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.

非裔美国人在癌症研究中的代表性明显不足。虽然最近有尽管努力让非裔美国人更多地参与癌症研究，但仍需要开展大量工作。慢性淋巴细胞白血病 (CLL) 是美国最常见的白血病，新增病例约 21,000 例每年都会确诊。尽管慢性淋巴细胞白血病（CLL）已经取得了重大进展，但它仍然无法治愈。治疗干预措施随后改善结果。初步调查结果表明非裔美国人和美国人之间 CLL 患者分子和临床特征的差异白种人。特别是非裔美国CLL患者发病年龄更小，侵袭性更强与相比，诊断时患有疾病，开始治疗的中位时间更短，总体生存率更低白人，即使在控制了治疗之后，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，但人们对其中的关系知之甚少基因组学、种族和 CLL 发病机制之间的关系。迄今为止，CLL 的遗传图谱已受到相当多的审查，但仅限于欧洲后裔。该应用程序的目标是直接评估非裔美国人 CLL 的遗传基础，总体假设是基因组非裔美国人和白人之间存在异质性，这可能在一定程度上造成了这种差异 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领域的丰富经验： CLL 并将其应用于我们患有 CLL 的非洲裔美国人的集合。在目标 1 中，我们将执行对非裔美国人 CLL 个体进行多组学（基因组、转录组和表观基因组）研究并进行比较该研究结果来自白种人 CLL 个体的公开测序数据。有了这些数据，我们将能够表征这两个群体的肿瘤异质性并识别新的体细胞发现。在目标 2 中，我们将评估通过全基因组确定的已知 CLL 易感位点非洲裔美国人 CLL 病例和对照中白种人的关联研究 (GWAS)，以便提供深入了解非裔美国人基因座中索引变异和任何其他变异的差异风险和白人人口。最后，在目标 3 中，我们将评估我们最近发现的普遍性：基因组汇总测量，肿瘤突变负荷，定义为复发性突变 CLL 的数量驱动基因对非裔美国人 CLL 具有预测作用。从该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颖见解，并提供了解白种人 CLL 中发现的遗传和体细胞遗传学发现的普遍性非洲裔美国人 CLL。这些结果共同可以改善风险分层和预测非洲裔美国人 CLL 病例，最终，它们可能为减少可能的途径提供新的见解 CLL 的健康差异。