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

项目2：种族/民族差异、对肿瘤微环境和死亡率的影响

• 批准号: 10466939
• 负责人: ULRIKE PETERS
• 金额: $ 38.05万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10466939
• 关键词: 16S ribosomal RNA sequencing; Address; African American population; Age; Alaska Native; Animals; Archives; Bacteria; Bacteroides fragilis; Behavioral; Biological Assay; Cancer Control; Cancer Etiology; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Communities; Consensus; Data; Development; Diet; Dietary Practices; Disease; Ensure; Environmental Exposure; Epithelial; Escherichia coli; Ethnic Origin; Ethnic group; Etiology; Fatty acid glycerol esters; Fiber; Fusobacterium nucleatum; Future; Gene Expression; Genomics; Goals; Health; Hispanic Populations; Human; Immune; Incidence; Individual; Inflammation; Intervention; Lesion; Light; Link; Minority Groups; Native-Born; Natural History; Normal tissue morphology; Not Hispanic or Latino; Oncogenes; Outcome; Pathway interactions; Patients; Pattern; Persons; Play; Population; Population Group; Prevalence; Prognosis; Race; Reporting; Resources; Risk Factors; Role; Shoulder; Specimen; Structure; Suggestion; Time; Tissues; Tumor Biology; Tumor Burden; Tumor Tissue; United States; bacterial community; base; burden of illness; cancer diagnosis; cancer health disparity; cancer initiation; cancer subtypes; cancer survival; case control; colon cancer patients; colon tumorigenesis; colorectal cancer progression; colorectal cancer risk; design; digital; ethnic difference; ethnic diversity; fruits and vegetables; gut bacteria; gut microbiome; gut microbiota; microbial community; microbiome; microbiome components; microbiota; molecular subtypes; mortality; polyketide synthase; premalignant; prognostic; racial and ethnic; racial and ethnic disparities; racial difference; sex; transcriptome sequencing; translational research program; tumor; tumor microbiome; tumor microenvironment; tumor progression

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.

项目概要/项目摘要2 在美国 (US)，结直肠癌 (CRC) 的发病率和死亡率因种族/民族的不同而存在很大差异。 阿拉斯加原住民的结直肠癌发病率是世界上最高的；非裔美国人也肩负着 与美国其他群体相比，这种疾病的负担更高。在探索可能的因素时 造成这些观察到的差异的原因是，对以下因素的潜在贡献给予了最低限度的考虑： 微生物组。尽管肠道微生物群落的存在在所有人群中都很常见， 该社区的组成因性别、饮食和种族/民族而差异很大。肠道的组成 微生物组对包括结直肠癌在内的各种相关健康结果具有合理的影响。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 CRC 的自然史。例如，具核梭杆菌被认为可以浸润结直肠 上皮细胞，通过增加癌基因表达和炎症来促进结直肠癌，并导致结直肠癌恶化 生存。然而，关于微生物组对人群结直肠癌的贡献仍然存在许多问题 群体，以及这些贡献的影响。本研究的目的是找出差异 按种族/民族划分的 CRC 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 CRC 细菌群落按种族/民族的差异，重点关注可疑候选细菌 在 CRC 途径中具有合理的作用（即具核梭菌、产肠毒素脆弱拟杆菌和聚酮化合物） 合酶阳性大肠杆菌 – 目标 1a) 和不可知的社区范围检测 (目标 1b)。在目标 2 中，我们将 检查我们如何评估候选细菌 (2a) 和细菌群落结构的不可知模式 (2b) 与基于预后相关基因表达的 CRC 亚型和 CRC 组织中的免疫特征相关， 考虑种族/民族可能存在的差异。最后，在目标 3 中，我们将评估以下关系： CRC 的可疑候选细菌 (3a) 和细菌群落结构的不可知模式 (3b) 生存，再次考虑种族/民族之间的关联可能存在的差异。为了实现这些目标，我们 将进行有针对性的候选物（例如，F. nucleatum特异性）和不可知的全局测定（即，16S rRNA基因 测序）来描述现有研究资源中 840 个 CRC 病例的 CRC 细菌群落特征 覆盖四个种族/族裔群体：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)。生成并对比肿瘤信息 跨种族/民族不同群体的相关微生物组，并将所有这些数据与 CRC 结果相关联 将为我们提供一个机会，加深我们对微生物群在结直肠癌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有针对性的干预措施和结直肠癌控制策略提供信息 减少结直肠癌发病率和死亡率方面观察到的差异的目标。