Genomic Analysis to Gain Insights into Novel and Clinically Relevant Mol

基因组分析可深入了解新颖且临床相关的分子

• 批准号: 8566797
• 负责人: herve Avet loiseau
• 金额: $ 16.07万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566797
• 关键词: Behavior; Biological; Bone Marrow; Cells; Clinical; Clinical Trials; Complex; DNA copy number; Diagnosis; Disease; Early treatment; Enrollment; Epigenetic Process; Gene Expression; Gene Expression Alteration; Gene Expression Profile; Gene Expression Profiling; Genetic; Genetic Screening; Genome; Genomics; Goals; Human; Lesion; Malignant - descriptor; Messenger RNA; MicroRNAs; Molecular; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mutation; Newly Diagnosed; Outcome; Pathogenesis; Patients; Predictive Value; RNA Splicing; Recurrence; Sampling; Series; Therapeutic; Therapeutic Intervention; Time; Validation; cancer genomics; clinically relevant; cohort; insight; novel; outcome forecast; prognostic; progression marker; response; therapeutic target; tool

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.

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。我们全面的肿瘤基因组分析表明，在MM基因组中存在许多紧密复发性和紧密局灶性扩增/缺失。事实上，人类MM的综合肿瘤基因组分析已经确定了位于预测参与MM发病和进展的扩增/缺失区域的候选基因。利用来自患者样本的临床和基因组信息，我们的目标是识别具有临床预后和治疗相关性的新型分子病变。我们的初步肿瘤基因组研究证实了我们对患者骨髓（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，这也是有吸引力的治疗靶点。在这个项目中，我们将：表征与未确定意义的单克隆γ病(MGUS)/阴燃型MM （SMM）到活动性MM （Sp Aim 1）的发病和进展相关的基因组病变谱；鉴定1000名新诊断的统一治疗患者与临床结果相关的基因组改变（Sp Aim 2）；并确定修饰转录组的机制是否与临床结果相关（Sp Aim 3）。该项目将更好地了解拷贝数和基因表达改变对MM发生和进展的影响及其功能后果，并确定治疗干预的新靶点。