Molecular characterization of myeloma and related asymptomatic precursor states

描述(申请人提供)：多发性骨髓瘤(MM)是西方国家第二常见的血液系统恶性肿瘤，约占所有癌症的1%。尽管最近在治疗方法上取得了进展，但它仍然无法治愈，复发率和耐药率都很高，中位生存期为~5年。虽然MM的病因尚不清楚，但它之前的先兆无症状性浆细胞营养不良被称为未确定意义的单克隆性伽马病(MGUS)和阴燃骨髓瘤(SMM)。尽管已有临床风险模型、基因组异常和成像技术，但利用这些技术的努力 准确地对早期先兆疾病进行分类和监测临床病程的指标尚未成功。相反，最近在转录组测序方面的进展为将miRNAs表征为新的生物标记物提供了新的机会，这可能显著改变多发性骨髓瘤分类的范式，并最终改变治疗和治疗。拟议研究的目的是确定和表征血清外切体中miRNAs在MM、MGUS和SMM进展过程中的作用。我们将检验最重要的假设，即不同的血清外切体miRNAs将与每种前驱疾病和骨髓瘤表型的存在相关，而血清外切体miRNAs的子集将与所有前驱疾病和骨髓瘤表型的存在相关联，从而产生对MM风险重要的高优先级靶点。此外，我们假设miRNAs通过改变靶基因的表达来影响先兆疾病和骨髓瘤的表型。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来识别与MM及其无症状前体状态的存在相关的miRNAs；(2)使用完整的转录组miRNA-mRNA方法来表征对MM及其无症状前体状态的存在至关重要的miRNA靶基因。对miRNA-mRNA关系的直接建模对于促进我们对miRNAs在调控靶基因转录后表达中的作用的理解以及在此过程中提供对疾病病因学基本生物学机制的洞察至关重要。该项目利用现有的合作伙伴关系、资源以及在人口网络中收集的全面、高质量的临床数据和生物标本，以填补知识方面的关键空白，以提高我们对骨髓瘤病因和与进展相关的疾病状态的理解。这些特征可用于显著改变当前的疾病监测范式，方法是推进一组生物标志物，瞄准可能受益于早期发现和个体化临床管理的高危人群。

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.