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 在结直肠癌存活率方面存在差异，非洲裔美国人的结直肠癌死亡率比 非西班牙裔美国白人的死亡率。有证据表明，可能存在内在的种族差异 结直肠癌肿瘤生物学。我们假设平均而言，结直肠癌的分子图谱更具侵袭性。 对于非裔美国人而不是白人美国人来说，这些肿瘤差异导致了种族差异 在生存中。该项目的首要目标是确定儿童生存差距是如何经历的。 非裔美国人可能受到肿瘤特征的复杂生物差异的影响， 通过分子亚型、驱动基因状态和临床病理标记物进行测量。研究计划 使用分子流行病学和癌症生物学方法来实现我们的研究目标 资源来自三项已建立的研究，包括来自大约420个结直肠癌肿瘤组织的数据 来自南方社区的非洲裔美国人结直肠癌患者和404名非西班牙裔白人结直肠癌患者 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 将从白人和非裔美国人的结直肠癌患者身上鉴定结直肠癌的临床病理标志 (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 最近确定的结直肠癌共识分子亚型。拟议中的项目将是第一个确定 非裔美国人的CRC共识分子亚型。生物信息学方法将识别新的基因- 表达分子亚型，用RNA-seq测量，以探索检测分子的可能性 在非裔美国人肿瘤中更为常见的亚型，可能与CRC的预后有关。 (目标2)。最后，为了实现目标3，将确定上述肿瘤之间的关联 特征和结直肠癌存活率，并根据种族评估差异。建议的科学影响 研究将确定导致结直肠癌存活率差异的生物学机制 非裔美国人通过揭示肿瘤本身的分子属性。该研究的结果 将为今后的介入研究奠定必要的基础。目前，CRC处理已确定 这是包括分期和体细胞突变在内的多种分子因素共同作用的结果。新兴的CRC 治疗可以由额外的肿瘤因素来指导，例如肿瘤基因的表达或其他 有针对性的特征。现有对非裔美国人CRCs生物学特性的有限了解 降低了精准医学将有效的前景。拟议的研究旨在提供以下方面的数据 非裔美国人结直肠癌分子图谱支持亚型特异性治疗和精确健康 减少死亡率和缩小种族差距的战略。

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.