The genetic and epigenetic etiology of progression from the precursor state to chronic lymphocytic leukemia (CLL)

从前体状态进展为慢性淋巴细胞白血病（CLL）的遗传和表观遗传病因学

• 批准号: 10369783
• 负责人: Esteban Braggio
• 金额: $ 87.01万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-08 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369783
• 关键词: Address; African American; African American population; Age; Aggressive Clinical Course; Anxiety; B-Lymphocytes; Biological Markers; Calibration; Caucasians; Cell Count; Chronic Lymphocytic Leukemia; Clinical; Cohort Studies; DNA Methylation; Data; Development; Discrimination; Disease; Distress; Early treatment; Epigenetic Process; Etiology; Evaluation; First Degree Relative; Future; Genes; Genetic; Genotype; Goals; Immune response; Immunophenotyping; Impairment; Individual; Indolent; Infection; Inherited; Knowledge; Lymphocytosis; Lymphoproliferative Disorders; Malignant - descriptor; Malignant Neoplasms; Methylation; Morbidity - disease rate; Mutate; Mutation; Patients; Phase; Practice Guidelines; Prevalence; Prevention strategy; Public Health; Quality of life; Recommendation; Reporting; Resources; Risk; Risk Factors; Role; Second Primary Cancers; Single Nucleotide Polymorphism; Somatic Mutation; Susceptibility Gene; Techniques; Testing; Time; United States; Work; base; cohort; genetic analysis; genetic risk factor; genome wide association study; high risk; improved; infection risk; leukemia; mortality; predictive modeling; predictive signature; premalignant; prospective; risk prediction; risk stratification; screening; targeted sequencing; tool; trend

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the United States and still remains incurable. Due to its impaired immune response, CLL has high number of morbidity and mortality complications including increase risk of infections and second cancers. Therefore, identifying individuals who are at markedly higher risk of developing this disease may enable future prevention strategies. Monoclonal B- cell lymphocytosis (MBL) is the precursor state to CLL. The prevalence of MBL increases with age and is found in almost a third of Caucasians older than 60 years. The prevalence of MBL in African Americans (AA) is not well established. Although all individuals with CLL pass through the MBL precursor state, the reason why some individuals with MBL progress to CLL yet many do not is unclear. Therefore, there is a need to identify biomarkers that differentiate those MBL who will progress versus those who will remain asymptomatic. The overall goal of this application is to address this knowledge gap by evaluating genetic and epigenetic factors associated with risk of progression to CLL among an established cohort of 1,729 Caucasian individuals with MBL. Importantly there is a widening equity gap with respect to our understanding of MBL and progression to CLL in AA populations. Motivated by this, we will also take the initial steps to begin reducing this gap by developing an MBL cohort of AA individuals through screening of 4,000 AAs and then undertake important preliminary work of evaluating the genetic and epigenetic factors in our new AA MBL cohort. In Aim 1 we will analyze the polygenetic risk score (PRS) comprised of a weighted average of 41 inherited single nucleotide polymorphisms (SNPs) that have been previously identified through genome wide association studies (GWAS) of CLL with risk of progression to CLL. In Aim 2 we will perform deep targeted sequencing of 59 putative CLL driver genes to investigate if individual genes with high-impact mutations or the aggregate number of mutated genes leads to an increased risk of progression from MBL to CLL. Finally, in Aim 3 we will evaluate whether methylation signatures that classify MBL individuals into low-, intermediate-, and high-risk predict progression to CLL. At the completion of this application, we will have identified three complementary yet independent genetic and epigenetic factors that we hypothesize will be strong predictors of progression to CLL among a cohort of Caucasian MBLs. Our preliminary data support our hypotheses. We have the largest cohort of individuals with MBL collected in US, putting us in an unsurpassed situation to prospectively evaluate the effect of known CLL risk factors at the precancer phase. Our integrative predictive model of all three biomarkers may change current practice guidelines and ultimately improve quality of life by reducing anxiety and distress for individuals in pre-malignant phase. Finally, because little is known about the generalizability of these genetic and epigenetic factors in AA, we enhanced the significance of our application by taking the initial and vital steps to build resources to begin the explorations of these genetic and epigenetic factors in AA individuals.

慢性淋巴细胞白血病（CLL）是美国最常见的白血病，仍然存在 无法治愈。由于其免疫反应受损，CLL的发病率和死亡率数量很高 并发症，包括增加感染风险和第二癌的风险。因此，确定个人 患上这种疾病的风险显着更高，可以实现未来的预防策略。单克隆b- 细胞淋巴细胞增多（MBL）是CLL的前体状态。 MBL的患病率随着年龄的增长而增加，IS 在60岁以上的高加索人中，几乎三分之一发现。非裔美国人（AA）中MBL的流行率 没有很好地确定。尽管所有患有CLL的人都通过MBL前体状态，但原因 为什么有些拥有MBL的人会进展到CLL，而许多人尚不清楚。因此，有必要 确定将会与那些将进步与将保持无症状的MBL区分的生物标志物。 该应用的总体目标是通过评估遗传和表观遗传来解决此知识差距 与1,729个高加索人群的既定队列中有进展风险相关的因素 与MBL。重要的是，就我们对MBL和进展的理解而言，公平差距扩大 在AA人群中进行CLL。由此激励，我们还将采取初始步骤开始减少这一差距 通过筛选4,000个AA，然后进行重要 在我们新的AA MBL队列中评估遗传和表观遗传因素的初步工作。在目标1中，我们将 分析由41个遗传单核苷酸的加权平均值组成的多基因风险评分（PRS） 以前通过基因组广泛关联研究（GWAS）鉴定的多态性（SNP） CLL的风险，有进展到CLL的风险。在AIM 2中，我们将执行59个推定CLL的深度靶向测序 驱动基因研究是否具有高影响突变的单个基因或突变的骨料数量 基因导致从MBL到CLL的进展风险增加。最后，在AIM 3中，我们将评估是否 将MBL个体分类为低，中和高风险的甲基化特征预测进展 到Cll。本申请完成时，我们将确定三个互补但独立的 我们假设的遗传和表观遗传因素将是在A中进展为CLL的有力预测指标 高加索MBL的队列。我们的初步数据支持我们的假设。我们有最大的队列 有MBL在我们中收集的人，使我们处于无与伦比的情况下，以预先评估效果 在预科阶段已知的CLL风险因素的。我们所有三种生物标志物的综合预测模型可能 改变当前的实践指南，并最终通过减少焦虑和困扰来改善生活质量 处于恶性阶段的个体。最后，因为对这些遗传的普遍性知之甚少 和AA中的表观遗传因素，我们通过采用初始和重要的来增强了应用的重要性 建立资源的步骤开始探索AA个体中这些遗传和表观遗传因素的探索。