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: 10699957
• 负责人: Esteban Braggio
• 金额: $ 80.49万
• 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/10699957
• 关键词: Address; African American; African American population; Age; Aggressive Clinical Course; B-Lymphocytes; Biological Markers; Calibration; Caucasians; Cell Count; Chronic Lymphocytic Leukemia; Classification; 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; anxiety reduction; biomarker identification; cohort; disparity gap; genetic analysis; genetic risk factor; genome wide association study; high risk; improved; infection risk; leukemia; mortality; predictive modeling; predictive signature; predictive tools; premalignant; progression risk; prospective; risk prediction; risk stratification; screening; targeted sequencing; 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，至今仍然存在 无法治愈由于其免疫应答受损，CLL具有高发病率和死亡率 并发症，包括增加感染和第二次癌症的风险。因此，确定 患这种疾病的风险明显更高，这可能有助于未来的预防策略。单克隆B- 细胞淋巴细胞增多症（MBL）是CLL的前体状态。MBL的患病率随着年龄的增长而增加， 几乎三分之一的60岁以上的白种人都有这种情况。MBL在非裔美国人（AA）中的患病率 并没有很好地建立起来。尽管所有CLL患者都会经历MBL前体状态， 为什么有些MBL患者进展为CLL，而许多人却没有进展，目前尚不清楚。因此，有必要 鉴定区分那些将进展的MBL与那些将保持无症状的MBL的生物标志物。 本申请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1，729名白人个体的既定队列中，与进展为CLL风险相关的因素 关于MBL重要的是，在我们对MBL和进步的理解方面， 在AA人群中的CLL。在此基础上，我们还将采取初步措施，开始缩小这一差距， 通过筛选4，000名AA，建立一个AA个体的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， 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） 先前通过全基因组关联研究（GWAS）鉴定的多态性（SNP） 有进展为CLL的风险。在目标2中，我们将对59个推定的CLL进行深度靶向测序 驱动基因，以调查具有高影响突变的单个基因或突变的总数量， 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 将MBL个体分类为低风险、中等风险和高风险的甲基化特征可预测进展 到CLL。在这个应用程序完成后，我们将确定三个互补但独立的 我们假设遗传和表观遗传因素将是慢性淋巴细胞白血病进展的强有力的预测因素， 高加索人MBL队列。我们的初步数据支持我们的假设。我们有世界上最大的 在美国收集的MBL患者，使我们处于一个无与伦比的情况下，前瞻性地评估影响 已知的CLL风险因素在癌前阶段。我们对所有三种生物标志物的综合预测模型可能 改变目前的实践指南，并通过减少焦虑和痛苦， 处于癌前阶段的个体。最后，由于对这些基因的普遍性知之甚少， 和表观遗传因素在AA，我们加强了我们的应用的意义，采取了最初的和重要的 步骤，建立资源，开始探索这些遗传和表观遗传因素在AA个人。