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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：
10301115
负责人：
Esteban Braggio
金额：
$ 67.71万
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/10301115
关键词：
Address African American 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 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 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.

非裔美国人在癌症研究中的代表性明显不足。虽然最近有尽管我们努力使更多的非洲裔美国人参与癌症研究，但仍需要做大量的工作。慢性淋巴细胞白血病（CLL）是美国最常见的白血病，新发病例约为21，000例每年诊断。CLL仍然是不可治愈的，尽管事实上，已经有重大的发展，治疗干预，随后改善结果。初步调查结果显示非裔美国人和非裔美国人之间CLL患者的分子和临床特征差异白种人特别是，非裔美国人CLL患者的发病年龄更小，更具侵袭性，诊断时的疾病，治疗开始的中位时间较短，与白种人，即使在控制治疗后，也表明可能存在其他因素可能导致这种情况。差距尽管这两个人群之间存在这些差异，但人们对这种关系知之甚少基因组学种族和CLL发病机制之间的联系到目前为止，CLL的遗传景观已经被这是一个相当严格的审查，但只在欧洲后裔的个人。此应用程序的目标是直接评估非裔美国人慢性淋巴细胞白血病的遗传基础，总体假设是基因组非洲裔美国人和高加索人之间存在异质性，这可能在一定程度上导致这种差异。 CLL的风险、发病率和死亡率。为了验证这一假设，我们将利用我们在以下方面的丰富经验： CLL并将其应用于我们收集的非裔美国人CLL患者。在目标1中，我们将执行在非裔美国人CLL个体中进行多组学（基因组学、转录组学和表观基因组学）研究，并比较这些发现与来自高加索CLL个体的公开可用的测序数据相比较。有了这些数据，我们将能够表征这两个人群中的肿瘤异质性，并识别新的体细胞调查结果。在目标2中，我们将评估通过全基因组鉴定的已知CLL易感基因座，在非裔美国人CLL病例和对照中对高加索人进行关联研究（GWAS），以提供深入了解非裔美国人基因座中指数变异和任何其他变异的差异风险高加索人。最后，在目标3中，我们将评估我们最近发现的普遍性，基因组综合测量，肿瘤突变负荷，定义为复发突变CLL的数量驱动基因在非裔美国人CLL中具有预后性。从这个应用程序中获得的知识可以提供对这两个种族群体白血病发生的生物学差异的新见解，以及提供了解在高加索CLL中发现的遗传和体细胞遗传结果的普遍性，美国黑人CLL总之，这些结果可能会改善风险分层和诊断，非洲裔美国人CLL病例，最终，他们可能会提供新的见解，以减少可能的途径， CLL中的健康差异。