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: 10332337
• 负责人: ELIZABETH A. PLATZ
• 金额: $ 60.42万
• 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/10332337
• 关键词: Address; Administrative Coordination; Age; Anti-Inflammatory Agents; Aspirin; Atherosclerosis Risk in Communities; Black race; CHEK2 gene; Cells; Clonal Expansion; Clone Cells; Cohort Studies; Communities; Complement; DNA Damage; DNA Sequence Alteration; DNA Sequencing Facility; DNA sequencing; 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; Myeloproliferative disease; Obesity; PPM1D gene; Participant; Persons; Pharmaceutical Preparations; Prevalence; Proteomics; Recurrence; Resolution; Resources; Risk; Risk Factors; Smoking; TP53 gene; Testing; Time; Variant; Visit; adjudicate; base; cell transformation; 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.

项目概要/摘要 项目 3 将检验以下假设：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的造血干细胞和祖细胞 (HSPC) 克隆的扩增， 我们将确定与 HSPC 相关的可改变的危险因素。 一项涉及 9,513 人的前瞻性流行病学研究中的克隆扩增和恶性转化（黑人 27%，女性 55%）现在都超过 75 岁，来自 ARIC，这是一项长期的社区队列研究。 用于单细胞 DNA 测序的血沉棕黄层，并利用完整的外周血白细胞 (PBL) 整体 外显子组测序 (WES)、甲基化和蛋白质组分析 目标 1 将确定克隆的长期变化。 利用 Core A 的资源在单细胞水平上进行成分分析，并识别炎症和 DNA 损伤 - 对于 250 名 ARIC 参与者，WES 当时发现了与这些变化相关的相关因素。 1 或时间 2（20 年后）和/或时间 2 之后的血液恶性肿瘤，我们将测量单个白细胞 通过单细胞 DNA 测序以前所未有的速度追踪单个克隆，获得变异概况。 决议中，我们将评估克隆适应性并确定可修改的风险因素，以扩展具有特定功能的克隆 我们的研究首次解决了血液恶性肿瘤中克隆组成的变化。 在目标 2 中，我们将评估克隆组成、变异等位基因频率的关联。 （VAF），以及已知的骨髓恶性肿瘤驱动基因的变化和血液学方面的新的复发性变异 我们将在 9,513 名参与者中询问时间 1 和时间 1 的 WES 数据。 2（相隔 20 年）识别具有不断变化的 VAF 的新的复发变异，并按克隆对参与者进行分类 对于驱动基因，我们将估计克隆变化的关联。 我们预测 341 是第一原发性的，66 是第二原发性的。 我们的队列中的血液恶性肿瘤将评估炎症和 DNA 的关联。 具有可检测到的克隆变异的人的血液恶性肿瘤风险的损伤相关因素到时间2， 我们预计超过 10% 的参与者将在驱动基因和新基因中检测到 WES 克隆变异。 评估可改变因素与患有或不患有特定疾病的人的血液恶性肿瘤的关联 项目 3 将确定用于克隆扩增干预措施的药物进行测试。 项目 1 和 2 中小鼠的恶性转化。我们还将测试改变的细胞因子之间的关联 和项目 1 中鉴定的 CpG 甲基化，并确定是否观察到项目 2 中鉴定的突变 该项目通常使用 Core A 进行单细胞分析。 核心B用于协调识别驱动克隆扩张和恶性的可改变因素。 转化将提供拦截克隆扩张和恶性转化的机会，并使 由于遗传和可改变的危险因素特征，对高危人群进行早期检测。