Project 2: Racial/ethnic differences, impact on tumor microenvironment and mortality

项目概要/项目2摘要 在美国（US），不同人种/种族的结直肠癌（CRC）发病率和死亡率差异很大。 阿拉斯加原住民是世界上报告的CRC发病率最高的地区之一;非裔美国人也肩负着 与美国其他人群相比，这种疾病的负担增加。在探索可能 造成这些观察到的差异，很少考虑到潜在的贡献， 微生物组尽管肠道微生物群落的存在在所有人群中是普遍的， 该社区的组成因性别、饮食和种族/民族而有很大差异。肠道的组成 微生物组对各种相关的健康结果有合理的影响，包括CRC。增加 有证据表明，特定的肠道细菌，或细菌种群的不平衡，可能在肠道疾病中发挥作用。 CRC的自然史例如，有研究表明具核梭杆菌可浸润结肠直肠， 上皮，通过增加癌基因表达和炎症促进CRC，并导致CRC恶化 生存然而，关于微生物组对整个人群CRC的贡献，仍存在许多问题。 这些贡献的影响。本研究的目的是确定差异， 按人种/种族列出的CRC中的肿瘤相关微生物组，肿瘤相关微生物组与 肿瘤微环境的其他方面，以及对CRC生存的影响。在目标1中，我们将评估 按人种/种族列出的CRC中细菌群落的差异，重点关注两种疑似候选细菌 在CRC途径中具有合理的作用（即，F.具核类杆菌、产肠毒素脆弱拟杆菌和聚酮化合物 大肠杆菌-目的1a）和不可知的全社区检测（目的1b）。在目标2中，我们将 研究我们评估的候选细菌（2a）和细菌群落结构的不可知模式（2b） 涉及CRC组织中基于病理相关基因表达的CRC亚型和免疫谱， 考虑到种族/民族的可能差异。最后，在目标3中，我们将评估 疑似候选细菌（3a）和CRC细菌群落结构的不可知模式（3b） 生存率，再次考虑种族/民族相关性的可能差异。为了实现这些目标，我们 将引导目标候选人（例如，F.核特异性）和不可知全局分析（即，16s rrna基因 测序）来表征来自现有研究资源的840个CRC病例的CRC中的细菌群落 覆盖四个种族/族裔群体：阿拉斯加土著人（n = 210），非洲裔美国人（n = 210）， 西班牙裔（n = 210）和非西班牙裔白人（n = 210）。生成并对比肿瘤的信息- 跨种族/人种不同群体的相关微生物组，并将所有这些数据与CRC结局相关 将提供一个机会，以促进我们对微生物群在CRC健康差异中的作用的理解。 从该项目中获得的信息将为未来的有针对性的干预和CRC控制战略提供信息， 目标是减少CRC发病率和死亡率的明显差异。

Project Summary/Abstract of Project 2 Colorectal cancer (CRC) incidence and mortality vary substantially by race/ethnicity in the United States (US). Alaska Natives have among the highest reported rates of CRC in the world; African Americans also shoulder an elevated burden from this disease compared to other groups within the US. In exploring factors that may contribute to these observed disparities, minimal consideration has been paid to the potential contribution of the microbiome. Although the presence of a gut microbial community is common across all human populations, the composition of that community varies greatly – by sex, diet, and race/ethnicity. The composition of the gut microbiome has plausible implications for a variety of pertinent health outcomes, including CRC. Increasing evidence indicates that specific gut bacteria, or imbalances in bacterial populations, could play a role in the natural history of CRC. For example, Fusobacterium nucleatum has been suggested to infiltrate the colorectal epithelium, promote CRC by increasing oncogene expression and inflammation, and contribute to poorer CRC survival. However, many questions remain as to the contributions of the microbiome to CRC across population groups, and the implications of those contributions. The objective of this study is to identify differences in the tumor-associated microbiome in CRC by race/ethnicity, associations of the tumor-associated microbiome with other aspects of the tumor microenvironment, and the impact on CRC survival. In Aim 1, we will assess differences in the bacterial community in CRC by race/ethnicity, focusing on both suspected candidate bacteria with plausible roles in CRC pathways (i.e., F. nucleatum, enterotoxigenic Bacteroides fragilis, and polyketide synthase-positive Escherichia coli – Aim 1a) and agnostic community-wide assays (Aim 1b). In Aim 2, we will examine how our evaluated candidate bacteria (2a) and agnostic patterns of bacterial community structure (2b) relate to prognostically-relevant gene-expression-based CRC subtypes and immune profiles in CRC tissue, considering possible differences by race/ethnicity. Lastly, in Aim 3, we will evaluate the relationship of suspected candidate bacteria (3a) and agnostic patterns of bacterial community structure (3b) with CRC survival, again considering possible differences in associations by race/ethnicity. In pursuit of these Aims, we will conduct targeted candidate (e.g., F. nucleatum-specific) and agnostic global assays (i.e., 16S rRNA gene sequencing) to characterize the bacterial community in CRC for 840 CRC cases from existing study resources with coverage of four racial/ethnic groups: Alaska Native people (n=210), African Americans (n=210), Hispanics (n=210), and non-Hispanic whites (n=210). Generating and contrasting information on the tumor- associated microbiome across racially/ethnically diverse groups, and relating all these data to CRC outcomes will provide an opportunity to advance our understanding of the microbiota’s role(s) in CRC health disparities. Information gained from this project will inform future strategies for targeted interventions and CRC control with the goal of reducing observed disparities in CRC incidence and mortality.