Biological determinants of colorectal cancer outcomes in Latinos of diverseýancestral origins

摘要 拉美裔/拉丁裔(拉丁裔)是美国第二大、增长最快的族群。虽然 拉美裔人通常被归类为一个单一的少数民族，是一个具有不同民族的不同群体。 起源、独特的遗传混合模式(非洲人、欧洲人和美洲土著人的祖先)，以及广泛的 社会人口学特征的光谱。结直肠癌(CRC)是第二常见和致命的癌症。 所有拉丁裔人群中的癌症；然而，拉丁裔亚群之间的死亡率有很大差异 到目前为止，由出生地定义的。波多黎各人和古巴人的失业率要高得多，这两个亚群 非洲血统最高，比墨西哥人和非西班牙裔白人(Nhw)更高。在考虑了 社会经济地位和获得护理的机会不平等，死亡率的差异依然存在，突出表明有必要 准确描述和批判性地评估造成种族内部和种族间差异的生物因素。 为了克服拉丁裔在公开可用的数据集中代表性不足的问题，我们建议将来自Well- 带注释的流行病学研究，包括西班牙裔结直肠癌研究(HCCS，R01CA155101)， 波多黎各生物银行(PRBB，U54CA163068)和莫菲特癌症中心全面癌症护理(TCC)队列 成立了一个新的联盟，即拉丁裔结直肠癌联盟(LC3)。这一战略使我们能够最大限度地 样本量和足以代表美国最常见的拉丁裔亚群(即墨西哥人，高 土著美国人血统、波多黎各人和古巴人)。我们将描述体细胞突变的特征 使用先前从HCCS、PRBB和PRBB收集的组织通过整个外显子组测序来检测拉丁裔CRC 膀胱移行细胞癌600例。对于跨种族/民族的比较，我们将利用现有的肿瘤测序数据 NHW和非裔美国人(AA)CRC在结直肠癌遗传学和流行病学中的作用 联合会(GECCO；7,000 nhw)、癌症基因组图谱(283 nhw和61 aa)和TCC(589 nhw 和40个AA)。在这里，我们将检查与估计的局部和全局相关的驱动程序突变频率 拉丁裔结直肠癌病例的遗传血统(目标1)，进行跨种族分析，比较 拉丁裔中与祖先相关的已知临床可操作的驱动基因突变为nhw和aa(目标2)，以及 评估遗传祖先对生存的影响以及传统和传统的不同疗效 基于患者来源异种移植(PDX)的体外活体组织治疗转移性结直肠癌的潜在靶向治疗 药敏分析(LTSA)(AIM 3)。将使用40个新鲜组织建立特定于祖先的PDX模型 预期招募拉丁裔、AA和NHW TCC参与者。我们创新的LTSA方法允许及时 维持肿瘤微环境和可靠预测的多种治疗药物的筛选 临床反应。这项研究的结果将有助于我们更好地了解 拉丁裔亚群之间的结果差异，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.