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

项目概要/摘要 虽然在过去的几十年里，结直肠癌（CRC）的预后有所改善， 在美国，不同种族/民族的CRC发病率和死亡率存在显著差异。在 特别是，阿拉斯加原住民的CRC发病率和死亡率（特别是研究不足的 与全国总体比率相比， 非洲裔美国人分别高出21%和39%。我们的首要目标是减少 CRC死亡率的差异，特别是阿拉斯加原住民和非裔美国人， 改善诊断时识别侵袭性CRC患者的方法，并发现新的潜力 与这些人群相关的治疗目标。为了实现这一目标，我们将进行一个嵌套的病例对照 一项利用高度临床注释的肿瘤组织标本的研究，这些标本可从几个 资源病例是在诊断后5年内死于CRC的CRC患者，对照是 匹配的CRC患者，其存活时间至少与病例诊断和死亡之间的持续时间一样长 与之匹配的我们将纳入按种族/民族定义的四组患者：阿拉斯加原住民 非裔美国人、西班牙裔和非西班牙裔白人，70例致命性CRC和140例CRC 每组的对照组（总共n=840）。为了发现新的预后标志物，我们将进行RNAseq 分析从福尔马林固定的石蜡包埋的肿瘤材料中提取的RNA。具体目标是 建议如下：1.评估四个种族/民族群体的基因表达谱差异， 它们与选定的CRC风险因素的关系; 2.发现四年内CRC死亡率的预测因素 不同的种族/族裔群体;以及3.表征和评价免疫细胞和基质细胞的差异 肿瘤微环境中与CRC死亡率相关的人群，总体和人种/种族。这 研究将产生新的多种族高维数据，我们设想将其输入更大的研究， 转化目标侧重于推进初级和二级预防的新干预目标， 开发临床上有用的CRC不良结局预测因子，用于指导临床决策 制作。这项研究的目的是产生的结果，将特别有利于服务不足的人口 因为这项工作的直接目的是减少《儿童权利公约》成果方面长期存在的种族/族裔差异。

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.