The microbiome ecosystem of Barrett's esophagus and progression to cancer

巴雷特食管的微生物生态系统和癌症进展

• 批准号: 10656496
• 负责人: THOMAS G PAULSON
• 金额: $ 20.16万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10656496
• 关键词: Address; Affect; Antibiotic Therapy; Antibiotics; Bacteria; Barrett Esophagus; Benign; Bile Acids; Biological Assay; Biological Markers; Biopsy; Cancer Etiology; Case/Control Studies; Cataloging; Chronic; Clinical; Clinical Management; Colon; Computing Methodologies; Country; Data; Development; Diet; Disease; Ecosystem; Epidemiologic Factors; Esophageal Adenocarcinoma; Esophagus; Etiology; Fusobacterium nucleatum; Gastroesophageal reflux disease; Gastrointestinal tract structure; Helicobacter pylori; In Situ Hybridization; Incidence; Knowledge; Lesion; Location; Malignant Neoplasms; Mediating; Methods; Microbe; Morbidity - disease rate; Obesity; Oncogenic; Outcome; Pathogenesis; Patients; Pattern; Persons; Pharyngeal structure; Populations at Risk; Probiotics; Prospective Studies; Prospective cohort; Publishing; Risk; Role; Sampling; Smoking; Stomach; Study Subject; Study models; Time; Time trend; Virus; analysis pipeline; base; cancer risk; cohort; digital; dysbiosis; environmental change; genome sequencing; innovation; microbiome; microbiome alteration; microbiome composition; mortality; patient subsets; probiotic therapy; progression risk; prospective; tumor; tumor progression; tumorigenesis; tumorigenic; whole genome

Project Summary/abstract. Esophageal adenocarcinoma (EAC) is a major cause of cancer morbidity and mortality in the US, affecting nearly 20,000 people each year. The known epidemiological factors associated with EAC and its precursor Barrett’s esophagus (BE) - gastroesophageal reflux disease, smoking, and obesity - do not completely explain why EAC has continued to increase in incidence over the past four decades. Elucidating the full repertoire of factors that modulate the initiation and progression of EAC will advance our understanding of EAC tumorigenesis and impact clinical management of patients with BE. Emerging evidence suggests microbiome alterations, potentially due to antibiotics or diet changes, are possible causative factors for BE and EAC. Exploratory studies have identified microbiome differences between BE and EAC patients and healthy study subjects, which suggests dysbiotic microbiomes or the presence of absence of specific oncogenic microbiome species in the lower esophagus may mediate the initiation of BE and/or progression of BE to EAC. We propose to use state-of-the-art computational methods to identify and characterize both candidate dysbiotic esophageal microbiomes and candidate oncogenic microbiome species in an existing, well-characterized cohort of patients with BE who either progressed to EAC (n=40) or remained non-progressing and stable with benign disease (n=40). The patients from this case-control study have previously been evaluated by whole genome sequencing of biopsies obtained from two locations in the esophagus at each of two time points. Using an analysis pipeline developed by Dr. Sam Minot of our group, we will identify the different microbiome species present in these biopsies from the whole genome sequencing data. By comparing the microbiome species present in either non-progressing patients, progressing patients, or in both, we will be able to determine which microbiome species are associated with BE in general and which are indicative of patients who progress to EAC. We will validate our findings using microbiome specific digital droplet PCR analysis and in-situ hybridization. The results of this exploratory study will inform development of a larger, prospective study examining the direct role of the microbiome in the development of EAC. The ultimate clinical impact of this study would be identification of an easily assayed target for determining cancer progression risk in patients with BE, as well as suggesting means of modulating EAC risk through elimination of the oncogenic microbe(s) or introduction of tumor suppressive microbe(s) through antibiotic or probiotic treatments.

项目摘要/摘要。食道腺癌（EAC）是癌症的主要原因 美国的发病率和死亡率每年影响近20,000人。这 与EAC及其前体Barrett食管（BE）相关的已知流行病学因素 - 胃食管反道疾病，吸烟和肥胖症 - 不能完全解释为什么EAC 在过去的四十年中，发病率一直在增加。阐明完整的曲目 调节EAC主动性和进步的因素将提高我们对 EAC肿瘤发生并影响BE患者的临床管理。新兴证据 建议可能由于抗生素或饮食改变引起的微生物组改变是可能的 BE和EAC的病因因素。探索性研究确定了微生物组差异 在BE和EAC患者和健康研究对象之间，这表明 不植物微生物组或不存在特定的致癌微生物组物种 下食道可以介导BE和/或BE向EAC的倡议。我们 建议使用最先进的计算方法来识别和表征 候选食管食管微生物组和候选肿瘤微生物组的候选疾病 现有的，良好的患者群体中的物种，他们要么发展到 EAC（n = 40）或保持良性疾病（n = 40）的稳定或稳定。病人 从该病例对照研究中，先前已经通过整个基因组测序进行了评估 在两个时间点的每个位置从食道的两个位置获得的活检。使用一个 分析管道由我们小组的Sam Minot博士开发，我们将确定不同的 这些活检中存在的微生物组物种来自整个基因组测序数据。经过 比较任何非促进患者中存在的微生物组物种， 患者或两者中，我们将能够确定哪些微生物组与 一般而言，这表明患者发展为EAC。我们将验证我们的 使用微生物组特异性数字液滴PCR分析和原位杂交的发现。这 这项探索性研究的结果将为一项更大的前瞻性研究的开发提供信息 微生物组在EAC开发中的直接作用。最终的临床影响 研究将是确定易于分配的确定癌症进展风险的目标 在有BE的患者中，并建议通过消除EAC风险调节EAC风险 通过抗生素或 益生菌治疗。