Biological determinants of colorectal cancer outcomes in Latinos of diverse ancestral origins

不同祖先起源的拉丁裔结直肠癌结果的生物学决定因素

• 批准号: 9917741
• 负责人: Jane C. Figueiredo
• 金额: $ 69.29万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917741
• 关键词: Accounting; Address; Admixture; African; African American; Age; Area; Attention; Biological; Biological Assay; Biological Factors; Biological Products; Birth Place; Cancer Center; Caribbean region; Central American; Cessation of life; Characteristics; Clinical; Colorectal Cancer; Communities; Cuban; Data; Data Set; Ethnic Origin; Ethnic group; European; Frequencies; Fresh Tissue; Genetic; Goals; Haplotypes; Health Services Accessibility; Hispanics; Indigenous American; Individual; Inequality; KRAS2 gene; Latino; Malignant Neoplasms; Mexican; Microsatellite Instability; Minority; Mutation; National origin; Not Hispanic or Latino; Outcome; Participant; Pathway interactions; Patient Self-Report; Patients; Pattern; Play; Population; Population Heterogeneity; Positioning Attribute; Prevalence; Prognostic Factor; Puerto Rican; Puerto Rico; Race; Research; Resources; Role; Sample Size; Shapes; Socioeconomic Status; Somatic Mutation; South American; Subgroup; Testing; The Cancer Genome Atlas; Therapeutic Agents; Time; Tissues; Treatment Efficacy; United States; Variant; Woman; Xenograft Model; Xenograft procedure; base; biobank; cancer care; cancer health disparity; caucasian American; chemotherapy; clinical application; clinical predictors; clinically actionable; cohort; demographics; driver mutation; epidemiology study; ethnic minority population; evidence base; exome; exome sequencing; experience; genetic epidemiology; individualized medicine; innovation; leukemia; men; metastatic colorectal; mortality; novel; outcome forecast; predictive modeling; prognostic; prospective; racial and ethnic; recruit; relapse risk; response; screening; sociodemographic factors; sociodemographics; targeted treatment; treatment guidelines; treatment optimization; treatment response; treatment strategy; tumor; tumor microenvironment; tv watching

ABSTRACT Hispanics/Latinos (Latinos) are the 2nd largest and fastest growing ethnic group in the United States. Although typically grouped as a single ethnic minority, Latinos are a heterogeneous population with diverse national origins, unique genetic admixture patterns (African, European, and Indigenous American ancestry), and a wide spectrum of socio-demographic characteristics. Colorectal cancer (CRC) is the second most common and fatal cancer among all Latinos combined; however, mortality rates differ substantially within Latino subpopulations defined, thus far, by place of birth. Rates are substantially higher in Puerto Ricans and Cubans, the subgroups with the highest African ancestry, than in Mexicans and non-Hispanic Whites (NHW). After accounting for socioeconomic status and access to care inequalities, differences in mortality persist, highlighting the need to accurately characterize and critically assess biological contributors to intra- and inter-ethnic group disparities. To overcome Latino underrepresentation in publicly available datasets, we propose to join resources from well- annotated epidemiologic studies including the Hispanic Colorectal Cancer Study (HCCS, R01CA155101), the Puerto Rico Biobank (PRBB, U54CA163068), and the Moffitt Cancer Center Total Cancer Care (TCC) cohort into a new consortium, the Latino Colorectal Cancer Consortium (LC3). This strategy allows us to maximize sample size and adequately represent the most common Latino subgroups in the US (i.e. Mexican, with high Indigenous American ancestry; Puerto Rican; and Cuban). We will characterize the somatic mutational profiles of Latino CRCs by whole exome sequencing using previously-collected tissues from the HCCS, PRBB, and TCC (n=600). For comparisons across racial/ethnic groups, we will leverage existing tumor sequencing data from NHW and African American (AA) CRCs in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO; 7,000 NHW), The Cancer Genome Atlas (283 NHW and 61 AA), and TCC (589 NHW and 40 AA). Here, we will examine driver mutation frequencies associated with estimated local and global genetic ancestry in Latino CRC cases (Aim 1), conduct a trans-ethnic analysis comparing frequencies of ancestry-associated and known clinically-actionable driver mutations in Latinos to NHW and AA (Aim 2), and assess the implications of genetic ancestry for survival as well as differential efficacy of conventional and potential targeted therapies for metastatic CRC using patient-derived xenograft (PDX)-based ex vivo live tissue sensitivity assays (LTSA) (Aim 3). Ancestry-specific PDX models will be established using fresh tissue from 40 prospectively recruited Latino, AA, and NHW TCC participants. Our innovative LTSA approach permits timely screening of multiple therapeutic agents while maintaining the tumor microenvironment and reliably predicting clinical responses. Results from this study will help us better understand the biological underpinnings of outcome disparities in Latino subgroups to inform translational efforts towards precision clinical applications.

抽象的 西班牙裔/拉丁美洲人（拉丁裔）是美国第二大，增长最快的族裔。虽然 拉丁美洲人通常被分为一个单一的少数民族，是一个异质的人口 起源，独特的遗传混合模式（非洲，欧洲和土著美国血统）以及广泛的 社会人口统计学特征的频谱。结直肠癌（CRC）是第二常见且致命的 所有拉丁美洲人的癌症;但是，在拉丁裔亚群中的死亡率有很大差异 到目前为止，定义了出生地。波多黎各人和古巴人的速率要高得多，亚组 与墨西哥人和非西班牙裔白人（NHW）相比，非洲血统最高。核算后 社会经济地位和获得护理不平等的机会，死亡率的差异持续存在，强调了需要 准确地表征和批判性地评估了种族间和种族间差异的生物学贡献者。 为了克服拉丁裔在公开可用数据集中的代表性不足，我们建议加入从良好的 带注释的流行病学研究在内 波多黎各生物库（PRBB，U54CA163068）和莫菲特癌症中心总癌症护理（TCC）队列 进入一个新的联盟，即拉丁裔大肠癌联盟（LC3）。这种策略使我们能够最大化 样本量并充分代表了美国最常见的拉丁裔亚组（即墨西哥人，高 美国土著血统；波多黎各;和古巴）。我们将表征躯体突变曲线 使用HCCS，PRBB和 TCC（n = 600）。对于跨种族/族裔的比较，我们将利用现有的肿瘤测序数据 从NHW和非裔美国人（AA）CRC中的结直肠癌遗传学和流行病学 财团（GECCO； 7,000 NHW），癌症基因组图集（283 NHW和61 AA）和TCC（589 NHW 和40 aa）。在这里，我们将检查与估计本地和全局相关的驱动器突变频率 拉丁裔CRC病例中的遗传血统（AIM 1）进行了跨种族分析，以比较的频率 拉丁美洲人与NHW和AA（AIM 2）的祖先相关和已知的临床驱动器突变（AIM 2），并且 评估遗传血统对生存的含义以及常规和常规的差异功效 使用患者衍生的异种移植（PDX）基于体内活体组织的转移性CRC的潜在靶向疗法 灵敏度测定（LTSA）（AIM 3）。祖先特异性的PDX模型将使用40个新鲜组织建立 前瞻性招募拉丁裔，AA和NHW TCC参与者。我们创新的LTSA方法允许及时 在保持肿瘤微环境的同时筛选多种治疗剂并可靠地预测 临床反应。这项研究的结果将有助于我们更好地了解 拉丁裔亚组中的结果差异，以告知转化工作，以实现精确的临床应用。