Genomic Analysis to Gain Insights into Novel and Clinically Relevant Mol

多发性骨髓瘤(MM)是一种由大量遗传和表观遗传改变引起的复杂疾病。我们的综合性肿瘤基因组分析表明，MM基因组中存在许多紧密重复和紧密集中的扩增/缺失。事实上，对人类多发性骨髓瘤的综合肿瘤基因组分析已经确定了存在于扩增/缺失区域内的候选基因，这些区域预计与多发性骨髓瘤的发病和进展有关。利用患者样本的临床和基因组信息，我们的目标是识别与临床预后和治疗相关的新的分子病变。我们的初步肿瘤基因组研究证实，我们有能力对患者骨髓(BM)样本中的骨髓瘤细胞进行大规模高通量基因组图谱分析。我们假设多发性骨髓瘤的生物学行为和临床结果取决于分子决定因素，分子决定因素也是有吸引力的治疗靶点。在这个项目中，我们将：描述与未确定意义的单克隆性伽马病(MGUS)/阴燃MM(SMM)到活动期MM(Sp目标1)的发病机制和进展相关的基因组损伤的谱；确定1,000名新诊断的接受统一治疗的与临床结果相关的基因组变化(Sp目标2)；并确定转录组修改机制是否与临床结果相关(Sp目标3)。该项目将更好地了解拷贝数和基因表达改变对多发性骨髓瘤发病和进展的影响及其功能后果，并为治疗干预确定新的靶点。

Multiple Myeloma (MM) Is a complex disease driven by numerous genetic and epigenetic alterations. Our compretiensive oncogenomic analysis indicates the presence of many tightly recurrent and tightly focal amplifications/deletions in the MM genome. Indeed, integrated oncogenomic analyses of human MM have identified candidates resident within regions of amplification/deletions predicted to be involved in MM pathogenesis and progression. Using the clinical and genomic information from patient samples, our goals are to identify novel molecular lesions with clinical prognostic and therapeutic correlation. Our preliminary oncogenomic studies have confirmed our ability to perform large-scale high-throughput genomic profiling on myeloma cells from patient bone marrow (BM) samples. We hypothesize that the biological behavior and clinical outcome in MM is dependent on molecular determinants, which are also attractive therapeutic targets. In this Project we will: characterize the spectrum of genomic lesions associated with pathogenesis and progression of monoclonal gammopathy of undetermined significance (MGUS)/Smoldering MM (SMM) to active MM (Sp Aim 1); identify genomic alterations in 1,000 newly diagnosed uniformly treated patients correlating with clinical outcome (Sp Aim 2); and determine whether mechanisms modifying transcriptome are associated with clinical outcome (Sp Aim 3). This project will provide a better understanding of the impact of copy number and gene expression alterations and their functional consequences on MM initiation and progression, as well as identify novel targets for therapeutic intervention.