Genomic Analysis to Gain Insights into Novel and Clinically Relevant Mol

多发性骨髓瘤（MM）是一种由许多遗传和表观遗传改变驱动的复杂疾病。我们的重复性癌基因组分析表明MM基因组中存在许多紧密复发和紧密局灶性扩增/缺失。事实上，人MM的整合癌基因组分析已经确定了预测参与MM发病机制和进展的扩增/缺失区域内的候选者。利用患者样本的临床和基因组信息，我们的目标是鉴定具有临床预后和治疗相关性的新分子病变。我们初步的癌基因组学研究已经证实了我们对来自患者骨髓（BM）样本的骨髓瘤细胞进行大规模高通量基因组分析的能力。我们假设MM的生物学行为和临床结果取决于分子决定因素，这些决定因素也是有吸引力的治疗靶点。在本项目中，我们将：表征与意义不明的单克隆丙种球蛋白病（MGUS）/阴燃型MM（SMM）至活动性MM的发病机制和进展相关的基因组病变谱（Sp Aim 1）;在1，000例新诊断的统一治疗患者中鉴定与临床结局相关的基因组改变（Sp Aim 2）;并确定修饰转录组的机制是否与临床结局相关（Sp Aim 3）。该项目将更好地了解拷贝数和基因表达改变及其对MM启动和进展的功能后果的影响，并确定治疗干预的新靶点。

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.