Project 1: Discovery of novel tumor-tissue based predictors of lethal colorectal cancer by race/ethnicity

项目 1：按种族/民族发现基于肿瘤组织的新型致死性结直肠癌预测因子

• 批准号: 10044049
• 负责人: Christopher I Li
• 金额: $ 33.81万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044049
• 关键词: Address; Adjuvant; African American; Age; Alaska Native; Anti-Inflammatory Agents; Aspirin; Body mass index; Cancer Control; Cancer Etiology; Cessation of life; Clinical; Colorectal Cancer; Consensus; Data; Development; Diagnosis; Ensure; Ethnic Origin; Ethnic group; Etiology; Expression Profiling; Family history of; Formalin; Frequencies; Gene Expression; Goals; Hispanics; Immune; Immune response; Incidence; Individual; Intervention; Malignant Neoplasms; Methods; Molecular; Molecular Profiling; Mutation; Native Americans; Native-Born; Nested Case-Control Study; Not Hispanic or Latino; Outcome; PIK3CA gene; Paraffin Embedding; Patients; Population; Prevention strategy; Primary Prevention; Prognostic Marker; RNA; Race; Resources; Risk; Risk Factors; Sample Size; Sampling; Secondary Prevention; Selection for Treatments; Smoking History; Specimen; Stromal Cells; Survival Rate; Time; Tumor Tissue; Underserved Population; United States; Work; base; cancer diagnosis; cancer health disparity; cancer prevention; clinical decision-making; clinically actionable; colon cancer patients; colorectal cancer risk; design; disparity reduction; experience; feeding; genetic signature; improved; improved outcome; malignant breast neoplasm; medically underserved population; molecular subtypes; mortality; multidimensional data; new therapeutic target; novel; novel therapeutics; racial and ethnic; racial and ethnic disparities; racial difference; sex; success; therapeutic target; transcriptome sequencing; translational research program; tumor; tumor microenvironment

Project summary/abstract While improvements in colorectal cancer (CRC) outcomes have been made over the past several decades, pronounced disparities in CRC incidence and mortality rates by race/ethnicity persist in the United States. In particular, CRC incidence and mortality rates among Alaska Native people (a particularly understudied population) are 124% and 148% higher, respectively, compared to the overall national rates, and among African Americans they are 21% and 39% higher, respectively. Our primary overarching goal is to reduce disparities in CRC mortality, particularly those experienced by Alaska Natives and African Americans, through improving approaches to identify patients with aggressive CRC at diagnosis and discovering novel potential therapeutic targets relevant to these populations. To address this goal, we will conduct a nested case-control study that utilizes highly clinically annotated tumor tissue specimens that are readily available from several resources. Cases are CRC patients who died of CRC within 5 years of their diagnosis, and controls are matched CRC patients who survived at least as long as the duration between diagnosis and death of the case that they are matched to. We will include four groups of patients defined by race/ethnicity: Alaska Native people, African Americans, Hispanics, and non-Hispanic whites with 70 cases of lethal CRC and 140 CRC controls from each group (total n=840). To discover novel prognostic markers, we will perform RNAseq analyses on RNA extracted from formalin-fixed paraffin embedded tumor material. The specific aims of this proposal are as follows: 1. Assess differences in gene expression profiles across four racial/ethnic groups and their relationships to selected CRC risk factors; 2. Discover predictors of CRC mortality across and within four different racial/ethnic groups; and 3. Characterize and evaluate differences in the immune and stromal cell populations in the tumor microenvironment associated with CRC mortality, overall and by race/ethnicity. This study will generate novel multi-ethnic high-dimensional data that we envision feeding into larger studies with translational goals focused on advancing novel intervention targets for primary and secondary prevention, and developing clinically useful predictors of poor CRC outcomes that can be used to guide clinical decision making. This study is designed to generate findings that will be of particular benefit to underserved populations as this work is aimed directly at reducing long-standing racial/ethnic disparities in CRC outcomes.

项目摘要/摘要 在过去几十年中，结直肠癌（CRC）结果的改善已得到改善，但 在美国，种族/种族因CRC发病率和死亡率的明显差异持续存在。在 特别是阿拉斯加土著人的CRC发病率和死亡率（一个特别研究的 与总体总利率相比，人口分别高124％和148％。 非裔美国人分别高21％和39％。我们的主要总体目标是减少 CRC死亡率的差异，尤其是阿拉斯加原住民和非裔美国人经历的差异， 改进方法以识别诊断时具有侵略性CRC的患者并发现新的潜力 与这些人群相关的治疗靶标。为了解决这个目标，我们将进行嵌套的案例对照 利用高度临床注释的肿瘤组织标本的研究，可从几个 资源。病例是CRC患者在诊断后的5年内死于CRC，对照是 匹配的CRC患者至少与诊断与死亡之间的持续时间生存长期 它们与之匹配。我们将包括四组由种族/种族定义的患者：阿拉斯加本地人 人，非裔美国人，西班牙裔和非西班牙裔白人，有70例致命CRC和140例CRC 每个组的控制（总n = 840）。要发现新颖的预后标记，我们将执行RNASEQ 对从福尔马林固定石蜡嵌入的肿瘤材料提取的RNA进行分析。这个特定的目的 建议如下：1。评估四个种族/种族群体的基因表达谱的差异， 他们与选定的CRC风险因素的关系； 2。发​​现跨四个范围内CRC死亡率的预测指标 不同的种族/族裔群体； 3。表征和评估免疫和基质细胞的差异 与CRC死亡率，整体和种族/种族相关的肿瘤微环境中的种群。这 研究将产生新型的多种族高维数据 翻译目标的重点是推进针对初级和次要预防的新干预目标，以及 开发可用于指导临床决策的CRC结果的临床上有用的预测指标 制作。这项研究旨在产生对服务不足人群特别有益的发现 由于这项工作直接旨在减少CRC结果中长期存在的种族/种族差异。