Mutographs differentiating the racial and temporal incidence of multiple myeloma

区分多发性骨髓瘤种族和时间发病率的突变特征

• 批准号: 10468064
• 负责人: Gareth John Morgan
• 金额: $ 108.92万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-11 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10468064
• 关键词: 16S ribosomal RNA sequencing; Address; Adenine; Affinity; African American population; Age of Onset; Alabama; American; Antigens; Archaeology; Biocompatible Materials; Biological; Biometry; Bone Marrow; Cancer Center; Case Study; Chronic; Chronology; Clinical; Collection; Comprehensive Cancer Center; Computational algorithm; Cross-Sectional Studies; DNA; Data; Data Set; Deaminase; Disease; Environment; Environmental Exposure; Epidemiology; Etiology; European; Event; Exposure to; Fingerprint; Generations; Genetic; Genetic Predisposition to Disease; Genomics; Goals; Immune; Immune response; Immunologics; Immunosuppression; Incidence; Indiana; Individual; Induced Mutation; Inflammation; Infrastructure; Intervention; Knowledge; Link; Longitudinal cohort study; Malignant Neoplasms; Mediating; Memorial Sloan-Kettering Cancer Center; Molecular; Molecular Abnormality; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mutation; New York; Pathogenesis; Pathologic Mutagenesis; Phase; Play; Process; Prospective cohort study; Race; Reaction; Risk; Role; Sampling; Series; Structure of germinal center of lymph node; System; T cell response; T-Lymphocyte; Therapeutic; Time; Universities; anticancer research; base; biobank; early onset; effective intervention; genetic variant; genome sequencing; gut microbiome; gut microbiota; high risk; immunological status; insight; microbiome; pre-clinical; premalignant; racial difference; racial disparity; racial diversity; racial population; reconstruction; response; tumor-immune system interactions; whole genome

PROJECT SUMMARY/ABSTRACT African Americans (AA) have a higher incidence of multiple myeloma (MM) compared to European Americans (EA) due to genetic predisposition, environmental exposure or both. MM is preceded by two precursor phases, monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) that are also increased in AA. We have shown using European MM samples that there is a long lag period between the genetic initiation of the disease and the time at which precursor clinical stages are detectable. It is critical to understand the genetic basis of these early evolutionary steps if we are to truly understand the excess risk of MM in AA. During the evolutionary progression of MM after genetic initiation, genetic hits are accumulated providing a unique archeological fingerprint of the mutational signatures or “mutographs” over time. Using whole genome sequencing (WGS) analyzed with advanced computer algorithms based on a-priori knowledge of the timing of acquired genetic variants we have been able to extract mutographs active at different time points. This analysis has shown in EA that MM is shaped by mutational processes variably active during the early, intermediate and late evolutionary phases of disease. A key finding of our pilot data is the identification of a mutograph occurring as a consequence of the immune response in the germinal center reaction and this differs by race. We will address the hypothesis that a major contributor to the observed excess of MM in AA compared to EA is due to an excess immune response that can be recognized by a GC mutograph that is active in the early evolutionary phases of disease. To accurately extract early mutographs sequential samples from the same individual cases are needed. SMM, which transforms to MM at a rate of 10% per annum, provides a system where samples can be obtained at different time points in the absence of treatment. To address our hypothesis we will generate mutographs from new WGS data from AA SMM and compare them to existing datasets of EA with SMM as well as from a large pre-existing set of MM from which we will infer ancestry directly. We will also establish a longitudinal cohort study of SMM cases and study mutographs over time and compare the profiles between AA and EA. In addition to genetic mutographs we will characterize and compare immunological mutographs of T-cell response in the bone marrow immune microenvironment identified using a flow-cytometric approach. To provide a link to the external environment we will characterize bacterial species signatures derived from 16S rRNA sequencing of the gut flora, and link findings to the genetic and T-cell mutographs. This study will identify genomic, immune and environmental signatures responsible for the higher risk of MM observed among AAs and will provide new insights into the immune response in MM pathogenesis, opening the way for the generation of effective intervention strategies. 1

项目概要/摘要 与欧洲裔美国人相比，非洲裔美国人 (AA) 的多发性骨髓瘤 (MM) 发病率更高 (EA) 由于遗传倾向、环境暴露或两者兼而有之，MM 之前有两个前兆阶段， 意义未明的单克隆伽马病 (MGUS) 和冒烟型骨髓瘤 (SMM) 我们使用欧洲 MM 样本表明，AA 之间存在较长的滞后期。 疾病的遗传起始和可检测到的前期临床阶段的时间至关重要。 如果我们要真正了解过度风险，就必须了解这些早期进化步骤的遗传基础 AA 中的 MM 在遗传起始后的进化过程中，遗传命中不断积累。 随着时间的推移，提供突变特征或“突变谱”的独特考古指纹。 使用基于先验知识的先进计算机算法进行全基因组测序 (WGS) 分析 根据获得性遗传变异的时间，我们已经能够提取在不同时间活跃的突变特征 该分析在 EA 中表明，MM 是由在不同时期活跃的突变过程形成的。 我们试点数据的一个关键发现是疾病的早期、中期和晚期进化阶段。 由于生发中心反应中的免疫反应而发生的突变现象 我们将讨论以下假设：AA 中观察到的 MM 过多的一个主要因素。 与 EA 相比，这是由于过度的免疫反应，可以通过 GC 突变图识别 活跃于疾病的早期进化阶段，准确提取早期突变序列样本。 需要从相同的个案中转换为 MM，每年 10%， 提供了一种可以在不进行处理的情况下在不同时间点获取样本的系统。 为了解决我们的假设，我们将从 AA SMM 的新 WGS 数据生成突变图谱，并将它们与 带有 SMM 的 EA 的现有数据集以及我们将从中推断的大量预先存在的 MM 数据集 我们还将建立 SMM 病例的纵向队列研究并研究突变谱。 时间并比较 AA 和 EA 之间的概况 除了遗传突变图之外，我们还将表征和分析。 比较骨髓免疫微环境中 T 细胞反应的免疫突变图 为了提供与外部环境的联系，我们将表征。 源自肠道菌群 16S rRNA 测序的物种细菌特征，并将结果与​​遗传联系起来 这项研究将确定基因组、免疫和环境特征。 在 AA 中观察到的 MM 风险较高，将为 MM 免疫反应提供新的见解 发病机制，为产生有效的干预策略开辟了道路。 1