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.

慢性淋巴细胞性白血病(CLL)是美国最常见的白血病，至今仍 不治之症。由于免疫反应受损，慢性淋巴细胞性白血病的发病率和死亡率都很高。 并发症包括增加感染和第二次癌症的风险。因此，确定哪些人 发生这种疾病的风险明显较高，这可能使未来的预防策略成为可能。单抗B- 细胞淋巴细胞症(MBL)是CLL的前驱状态。MBL的患病率随着年龄的增长而增加， 在几乎三分之一的60岁以上的高加索人身上发现了这种病毒。非裔美国人中MBL的患病率(AA) 并不是很成熟。尽管所有CLL患者都经历了MBL前体状态，但原因是 为什么一些患有MBL的人进展到CLL，而许多人却不知道。因此，有必要 识别生物标志物，以区分那些将进展的MBL和那些将保持无症状的MBL。 这个应用程序的总体目标是通过评估遗传和表观遗传学来解决这一知识差距 1,729名高加索人队列中与进展为慢性淋巴细胞性白血病风险相关的因素 使用MBL。重要的是，在我们对MBL和进展的理解方面，存在着越来越大的股权差距 在AA人群中对CLL的易感性。为此，我们还将采取初步步骤，通过以下方式开始缩小这一差距 通过对4,000名AA的筛查建立一个AA个人的MBL队列，然后进行重要的 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分数(PRS) 先前已通过全基因组关联研究确定的多态(SNPs) 慢性淋巴细胞性白血病进展为慢性淋巴细胞性白血病的风险。在目标2中，我们将对59个可能的CLL进行深度靶向测序 驱动基因调查单个基因是否具有高影响突变或突变的总数 基因导致从多发性骨髓瘤进展为慢性淋巴细胞性白血病的风险增加。最后，在目标3中，我们将评估 将MBL个体分为低风险、中风险和高风险预测进展的甲基化特征 致CLL。在完成本申请后，我们将确定三个相辅相成但独立的 我们假设的遗传和表观遗传因素将是急性淋巴细胞性白血病进展的有力预测因素。 一群高加索混血儿。我们的初步数据支持我们的假设。我们拥有世界上最大的 在美国收集的MBL患者，使我们处于无与伦比的情况下，前瞻性地评估效果 癌症前期已知的慢性淋巴细胞性白血病危险因素。我们对所有三个生物标志物的综合预测模型可能 改变当前的实践指南，通过减少焦虑和痛苦来最终提高生活质量 处于癌前阶段的个体。最后，由于人们对这些基因的普适性知之甚少 和表观遗传因素，我们加强了我们的应用意义，通过最初和重要的 建立资源的步骤，开始在再生障碍性贫血个体中探索这些遗传和表观遗传因素。