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: 10601406
• 负责人: Christopher I Li
• 金额: $ 27.11万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10601406
• 关键词: Project; Discovery; novel; tumor; tissue

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.

项目概要/摘要 虽然结直肠癌 (CRC) 的治疗结果在过去几十年中已经取得了改善， 在美国，不同种族/民族的结直肠癌发病率和死亡率仍然存在显着差异。在 特别是，阿拉斯加原住民中的 CRC 发病率和死亡率（一项研究特别不足的研究） 与全国总体比率相比，分别高出 124% 和 148%， 非裔美国人的比例分别高出 21% 和 39%。我们的首要总体目标是减少 结直肠癌死亡率的差异，特别是阿拉斯加原住民和非裔美国人的死亡率， 改进诊断时识别侵袭性 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，我们将进行嵌套病例对照 这项研究利用了经过高度临床注释的肿瘤组织样本，这些样本可以很容易地从多个国家获得 资源。病例是诊断后 5 年内死于 CRC 的 CRC 患者，对照是 匹配的 CRC 患者存活时间至少与病例诊断和死亡之间的持续时间相同 他们匹配的。我们将包括按种族/民族定义的四组患者： 阿拉斯加原住民 人、非裔美国人、西班牙裔和非西班牙裔白人有 70 例致命 CRC 病例和 140 例 CRC 每组的对照（总数 n=840）。为了发现新的预后标志物，我们将进行 RNAseq 对从福尔马林固定石蜡包埋的肿瘤材料中提取的 RNA 进行分析。本次活动的具体目标 建议如下： 1. 评估四个种族/族裔群体基因表达谱的差异，并 它们与选定的 CRC 风险因素的关系； 2. 发现 4 年内 CRC 死亡率的预测因素 不同的种族/族裔群体； 3. 表征并评估免疫细胞和基质细胞的差异 肿瘤微环境中的人群与结直肠癌死亡率相关，总体而言以及按种族/民族划分。这 研究将产生新颖的多种族高维数据，我们设想将其输入到更大规模的研究中 转化目标侧重于推进初级和二级预防的新干预目标，以及 开发临床上有用的结直肠癌不良结局预测因子，可用于指导临床决策 制作。这项研究旨在得出对服务不足的人群特别有益的研究结果 因为这项工作的直接目的是减少儿童权利公约结果中长期存在的种族/民族差异。