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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.

非洲裔美国人在癌症研究中的代表性明显不足。尽管最近有一些在努力将非裔美国人更多地纳入癌症研究方面，仍然需要做大量的工作。慢性淋巴细胞白血病(CLL)是美国最常见的白血病，新增病例约21,000例每年都会确诊。慢性淋巴细胞性白血病仍然不治之症，尽管在治疗干预，并随后改善结果。有初步的发现表明非裔美国人与非裔美国人慢性淋巴细胞性白血病分子和临床特征的差异高加索人。特别是，非裔美国人CLL患者具有更年轻的发病年龄，更具侵袭性与对照组相比，在确诊时患病、开始治疗的中位时间更短、总存活率降低高加索人，即使在控制治疗后也是如此，这表明可能存在其他因素可能推动了这一现象贫富差距。尽管这两个人群存在这些差异，但人们对这种关系知之甚少基因组学、RACE和CLL发病机制之间的关系。到目前为止，CLL的遗传图景一直是受到了相当大的审查，但仅限于欧洲后裔的个人。此应用程序的目标是直接评估非裔美国人慢性淋巴细胞性白血病的遗传基础非裔美国人和高加索人之间存在着异质性，这可能在一定程度上导致了这种差异慢性淋巴细胞性白血病的风险、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并将其应用于我们收集的患有CLL的非裔美国人。在目标1中，我们将执行非裔美国人慢性淋巴细胞性白血病患者的多基因组(基因组、转录和表观基因组)研究及比较这一发现与可公开获得的高加索人慢性淋巴细胞白血病患者的测序数据相一致。有了这些数据，我们将能够表征这两个人群中肿瘤的异质性，并识别新的体细胞调查结果。在目标2中，我们将评估已知的通过全基因组鉴定的CLL易感基因座非裔美国人慢性淋巴细胞性白血病病例和对照中高加索人的协会研究洞察非裔美国人基因座中索引变种和任何其他变种的差异风险和高加索人。最后，在目标3中，我们将评估我们最近的发现的概括性，即基因组汇总指标，肿瘤突变负荷，定义为反复突变的CLL的数量在非裔美国人CLL中，驱动基因是预测预后的因素。从本申请中获得的知识可以提供对这两个种族之间白血病发生的生物学差异的新见解以及提供对高加索人慢性淋巴细胞性白血病遗传和体细胞遗传学发现的概括性的理解非裔美国人CLL。总之，这些结果可能会改善以下人群的风险分层和预测非洲裔美国人慢性淋巴细胞性白血病病例，最终，它们可能为减少慢性淋巴细胞性白血病患者的健康差异。