Molecular characterization of myeloma and related asymptomatic precursor states

骨髓瘤的分子特征和相关的无症状前体状态

• 批准号: 8722142
• 负责人: Elizabeth E Brown
• 金额: $ 64.2万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722142
• 关键词: Accounting; Address; Age; Biological Markers; Biology; Cancer Etiology; Cell Communication; Cells; Classification; Clinical; Clinical Data; Clinical Management; Country; Data; Diagnostic; Discipline; Disease; Drug resistance; Early Diagnosis; Etiology; Functional RNA; Gene Expression; Gene Expression Profile; Gene Mutation; Gene Targeting; Genes; Genetic Transcription; Genomics; Geography; Goals; Hematologic Neoplasms; Image; Investigation; Knowledge; Lead; Length; Malignant Neoplasms; Membrane; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Abnormality; Monitor; Monoclonal gammopathy of uncertain significance; Morbidity - disease rate; Multiple Myeloma; Mutation; Nucleotides; Oncogenes; Oncogenic; Participant; Peripheral Blood Lymphocyte; Phenotype; Plasma Cell Neoplasm; Play; Population; Property; Relapse; Relative (related person); Resources; Risk; Role; Sampling; Serum; Staging; Testing; Time; Tumor Biology; Tumor Suppressor Genes; Tumor Suppressor Proteins; Vesicle; advanced disease; case control; clinical risk; cost effective; deep sequencing; functional genomics; high risk; improved; indexing; innovation; insight; mRNA Expression; mortality; new therapeutic target; next generation sequencing; novel; public health relevance; sex; transcriptome sequencing

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is the 2nd most common hematologic malignancy accounting for ~1 percent of all cancers in the Western countries. Despite recent advances in treatment options, it remains incurable with high rates of relapse and drug resistance, with a median survival of ~5 years. Although the etiology of MM is unclear, it is preceded by precursor asymptomatic plasma cell dyscrasias known as monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Despite the availability of clinical risk models, genomic aberrations and imaging, efforts to utilize these indices to accurately classify early stage precursor disease and monitor clinical course have not been successful. In contrast, recent advances in transcriptome sequencing offer new opportunities to characterize miRNAs as novel biomarkers, which could significantly change the paradigm of MM classification, and ultimately, management and treatment. The goal of the proposed investigation is to identify and characterize the contribution of miRNAs in serum exosomes on the presence of MM, and within the spectrum of progression, MGUS and SMM. We will test the overarching hypothesis that distinct serum exosome miRNAs will correlate with the presence of each precursor disease and myeloma phenotype and a subset of serum exosome miRNAs will correlate with the presence of all precursor disease and myeloma phenotypes relative to controls, giving rise to high priority targets important for MM risk. In addition, we hypothesize that miRNAs influence precursor disease and myeloma phenotypes by altering target gene expression. To address this hypothesis we intend to: (1) identify miRNAs associated with the presence of MM and its asymptomatic precursor states using discovery and independent replication populations and (2) characterize miRNA target genes important for the presence of MM and its asymptomatic precursor states using a whole transcriptome miRNA-mRNA approach. Direct modeling of miRNA-mRNA relationships is critical to advance our understanding of the role miRNAs in regulating post-transcriptional expression of target genes and in so doing, providing insight into biologic mechanism fundamental to disease etiology. This project leverages existing partnerships, resources and comprehensive, high quality clinical data and biospecimens collected in a network of populations to fill a critical gap in knowledge required to improve our understanding of myeloma etiology and disease states associated with progression. Such characterizations can be used to significantly transform the current paradigm for disease surveillance by advancing a set of biomarkers to target high-risk populations who may benefit from early detection and individualized clinical management.

描述（由申请人提供）：多发性骨髓瘤（MM）是第二个最常见的血液性恶性肿瘤，占西方国家所有癌症的约1％。尽管最近的治疗方案取得了进步，但它仍然无法治愈，较高的复发率和耐药性，中位存活率约为5年。尽管MM的病因尚不清楚，但之前是前体无症状的浆细胞性神经症，称为单克隆性γ-不确定意义（MGUS）和闷闷不乐的骨髓瘤（SMM）。尽管有临床风险模型，基因组畸变和成像的可用性，但利用这些模型的努力 准确对早期前体疾病和监测临床过程进行准确分类的指数尚未成功。相反，转录组测序的最新进展为将miRNA描述为新的生物标志物提供了新的机会，这可能会大大改变MM分类的范式，并最终改变管理和治疗。拟议的研究的目的是识别和表征血清外泌体中miRNA对MM存在以及进展，MGU和SMM的贡献。我们将检验以下总体假设，即不同的血清外泌体miRNA将与每种前体疾病和骨髓瘤表型的存在相关，以及一部分血清外生组miRNA的子集将与所有前体疾病和骨髓瘤表型的存在相关，相对于对照组的存在，从而使高优先级对MM风险产生重要的目标。此外，我们假设miRNA通过改变靶基因表达来影响前体疾病和骨髓瘤表型。为了解决这一假设，我们打算：（1）使用发现和独立的复制群体确定与MM及其无症状前体态相关的miRNA，并且（2）使用整个转录组miRNA-MRNA方法来表征MIRNA靶基因对MM及其无症状前体态的重要性。 miRNA-mRNA关系的直接建模对于促进我们对miRNA在调节靶基因的转录后表达中的作用以及这样做的理解至关重要，从而提供了对疾病病因基础的生物学机制的见解。该项目利用现有的合作伙伴关系，资源和综合，高质量的临床数据和在人群网络中收集的生物素质，以填补需要提高我们对骨髓瘤病因和疾病状态与发展相关的疾病状态所需的重要差距。这种特征可用于通过推进一组生物标志物来针对可能受益于早期检测和个性化临床管理的高风险人群来显着改变当前的疾病监测范例。