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

摘要 拉美裔是美国第二大和增长最快的种族群体。虽然 拉丁裔通常被归类为单一的少数民族，是一个具有不同民族背景的异质人口。 起源，独特的遗传混合模式（非洲，欧洲和美洲土著血统），以及广泛的 一系列社会人口特征。结直肠癌（CRC）是第二常见和致命的 所有拉丁美洲人合并的癌症;然而，拉丁美洲亚群内的死亡率差异很大 到目前为止，由出生地定义。波多黎各人和古巴人的发病率要高得多， 最高的非洲血统，比墨西哥人和非西班牙裔白人（NHW）。并计入 由于社会经济地位和获得保健的机会不平等，死亡率方面的差异仍然存在，这突出表明需要 准确描述和严格评估种族内和种族间差异的生物因素。 为了克服拉丁裔在公开数据集中的代表性不足，我们建议将来自良好的资源- 注释的流行病学研究，包括西班牙裔结直肠癌研究（HCCS，R 01 CA 155101）， 波多黎各生物样本库（PRBB，U 54 CA 163068）和莫菲特癌症中心全面癌症护理（TCC）队列 拉丁裔结直肠癌联盟（Latino Colorectal Cancer Consortium，LC 3）该策略使我们能够最大限度地 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 美洲原住民血统;波多黎各人;和古巴人）。我们将描述体细胞突变谱 使用先前从HCCS、PRBB和 TCC（n=600）。对于跨种族/民族的比较，我们将利用现有的肿瘤测序数据， 来自NHW和非裔美国人（AA）CRC的结直肠癌遗传学和流行病学研究 联合会（GECCO; 7，000 NHW）、癌症基因组图谱（283 NHW和61 AA）和TCC（589 NHW 40 AA）。在这里，我们将检查与估计的局部和全局相关的驱动突变频率。 拉丁裔CRC病例的遗传祖先（目标1），进行跨种族分析，比较 拉丁美洲人中与NHW和AA相关的祖先相关和已知临床可行的驱动突变（Aim 2），以及 评估遗传祖先对生存的影响，以及传统和 使用基于患者来源的异种移植物（PDX）的离体活组织的转移性CRC的潜在靶向疗法 敏感性试验（LTSA）（目的3）。将使用来自40名患者的新鲜组织建立乳房特异性PDX模型。 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 筛选多种治疗药物，同时维持肿瘤微环境， 临床反应。这项研究的结果将有助于我们更好地了解 拉丁美洲亚组的结果差异，为精确临床应用的翻译工作提供信息。

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.