肿瘤亚组的病因和预后意义，并评估这些差异的影响 关于CRC的生存。在目标1中，我们将通过以下方式完善目前对核杆菌在结直肠癌中的作用的理解 确定不同肿瘤亚组之间富含核镰刀菌的差异 临床病理(例如，诊断阶段)和分子属性(例如，BRAF突变状态、锯齿状 子类型)。在目标2中，我们将扩大我们对肠道细菌群落的评估，以考虑更广泛的 细菌分类群(2a)平衡的差异，以及(2b)和(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 细菌群落结构与结直肠癌存活率。为达致这些目标，我们会善用 普吉特湾结直肠癌队列(PSCCC)：一项基于人群的事件个体研究 正在进行生存随访的侵袭性结直肠癌，流行病学数据可用，以及许多 已经对肿瘤属性进行了分析。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)和全局(即16S rRNA基因测序)分析来表征肠道细菌 1,250例结直肠癌患者的结直肠肿瘤和配对的正常结肠组织中的群落 PSCCC。将这些数据添加到PSCCC将提供一个全面调查的重要机会 肠道细菌生态系统与结直肠癌病原学亚型的关系及与结直肠癌的关系 生死存亡。通过这项研究获得的见解最终可能为更有针对性的CRC监测战略提供参考 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。

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.