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，并且仍然存在 无法治愈的。由于免疫反应受损，CLL 的发病率和死亡率很高 并发症包括增加感染和第二种癌症的风险。因此，确定个人 患这种疾病的风险明显较高，这可能有助于制定未来的预防策略。单克隆B- 细胞淋巴细胞增多症 (MBL) 是 CLL 的先兆状态。 MBL 的患病率随着年龄的增长而增加，并且 近三分之一 60 岁以上的白种人都有这种情况。非裔美国人 (AA) 中 MBL 的患病率 尚未建立。尽管所有 CLL 患者都会经历 MBL 前驱状态，但原因 为什么一些 MBL 患者会发展为 CLL，而许多人却没有发展为 CLL，目前尚不清楚。因此，有必要 确定生物标志物，区分那些将进展的 MBL 和那些将保持无症状的 MBL。 该应用程序的总体目标是通过评估遗传和表观遗传来解决这一知识差距 在由 1,729 名白人组成的既定队列中，与进展为 CLL 的风险相关的因素 与 MBL。重要的是，我们对 MBL 和进展的理解存在着不断扩大的公平差距 AA 人群中的 CLL。受此激励，我们还将采取初步措施，通过以下方式开始缩小这一差距： 通过筛选 4,000 名 AA 来开发 AA 个体的 MBL 队列，然后进行重要的研究 评估我们新的 AA MBL 队列中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遗传风险评分 (PRS) 先前通过全基因组关联研究 (GWAS) 鉴定的多态性 (SNP) CLL 有进展为 CLL 的风险。在目标 2 中，我们将对 59 个假定的 CLL 进行深度靶向测序 驱动基因来研究是否具有高影响力突变的单个基因或突变的总数 基因导致从 MBL 进展为 CLL 的风险增加。最后，在目标 3 中，我们将评估是否 将 MBL 个体分为低、中、高风险的甲基化特征可预测进展 慢性淋巴细胞白血病。完成本申请后，我们将确定三个互补但独立的项目 我们假设遗传和表观遗传因素将成为慢性淋巴细胞白血病（CLL）进展的有力预测因子。 白种人 MBL 队列。我们的初步数据支持我们的假设。我们拥有最大的群体 在美国收集的 MBL 个体，使我们处于无与伦比的状态来前瞻性评估其效果 癌前阶段已知的 CLL 危险因素。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，并通过减少焦虑和痛苦最终提高生活质量 处于癌前阶段的个体。最后，因为人们对这些遗传的普遍性知之甚少。 和 AA 中的表观遗传因素，我们通过采取最初和重要的措施来增强我们应用的重要性 建立资源以开始探索 AA 个体中的这些遗传和表观遗传因素的步骤。