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

项目 2：非裔美国人结肠癌突变特征的转化意义

• 批准号: 10227753
• 负责人: JOSEPH EDWARD WILLIS
• 金额: $ 23.25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-14 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227753
• 关键词: Adenocarcinoma; African; African American; Alcohols; Alleles; American; Anchorage-Independent Growth; Biological; CRISPR/Cas technology; Cancer Etiology; Cancer Model; Caucasians; Cells; Clinical; Cohort Studies; Colon; Colon Carcinoma; Colorectal Cancer; Communities; Complex; Data; Development; Diagnosis; Disease Outcome; Disease-Free Survival; Environmental Risk Factor; Ephrins; Epidemiology; Ethnic group; Etiology; European; Gene Mutation; Genes; Genetic; Genome; Genomics; Human; Incidence; Individual; Inherited; Intake; Intestinal Neoplasms; Intestines; Knock-in; Knockout Mice; Life Style; Link; Malignant Neoplasms; Meat; Modeling; Molecular; Mutate; Mutation; Mutation Analysis; Nigeria; North Carolina; Obesity; Organoids; Outcome; Patients; Physical activity; Play; Population; Population Sciences; Prevention; Process; Protein Truncation; RNA Splicing; Race; Risk; Risk Factors; Role; Site; Smoking; Somatic Mutation; Technology; Testing; Tissues; Tumor Biology; Tumor Suppressor Proteins; adenoma; cancer health disparity; cancer initiation; cell growth; clinically significant; colon cancer cell line; colon cancer patients; colorectal cancer progression; epidemiologic data; follow-up; genetic signature; genome-wide analysis; innovation; insight; knockout gene; lifestyle factors; loss of function mutation; migration; mortality; novel; novel strategies; premature; preventive intervention; prognostic; racial disparity; receptor; socioeconomic disparity; subcutaneous; success; tumor; tumor progression; tumor xenograft

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.

项目概要/摘要 非裔美国人 (AA) 仍然是结直肠癌发病率和死亡率最高的人群 所有种族和族裔群体。肿瘤生物学差异在多大程度上导致了显着的种族差异 差异在很大程度上仍然未知。我们的团队最近完成了首次全基因组分析 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颖的 15 个基因突变特征显示 AA 结直肠癌的突变率增加了 3 倍以上 41% 的 AA 型结直肠癌在 15 个基因中至少有一个存在体细胞突变，这显着 与源自白种人的结直肠癌不同。此外，14% 的 AA 结直肠癌含有 仅在 AA 中出现的突变，最突出的是肝配蛋白 A 型受体 6 基因 [EPHA6]。我们 进一步发现，这些突变在 AA 结直肠癌患者中带来不良的预后结果。 基于这些发现，当前的提案测试了我们的中心假设，即固有的生物 这种差异可能在一定程度上造成了 AA 地区结直肠癌负担的不同。特别是，我们 提议：（目标 1）验证并建立源自非洲的结直肠癌新突变亚型 祖先基因组并确定这些突变在 AA 结直肠癌进展中的作用； （目标 2）阐明 AA 结直肠癌突变特征的临床和病因学意义；和（目标 3）定义 AA 结直肠癌衍生的 EPHA6 突变的功能。高度转化的目标 1 和 2 将是 通过对一组独立的 AA 结直肠癌中的 15 个基因突变进行重新测序来完成 具有注释临床和流行病学信息的患者（与白人患者相比）。 我们将在目标3中使用CRISPR/Cas9和尖端类器官技术来定义功能意义 源自 AA 结直肠癌的 EPHA6 突变。我们的研究将对生物学产生新的见解 结直肠癌种族差异的基础，并为量身定制的预防和​​干预策略提供信息，以减少结直肠癌的发生 AA 人群结直肠癌的负担。