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.

项目摘要/摘要 项目3将检验以下假设：可修改的危险因素，包括注射和DNA损害因素， 影响造血茎​​和祖细胞（HSPC）克隆的扩展具有某些遗传突变和 它们转化为血液系统恶性肿瘤。我们将确定与HSPC相关的可修改风险因素 在9,513人的前瞻性流行病学研究中，克隆扩张和恶性转化（黑色 27％，女性为55％）现在，一项长期的社区人群研究Aric> 75岁。我们将使用存储 用于单细胞DNA测序的Buffy Coat，并杠杆完成外周血白细胞（PBL） 外显子组测序（WES），甲基化和蛋白质组学分析。 AIM 1将确定克隆的长期变化 来自核心A的资源的单细胞水平的组成，并识别注射和DNA损伤 - 与这些变化相关的相关因素。对于250名ARIC参与者，有WES的时间为“ 1克隆变体” 1或时间2（20年后）和/或时间2之后的血液系统恶性肿瘤，我们将测量单个白细胞 两次通过单细胞-DNA测序两次。通过在前所未有的情况下跟踪单个克隆 解决方案，我们将评估克隆适应性，并确定可修改的风险因素，以扩展具有特定的克隆 变体。我们的研究是第一个解决克隆组成变化而具有血液学恶性肿瘤的变化。 社区队列。在AIM 2中，我们将评估克隆成分的关联，变体等位基因频率 （VAFS），以及已知的髓样恶性驱动基因和具有血液学的新型复发变体的变化 在二十年的时间里，恶性风险。在9,513名参与者中，我们将在时间1和 2（相距20年），以识别随着变化的VAF的新型经常性变体，并将参与者通过克隆分类 已知驱动基因的组成和VAF。对于驱动基因，我们将估计克隆变化的关联 随着时间的流逝，成分和VAF具有血液学恶性风险。我们投射341第一和66秒 我们队列中的血液系统恶性肿瘤。 AIM 3将评估炎症和DNA的关联 具有可检测克隆变体的人的血液学恶性风险的损伤相关因素。到时间2， 我们预计> 10％的参与者将在驱动器和新基因中可以通过WES检测到克隆变体。我们将 估计可修改因素与患有和没有特定患者的血液系统恶性肿瘤的关联 克隆变体超过30年。项目3将确定测试药物作为克隆扩张的干预措施， 项目1和2中小鼠的恶性转化。我们还将测试细胞因子改变的关联 在项目1中鉴定出的CPG甲基化，并确定是否观察到项目2中确定的突变 在有DNA损害暴露的参与者中。该项目将广泛利用核心A进行单细胞分析 和核心B进行协调。识别驱动克隆扩张和恶性肿瘤的可修改因素 转型将为拦截克隆扩张和恶性转变提供机会，并启用 由于其遗传和可修改的危险因素概况，人们对处于较高风险的人的早期检测。