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

项目2的项目摘要/摘要 在美国，结直肠癌(CRC)的发病率和死亡率因种族/民族而有很大差异。 阿拉斯加原住民的CRC发病率是世界上报告的最高之一；非裔美国人也 与美国境内的其他人群相比，这种疾病带来的负担更高。在探索可能的因素时 造成这些观察到的差异，但最低限度地考虑了 微生物群。虽然肠道微生物群落的存在在所有人类群体中都很常见， 该社区的构成差异很大--按性别、饮食和种族/民族而定。内脏的组成 微生物组对包括CRC在内的各种相关的健康结果具有看似合理的影响。渐增 有证据表明，特定的肠道细菌，或细菌种群的失衡，可能在 中国铁路局的自然历史。例如，核梭杆菌被认为可以渗入大肠。 上皮细胞，通过增加癌基因表达和炎症促进结直肠癌，并导致较差的结直肠癌 生死存亡。然而，关于微生物组对整个人群中结直肠癌的贡献，仍然存在许多问题。 小组，以及这些贡献的影响。这项研究的目的是找出不同的 在结直肠癌中，按种族/民族分类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，以及对结直肠癌生存的影响。在目标1中，我们将评估 不同种族/民族的结直肠癌细菌群落的差异，重点放在两种可疑候选细菌上 在结直肠癌途径中可能扮演的角色(即核杆菌、产肠毒素脆弱类杆菌和聚酮 合酶阳性的大肠埃希氏菌-Aim 1a)和不可知的社区范围分析(Aim 1b)。在目标2中，我们将 检查我们如何评估候选细菌(2a)和细菌群落结构的未知模式(2b) 涉及结直肠癌组织中基于预后相关基因表达的结直肠癌亚型和免疫模式， 考虑到种族/民族可能存在的差异。最后，在目标3中，我们将评估 疑似候选细菌(3a)和细菌群落结构未知模式(3b)与结直肠癌 生存，同样考虑到按种族/族裔可能存在的联系差异。为了实现这些目标，我们 将进行有针对性的候选(例如，核杆菌特异的)和不可知的全球分析(即，16S rRNA基因 测序)对现有研究资源中840例结直肠癌病例的细菌群落进行特征分析 涵盖四个种族/民族群体：阿拉斯加原住民(n=210)，非裔美国人(n=210)， 西班牙裔(n=210)和非西班牙裔白人(n=210)。生成和对比关于肿瘤的信息- 种族/民族不同群体的相关微生物群，并将所有这些数据与儿童权利公约结果相关联 将提供一个机会，促进我们对微生物区系在结直肠癌健康差距中的作用的理解(S)。 从该项目获得的信息将为未来有针对性的干预和CRC控制战略提供信息 减少在结直肠癌发病率和死亡率方面观察到的差异的目标。

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.