Germline and Somatic Genomic Studies in CLL Minorities

CLL 少数群体的种系和体细胞基因组研究

基本信息

批准号：
10437017
负责人：
Esteban Braggio
金额：
$ 64.91万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10437017
关键词：
Address African American African American population Age of Onset Automobile Driving B-Cell Neoplasm Biological Biology Caucasians Characteristics Chromosomal Rearrangement Chronic Lymphocytic Leukemia Clinical Collection DNA sequencing Data Development Diagnosis Disease Etiology European Frequencies Gene Dosage Gene Frequency Genes Genetic Genetic Heterogeneity Genomics Genotype Goals Heterogeneity Incidence Individual Inherited Knowledge Measures Minority Molecular Morbidity - disease rate Mutate Mutation Outcome Pathogenesis Patients Population Predisposition Privatization Prognosis Prognostic Factor Public Health Race Recurrence Reduce health disparities Research Design Risk Single Nucleotide Polymorphism Somatic Mutation Susceptibility Gene Testing Therapeutic Intervention Time Variant Woman Work anticancer research base case control deep sequencing epigenomics exome sequencing experience genome sequencing genome wide association study health disparity improved indexing insight leukemia leukemogenesis men mortality multiple omics novel polygenic risk score prognostic prognostication racial difference racial population risk stratification targeted sequencing transcriptome transcriptomics tumor tumor DNA tumor heterogeneity whole genome

项目摘要

African Americans are significantly underrepresented in cancer research. Although there have been recent efforts toward more inclusion of African Americans in cancer research, substantial work is still needed. Chronic lymphocytic leukemia (CLL) is the most common leukemia in the U.S. with ~21,000 new cases diagnosed each year. CLL is still incurable despite the fact that there have been significant developments in therapeutic interventions with subsequent improvements in outcome. There are initial findings demonstrating differences in molecular and clinical characteristics of CLL patients between African Americans and Caucasians. In particular, African American CLL patients have a younger age of onset, a more aggressive disease at diagnosis, shorter median time to therapy initiation, and reduced overall survival compared to Caucasians, even after controlling for therapy, suggesting that other factors may exist that may be driving this disparity. Despite these differences across these two populations, little is known about the relationship between genomics, race, and CLL pathogenesis. To date, the genetic landscape of CLL has been considerably scrutinized but only among individuals of European descendent. The goal of this application is to directly evaluate the genetic basis of CLL among African Americans with the overall hypothesis that genomic heterogeneity exists between African American and Caucasian populations that may drive, in part, the disparity in risk, morbidity, and mortality in CLL. To test this hypothesis, we will leverage our extensive experience in CLL and applying it to our collection of African American individuals with CLL. In Aim 1 we will perform a multi-omic (genomic, transcriptomic, and epigenomic) study in African American CLL individuals and compare the findings with publicly available sequencing data from Caucasian CLL individuals. With these data, we will be able to characterize the tumor heterogeneity across these two populations and identify novel somatic findings. In Aim 2, we will evaluate the known CLL susceptibility loci identified through genome wide association studies (GWAS) of Caucasians in African American CLL cases and controls in order to provide insight into the differential risk of the index variants and any other variants in the loci across African American and Caucasian populations. Finally, in Aim 3, we will evaluate the generalizability of our recent findings that the genomic summary measure, the tumor mutational load, defined as the number of recurrently mutated CLL driver genes, is prognostic in African American CLLs. The knowledge gained from this application may provide novel insight into the biological differences in leukemogenesis across these two racial group as well as provide understanding of the generalizability of the inherited and somatic genetic findings found in Caucasian CLL to African American CLL. Together these results may improve risk stratification and prognostication among African American CLL cases, and ultimately, they may provide new insights into possible avenues to reduce health disparity in CLL.

在癌症研究中，非裔美国人的人数大大不足。尽管最近有为更多地包括非裔美国人在癌症研究中的努力，仍然需要大量工作。慢性淋巴细胞白血病（CLL）是美国最常见的白血病，新病例约为21,000例每年被诊断出。尽管有重大发展，但CLL仍然无法治愈治疗干预措施随后的结果改善。有初步发现证明非洲裔美国人与CLL患者分子和临床特征的差异高加索人。特别是，非裔美国人CLL患者的发病年龄较小，更具侵略性诊断时疾病，治疗开始时间较短，总体存活率降低高加索人即使在控制治疗后，也可能存在其他因素差距。尽管在这两个人群中存在这些差异，但对这种关系知之甚少在基因组学，种族和CLL发病机理之间。迄今为止，CLL的遗传景观已经经过相当大的审查，但仅在欧洲后代的个人中。该应用的目的是直接评估非裔美国人中CLL的遗传基础，总体假设是基因组非裔美国人和高加索人口之间存在异质性，可能部分驱动差异 CLL的风险，发病率和死亡率。为了检验这一假设，我们将利用我们的丰富经验 CLL并将其应用于我们与CLL的非裔美国人集合。在AIM 1中，我们将执行非裔美国人CLL个体中的多运动（基因组，转录组和表观基因组学）研究并进行比较来自高加索CLL个体的公开测序数据的发现。使用这些数据，我们将能够表征这两个人群中的肿瘤异质性并识别新型体细胞发现。在AIM 2中，我们将评估通过基因组广泛识别的已知CLL敏感性基因座在非裔美国人CLL病例和对照中，高加索人的协会研究（GWAS）为了提供深入了解非裔美国人的指数变体的差异风险和基因座的任何其他变体和高加索人口。最后，在AIM 3中，我们将评估我们最近发现的普遍性基因组摘要度量，肿瘤突变负荷，定义为经常突变的CLL的数量驾驶员基因在非裔美国人的CLL中是预后的。从本应用中获得的知识可能会提供对这两个种族群体中白血病的生物学差异的新洞察力，并提供了解在高加索CLL中发现的遗传和躯体遗传发现的普遍性非裔美国人CLL。这些结果共同改善了风险分层和预测非裔美国人CLL案件，最终，它们可能会提供有关减少可能途径的新见解 CLL的健康差异。