Molecular characterization of myeloma and related asymptomatic precursor states

描述（由申请人提供）：多发性骨髓瘤（MM）是第二常见的血液系统恶性肿瘤，占西方国家所有癌症的约1%。尽管最近在治疗选择方面取得了进展，但它仍然无法治愈，复发率和耐药性很高，中位生存期约为5年。虽然MM的病因尚不清楚，但其发生之前存在前驱无症状浆细胞恶液质，称为意义不明的单克隆丙种球蛋白病（MGUS）和郁积性骨髓瘤（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仍然是有限的。 准确分类早期前驱疾病和监测临床过程指数尚未成功。相比之下，转录组测序的最新进展为将miRNA表征为新型生物标志物提供了新的机会，这可能会显著改变MM分类的范式，并最终改变管理和治疗。拟议研究的目标是鉴定和表征血清外泌体中miRNA对MM存在的贡献，以及在进展谱内，MGUS和SMM。我们将检验总体假设，即不同的血清外泌体miRNA将与每种前驱疾病和骨髓瘤表型的存在相关，并且血清外泌体miRNA的子集将与相对于对照的所有前驱疾病和骨髓瘤表型的存在相关，从而产生对MM风险重要的高优先级靶标。此外，我们假设miRNAs通过改变靶基因的表达来影响前驱疾病和骨髓瘤的表型。为了解决这一假设，我们打算：（1）使用发现和独立复制群体鉴定与MM及其无症状前体状态的存在相关的miRNA，以及（2）使用全转录组miRNA-mRNA方法表征对MM及其无症状前体状态的存在重要的miRNA靶基因。miRNA-mRNA关系的直接建模对于促进我们对miRNAs在调节靶基因转录后表达中的作用的理解至关重要，并且在这样做的过程中，提供了对疾病病因学的基本生物学机制的深入了解。该项目利用现有的合作伙伴关系，资源和全面，高质量的临床数据和生物标本收集在网络的人群，以填补知识的关键差距，以提高我们的骨髓瘤病因和疾病状态的进展相关的理解。这种表征可用于通过推进一组生物标志物以靶向可能受益于早期检测和个体化临床管理的高危人群来显著改变当前的疾病监测范式。

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.