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

项目摘要/摘要 非洲裔美国人(AA)的结直肠癌发病率和死亡率仍然是最高的 所有种族和民族群体。肿瘤生物学上的差异在多大程度上导致了显著的种族差异 差距在很大程度上仍然是未知的。我们的团队最近完成了第一个全基因组的分析 特定于腹主动脉系统的结直肠癌的突变情况。这项里程碑式的研究确定了一部小说 15基因突变特征显示AA结直肠癌的突变率增加了3倍以上，并显示 41%的AA结直肠癌在15个基因中至少有一个发生了体细胞突变，这一点非常显著 不同于源于高加索人的结直肠癌。此外，14%的AA结直肠癌患者 突变仅见于AAs，最显著的包括肾上腺素A型受体6基因[EPHA6]。我们 进一步证实，这些突变对AA结直肠癌患者的预后有不良影响。 建立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 差异可能是AAS中结直肠癌负担不同的部分原因。特别是，我们 建议：(目标1)验证和建立非洲结直肠癌新的突变亚型 祖先基因组和确定这些突变在AA结直肠癌进展中的作用；(目标2)阐明 AA结直肠癌突变标志的临床和病因学意义；和(目标3)确定 AA结直肠癌来源的EPHA6突变的功能。高度翻译性的目标1和2将是 通过对一大组独立的AA结直肠癌的15个基因突变进行重新测序完成 已注明临床和流行病学信息的患者(与高加索患者相比)。 我们将在目标3中使用CRISPR/CAS9和尖端有机化合物技术来定义功能意义 来自再障结直肠癌的EPHA6突变。我们的研究将产生对生物学的新见解 为结直肠癌的种族差异提供依据，并提供量身定制的预防和干预战略，以减少 再生障碍性贫血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.