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

基本信息

批准号：
10686409
负责人：
Gareth John Morgan
金额：
$ 107.04万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10686409
关键词：
16S ribosomal RNA sequencing Address Adenine Affinity African American population Age of Onset Alabama American Antigens Biocompatible Materials Biological Biometry Bone Marrow Cancer Center Chronic Chronology Clinical Collection Comprehensive Cancer Center Computational algorithm Cross-Sectional Studies DNA Data Data Set Deaminase Disease Disparity 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 Shapes Structure of germinal center of lymph node System T cell response T-Lymphocyte Therapeutic Time Universities anticancer research 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

项目摘要

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

项目摘要/摘要与欧洲人相比（EA）由于遗传易感性，环境暴露或两者兼而有之。 MM之前有两个前体阶段，不确定意义（MGU）和闷烧的骨髓瘤（SMM）的单克隆性γ- 在AA中增加。我们已经使用欧洲MM样品表明，之间存在很长的滞后周期该疾病的遗传倡议以及前体临床阶段的时间。这是至关重要的如果我们要真正了解这些早期进化步骤的遗传基础 MM在AA中。在遗传启动后MM的进化进程中，积累了遗传命中随着时间的流逝，提供突变签名或“偶像”的独特考古指纹。使用基于APRIORI知识的高级计算机算法分析的整个基因组测序（WGS）在获得的遗传变异的时间安排中，我们能够在不同的时间提取活性点。该分析在EA中表明，MM在突变过程中的影响很大。疾病的早期，中期和晚期进化阶段。我们的试点数据的关键发现是标识由于生发中心反应中的免疫反应而发生的偶生仪种族差异。我们将解决以下假设：在AA中观察到的MM超过MM的主要贡献者与EA相比，是由于多余的免疫响应引起的活跃于疾病早期进化阶段。为了准确提取早期的二次样品需要从相同的案例中。 SMM以每年10％的速度转换为MM，提供一个系统，在没有治疗的情况下，可以在不同时间点获得样品。到解决我们的假设，我们将从AA SMM中从新的WGS数据中生成突变，并将其比较带有SMM的EA的现有数据集以及我们将从中推断出的大型先前的MM集合集祖先直接。我们还将建立对SMM病例的纵向队列研究，并研究互联时间并比较AA和EA之间的轮廓。除了遗传突变，我们还将表征和比较骨髓免疫微环境中T细胞反应的免疫互相互动使用流程度仪方法确定。为了提供指向外部环境的链接，我们将表征源自肠道菌群的16S rRNA测序的细菌物种特征，并将发现与通用性链接和T细胞杂交。这项研究将确定负责的基因组，免疫和环境特征在AAS中观察到MM的较高风险，并将为MM中的免疫反应提供新的见解发病机理，为产生有效的干预策略开辟了道路。 1

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identifying novel mechanisms of biallelic TP53 loss refines poor outcome for patients with multiple myeloma.

DOI：
10.1038/s41408-023-00919-2
发表时间：
2023-09-11
期刊：
BLOOD CANCER JOURNAL
影响因子：
12.8
作者：
Liu, Enze;Sudha, Parvathi;Becker, Nathan;Jaouadi, Oumaima;Suvannasankha, Attaya;Lee, Kelvin;Abonour, Rafat;Abu Zaid, Mohammad;Walker, Brian A.
通讯作者：
Walker, Brian A.

Alternative splicing in multiple myeloma is associated with the non-homologous end joining pathway.

DOI：
10.1038/s41408-023-00783-0
发表时间：
2023-01-20
期刊：
BLOOD CANCER JOURNAL
影响因子：
12.8
作者：
Liu, Enze;Becker, Nathan;Sudha, Parvathi;Dong, Chuanpeng;Liu, Yunlong;Keats, Jonathan;Morgan, Gareth;Walker, Brian A.
通讯作者：
Walker, Brian A.

Myeloma Genome Project Panel is a Comprehensive Targeted Genomics Panel for Molecular Profiling of Patients with Multiple Myeloma.