Project 2: Translational Significance of a Mutational Signature of African American Colon Cancers

项目概要/摘要 非裔美国人（AAs）的结直肠癌发病率和死亡率仍然最高， 所有种族和民族群体。肿瘤生物学的差异在多大程度上导致了显著的种族差异？ 差异在很大程度上仍然不为人所知。我们的团队最近完成了第一个全基因组分析， 特别是在AA中出现的结直肠癌的突变景观。这项具有里程碑意义的研究发现了一种新的 15-基因突变特征显示AA结直肠癌中突变率增加3倍以上，并显示 41%的AA结直肠癌在15个基因中的至少一个中具有体细胞突变，这是显著的。 与白种人的结直肠癌不同此外，14%的AA结直肠癌患者 仅在AA中观察到突变，最显著的包括肝配蛋白A型受体6基因[EPHA 6]。我们 进一步确定这些突变在AA结直肠癌患者中传达不良预后结果。 在这些发现的基础上，目前的提议测试了我们的中心假设，即固有的生物学特性。 这种差异可能部分地导致了AA中结肠直肠癌的不同负担。我们尤其 目的：（1）验证和建立一种新的非洲人大肠癌突变亚型， 祖先基因组，并确定这些突变在AA结直肠癌进展中的作用;（目的2）阐明 AA结直肠癌中突变标签的临床和病因学意义;以及（目的3）定义 AA结直肠癌衍生的EPHA 6突变的功能。高度转化的目标1和2将是 通过重新测序一个大型独立的AA结直肠癌组中的15个基因突变来完成 患者（与白人患者相比），他们有注释的临床和流行病学信息。 我们将在目标3中使用CRISPR/Cas9和尖端的类器官技术来定义功能意义 来自AA结直肠癌的EPHA 6突变。我们的研究将产生新的见解， 结直肠癌的种族差异的基础，并提供量身定制的预防和干预策略，以减少 AA人群的结直肠癌负担。

PROEJCT SUMMARY/ABSTRACT African Americans (AAs) continue to have the highest incidence and mortality rates of colorectal cancer among all racial and ethnicity groups. To what extent differences in tumor biology contribute to the striking racial disparities remain largely unknown. Our team has recently completed the first genome-wide analysis of the mutational landscape of colorectal cancers specifically arising in AAs. This landmark study has identified a novel 15-gene mutation signature showing an over 3-fold increased mutation rate in AA colorectal cancers, and shown that 41% of AA colorectal cancers have somatic mutations in at least one of the 15 genes, which is significantly different from colorectal cancers derived from Caucasians. Furthermore, 14% of AA colorectal cancers harbor mutations seen exclusively in AAs, most prominently including the ephrin type A receptor 6 gene [EPHA6]. We further identified that these mutations convey a poor prognostic outcome in AA colorectal cancer patients. Building upon these discoveries, the current proposal tests our central hypothesis that inherent biological differences may in part be responsible for the disparate burden of colorectal cancer in AAs. In particular, we propose to: (Aim 1) validate and establish a novel mutation subtype of colorectal cancer arising from African ancestry genome and define the role of these mutations in AA colorectal cancer progression; (Aim 2) elucidate the clinical and etiological significance of the mutation signature in AA colorectal cancer; and (Aim 3) to define the functionality of AA colorectal cancer-derived EPHA6 mutations. The highly translational aims 1 and 2 will be accomplished by re-sequencing the 15-gene mutations in a large independent set of AA colorectal cancer patients (in comparison with Caucasian patients) who have annotated clinical and epidemiological information. We will use CRISPR/Cas9 and cutting-edge organoid technologies in aim 3 to define the functional significance of EPHA6 mutations derived from AA colorectal cancers. Our study will generate novel insight into the biological basis for racial disparities in colorectal cancer and inform tailored prevention and intervention strategies to reduce the burden of colorectal cancer in AA population.