Understanding the Contribution of Colorectal Cancer Tumor Characteristics to Disparities in Colorectal Cancer Survival

项目摘要 结直肠癌（CRC）是美国男性和女性癌症死亡的第二大原因。种族 CRC生存率存在差异，非裔美国人的CRC死亡率比非裔美国人高40%。 非西班牙裔白色美国人的死亡率。有证据表明，可能存在种族差异的内在 CRC肿瘤生物学我们假设CRC肿瘤的分子谱平均更具侵袭性 非洲裔美国人比白色美国人更容易患上癌症，这些肿瘤差异导致了种族差异。 在生存中。该项目的总体目标是确定CRC生存差异如何经历 非洲裔美国人的癌症可能受到肿瘤特征中复杂生物学差异的影响， 通过分子亚型、驱动基因状态和临床病理标志物来测量。研究计划 使用分子流行病学和癌症生物学方法，通过利用 来自三项已建立的研究的资源，包括来自大约420个 非裔美国人CRC患者和404例来自南部社区的非西班牙裔白色CRC患者 队列研究，黑人妇女健康研究和癌症基因组图谱（TCGA）。为了实现目标1，我们 将描述来自白色和非裔美国人CRC患者的CRC肿瘤的临床病理标志物 （解剖部位，分期），微卫星不稳定性，驱动基因状态（BRAF和RAS突变状态），以及 最近定义的CRC共有分子亚型。拟议的项目将是第一项研究， 非裔美国人中的CRC共有分子亚型。生物信息学方法将识别新的基因- 表达分子亚型，使用RNA-seq测量，以探索检测分子亚型的可能性。 在非裔美国人肿瘤中更普遍的亚型，可能与CRC预后有关。 (Aim 2）。最后，为了实现目标3，将确定上述肿瘤之间的关联， 特征和CRC存活率，并评估种族差异。建议的科学影响 研究将确定导致CRC生存差异的生物学机制， 通过揭示肿瘤本身的分子属性来研究非洲裔美国人。研究结果 将为未来的干预性研究奠定必要的基础。目前，确定CRC治疗 包括阶段和体细胞突变的存在的分子因素的组合。新出现的CRC 治疗可以由另外的肿瘤因子如肿瘤基因表达或其它肿瘤因子的存在来指导。 目标特性。对非裔美国人CRC生物学特性的现有知识有限 降低了精准医疗有效的前景。拟议的研究旨在提供以下数据： 非裔美国人CRC肿瘤分子谱支持亚型特异性治疗和精准健康 降低死亡率和减少种族差异的战略。

PROJECT ABSTRACT Colorectal cancer (CRC) is the second leading cause of cancer death among U.S. men and women. Racial disparities in CRC survival exist, where the CRC mortality rate for African Americans is 40% higher than the mortality rate for non-Hispanic white Americans. Evidence suggests there may be racial differences in intrinsic CRC tumor biology. We hypothesize that the molecular profile of CRC tumors is more aggressive on average for African Americans than white Americans, and that these tumor differences contribute to the racial disparity in survival. The overarching goal of the project is to define how the CRC survival disparity experienced by African Americans may be influenced by complex biologic differences in tumor characteristics, measured by molecular subtypes, driver gene status, and clinicopathologic markers. The research plan uses molecular epidemiologic and cancer biology approaches to achieve our study aims by leveraging resources from three established research studies, including CRC tumor tissue data from approximately 420 African American CRC patients and 404 non-Hispanic white CRC patients from the Southern Community Cohort Study, the Black Women’s Health Study, and The Cancer Genome Atlas (TCGA). To fulfill Aim 1, we will characterize CRC tumors from white and African American CRC patients for clinicopathologic markers (anatomic site, stage), microsatellite instability, driver gene status (BRAF, and RAS mutation status), and the recently-defined CRC consensus molecular subtypes. The proposed project will be the first study to define CRC consensus molecular subtypes in African Americans. Bioinformatics approaches will identify novel gene- expression molecular subtypes, measured using RNA-seq, to explore the possibility of detecting molecular subtypes that are more prevalent among African American tumors and that may be linked to CRC prognosis. (Aim 2). Lastly, to fulfill Aim 3, associations will be determined between the abovementioned tumor characteristics and CRC survival, and assessed for differences by race. The scientific impact of the proposed study will be to determine the biological mechanisms contributing to CRC survival disparities experienced by African Americans by uncovering the molecular attributes of the tumors themselves. The results of the study will establish the essential foundation for future interventional studies. Currently, CRC treatment is determined by a combination of molecular factors including stage and the presence of somatic mutations. Emerging CRC therapies may be guided by additional tumor factors such as tumor gene-expression or the presence of other targetable features. The existing limited knowledge of the biologic properties of African American CRCs reduces the prospect that precision medicine will be effective. The proposed study aims to provide data on African American CRC tumor molecular profiles to support subtype-specific treatments and precision health strategies to decrease mortality and reduce racial disparities.