Project 3: Contribution of inflammation and DNA damaging factors to clonal expansion and malignant transformation in a community cohort of older adults

项目 3：炎症和 DNA 损伤因素对社区老年人群克隆扩张和恶性转化的影响

• 批准号: 10606559
• 负责人: ELIZABETH A. PLATZ
• 金额: $ 57.03万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-08 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606559
• 关键词: Address; Administrative Coordination; Age; Anti-Inflammatory Agents; Aspirin; Atherosclerosis Risk in Communities; Black race; CHEK2 gene; Cells; Classification; Clonal Expansion; Clone Cells; Cohort Studies; Communities; Complement; DNA Damage; DNA Sequence Alteration; DNA sequencing; DNMT3a; Data; Dependence; Early Diagnosis; Elderly; Evolution; Female; Gene Frequency; Genes; Genetic Risk; Genomics; Hematologic Neoplasms; Hematology; Hematopoiesis; Hematopoietic stem cells; Human; Individual; Inflammation; Inflammatory; Intercept; Intervention; JAK2 gene; Leukocytes; Malignant - descriptor; Malignant Neoplasms; Measures; Methylation; Mission; Mus; Mutate; Mutation; Myelogenous; Myeloproliferative disease; Obesity; PPM1D gene; Participant; Persons; Pharmaceutical Preparations; Prevalence; Proteomics; Recurrence; Resolution; Resources; Risk; Risk Factors; Smoking; TP53 gene; Testing; Time; Variant; Visit; adjudication; cohort; cytokine; design; epidemiology study; exome sequencing; experimental study; fitness; follow-up; genetic variant; high risk; mathematical model; modifiable risk; mouse model; novel; peripheral blood; programs; prospective; response; screening; single cell analysis; single cell sequencing

Project Summary/Abstract Project 3 will test the hypothesis that modifiable risk factors, including inflammation and DNA-damaging factors, influence expansion of hematopoietic stem and progenitor cell (HSPC) clones with certain genetic mutations and their transformation to hematologic malignancy. We will identify modifiable risk factors associated with HSPC clonal expansion and malignant transformation in a prospective epidemiologic study of 9,513 persons (Black 27%, female 55%) now all >75 years old from ARIC, a long-standing community cohort study. We will use stored buffy coat for single cell DNA sequencing, and leverage completed peripheral blood leukocyte (PBL) whole exome sequencing (WES), methylation, and proteomic profiling. Aim 1 will determine long-term changes in clonal composition at the single-cell level with resources from Core A and identify inflammation and DNA damage- related factors associated with those changes. For 250 ARIC participants with ³1 clonal variant by WES at Time 1 or at Time 2 (20 years later) and/or hematologic malignancy after Time 2, we will measure individual leukocyte variant profiles at both times by single cell-DNA sequencing. By tracking individual clones at unprecedented resolution, we will assess clonal fitness and identify modifiable risk factors for expansion of clones with specific variants. Our study is the first to address change in clonal composition with hematologic malignancy in a community cohort. In Aim 2, we will evaluate the association of clonal composition, variant allele frequencies (VAFs), and changes of known myeloid malignancy driver genes and novel recurrent variants with hematologic malignancy risk over the span of two decades. In 9,513 participants, we will interrogate WES data at Time 1 and 2 (20 years apart) to identify novel recurrent variants with changing VAFs and classify participants by clonal composition and VAFs of known driver genes. For driver genes, we will estimate associations of change in clonal composition and VAF over time with hematologic malignancy risk. We project 341 first and 66 second primary hematologic malignancies within our cohort. Aim 3 will evaluate the association of inflammation- and DNA damage-related factors with hematologic malignancy risk in persons with detectable clonal variants. By Time 2, we expect >10% of participants will have clonal variants detectable by WES in driver and novel genes. We will estimate the association of modifiable factors with hematologic malignancy in persons with and without specific clonal variants over 30 years. Project 3 will identify drugs to test as interventions for clonal expansion and malignant transformation in mice in Projects 1 and 2. We also will test associations between altered cytokines and CpG methylation identified in Project 1 and determine whether mutations identified in Project 2 are observed in participants with DNA-damaging exposures. This Project will extensively utilize Core A for single-cell analysis and Core B for coordination. Identifying modifiable factors that drive clonal expansion and malignant transformation will provide opportunities to intercept clonal expansion and malignant transformation and enable early detection in persons at higher risk due to their genetic and modifiable risk factor profile.

项目总结/摘要 项目3将测试可改变的风险因素，包括炎症和DNA损伤因素， 影响具有某些基因突变造血干细胞和祖细胞（HSPC）克隆的扩增， 它们转变为血液恶性肿瘤。我们将确定与HSPC相关的可改变的风险因素 在一项对9，513人进行的前瞻性流行病学研究中， 27%，女性55%），现在都>75岁，来自ARIC，一项长期的社区队列研究。我们将使用存储 血沉棕黄层用于单细胞DNA测序，并利用完成的外周血白细胞（PBL）全血 外显子组测序（WES）、甲基化和蛋白质组学分析。目的1将确定克隆的长期变化， 在单细胞水平上使用来自核心A的资源组合物，并识别炎症和DNA损伤- 与这些变化相关的因素。对于250名ARIC受试者，在时间点时通过WES检测存在≥ 1个克隆变体 在时间点1或时间点2（20年后）和/或时间点2后的血液学恶性肿瘤时，我们将测量个体白细胞 通过单细胞DNA测序，在两个时间点进行变异谱分析。通过以前所未有的速度追踪单个克隆体 决议，我们将评估克隆健身和确定可修改的风险因素，为扩大克隆与特定的 变体。我们的研究是第一个解决血液系统恶性肿瘤克隆组成的变化， 社区队列。在目标2中，我们将评估克隆组成、变异等位基因频率 （VAF），以及已知的骨髓恶性肿瘤驱动基因和新的复发性变异的变化， 恶性肿瘤的风险。在9，513名参与者中，我们将在时间1询问WES数据， 2（相隔20年），以确定具有变化的VAF的新的复发性变体，并通过克隆 已知驱动基因的组成和VAF。对于驱动基因，我们将估计克隆中的变化的关联， 随着时间的推移，血液学恶性肿瘤风险的组成和VAF。我们计划341个第一和66个第二小学 血液恶性肿瘤。目的3将评估炎症和DNA的关联 具有可检测克隆变异的人中具有血液恶性风险的损伤相关因素。到时间2， 我们预计>10%的参与者将在驱动基因和新基因中具有通过WES可检测到的克隆变体。我们将 评估有或无特异性免疫缺陷的患者中可改变因素与血液恶性肿瘤的相关性， 30年的克隆变异。项目3将确定药物作为克隆扩增的干预措施进行测试， 项目1和项目2中的小鼠恶性转化。我们还将测试改变的细胞因子 和CpG甲基化，并确定是否观察到项目2中鉴定的突变 DNA损伤的参与者。本项目将广泛利用A核心进行单细胞分析 以及用于协调的核心B。确定驱动克隆扩张和恶性肿瘤的可改变因素 转化将提供拦截克隆扩增和恶性转化的机会， 由于遗传和可改变的风险因素特征，早期发现风险较高的人。