P-5: Molecular markers of plasma cell neoplasm evolution

P-5：浆细胞肿瘤进化的分子标记

• 批准号: 7507318
• 负责人: Rafael Fonseca
• 金额: $ 15.92万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7507318
• 关键词: 13q14; 17p13; 8q24; Affect; Anatomy; Applications Grants; B lymphoid malignancy; B-Cell Neoplasm; B-Lymphocytes; Biological Markers; Bortezomib; CCND1 gene; Categories; Cells; Chromosomes; Clonal Expansion; Comparative Genomic Analysis; Counseling; Cross-Sectional Studies; Cyclin D1; Cytogenetics; DNA Sequence Rearrangement; Data; Data Set; Development; Diagnosis; Disease; Disease Progression; Evaluation; Event; Evolution; Excision; Facility Construction Funding Category; Funding; Gene Expression Profile; Gene Expression Profiling; Genetic; Genetic Markers; Genetic Risk; Genome; Genomics; Grant; Hairy Cell Leukemia; Immunoglobulin A; Immunoglobulin Somatic Hypermutation; In Situ; Lead; Lymphoma; Malignant Neoplasms; Mantle Cell Lymphoma; Mature B-Lymphocyte; Mining; Modeling; Molecular; Molecular Abnormality; Mono-S; Monoclonal Gammapathies; Multiple Myeloma; Mus; Mutation; NF-kappa B; NFKB Signaling Pathway; Neoplasms; Numbers; Oligonucleotides; Outcome; Pathway interactions; Patient Monitoring; Patients; Pattern; Plasma Cell Neoplasm; Predisposition; Principal Investigator; Proteasome Inhibition; Proteasome Inhibitor; Publishing; Risk; Sampling; Slide; Terminator Codon; Testing; Therapeutic Effect; Thinking; Translations; Up-Regulation; Variant; Waldenstrom Macroglobulinemia; base; cohort; comparative; comparative genomic hybridization; density; genome wide association study; novel; novel therapeutics; outcome forecast; prognostic; programs; protein expression; response; single cell analysis; t(11; 14)(q13; q32); therapeutic target; tumor

In this grant application we want to continue the search for markers causative and predictive of progression from MGUS to myeloma (MM). We previously established a reference cohort of patients in whom we have slides and samples to perform in situ single cell analysis. Since our last grant submission we have developed the expertise and published using the oligo based array comparative genomic hybridization (aCGH). We propose the following aims to better understand the cause of progression of MGUS to MM and to be able to predict better, so that a more appropriate counseling can occur with patients. Ultimately this information will be used for development of novel therapeutics. In Specific Aim 1 we wish to mine the existing genomic data on MM (both anatomic and functional) and to explore the possibility that some of the newfound markers are indeed progression events. We will subtract from these those already present in MGUS. We will test them as predictive markers, studying MGUS slides, and search for associations with existing baseline cytogenetic categories. In Specific Aim 2 we will explore the possibility that myc is a driver event in the progression to MM through a comprehensive genomic approach, including whole genome, high density, tiling aCGH; the tiling centered on myc at 8q24. We postulate that by either cis or trans deregulation, myc abnormalities contribute to the progression of the disease. We have found, using a murine model that introduces myc activation via somatic hypermutation, and by analysis gene expression signatures in MM and MGUS, that myc deregulation is a candidate mechanisms for disease progression. In Specific Aim 3 we wish to provide the long term outcome of patients initially studied by us. We.will monitor patients in a longitudinal fashion and will introduce the long-term outcome data to that already existing in the cohort and also include the novel markers identified in Specific Aim 1. Lastly, in Specific Aim 4 we would like to do a comparative genomic analysis between MM and other mature B-cell malignancies such as mantle cell lymphoma, marginal zone lymphoma and Waldenstrom macroglobulinemia. Mantle cell lymphoma, like MM, shares cyclin D upregulation (usually D1 but also occasionally D2 and D3) as a pathogenic, such as is the case in MM. Marginal zone lymphoma and Waldenstrom macroglobulinemia share the NF-kB activation state that MM has, and,all these tumors have enhanced responsiveness to bortezomib.

在这个基金申请中，我们希望继续寻找导致和预测疾病进展的标志物。 从MGUS到骨髓瘤（MM）。我们之前建立了一个参考队列的患者中，我们有 载玻片和样品进行原位单细胞分析。自从我们上次提交资助申请以来， 发展了专业知识，并发表了使用基于寡核苷酸的阵列比较基因组杂交 （aCGH）。我们提出以下目标，以更好地了解MGUS进展为MM的原因， 能够更好地预测，以便对患者进行更适当的咨询。最终这 这些信息将用于开发新的治疗方法。在具体目标1中，我们希望挖掘 现有的MM基因组数据（解剖学和功能性），并探索一些可能性， 新发现的标记物确实是进展事件。我们将从中减去那些已经存在于 MGUS。我们将测试它们作为预测标记，研究MGUS幻灯片，并寻找与 现有基线细胞遗传学分类。在具体目标2中，我们将探讨myc是驱动程序的可能性 通过全面的基因组方法，包括全基因组，高 密度，平铺aCGH;平铺以8 q24的myc为中心。我们假设无论顺式或反式 myc基因的异常导致疾病的进展。我们发现，用老鼠 通过体细胞超突变和分析基因表达特征引入myc激活的模型 在MM和MGUS中，myc失调是疾病进展候选机制。在特定 目的3：我们希望提供我们最初研究的患者的长期结果。我们将监测患者， 纵向方式，将长期结局数据引入队列中已有的数据， 还包括在特定目标1中鉴定的新标记。最后，在具体目标4中，我们想做一个 MM与其他成熟B细胞恶性肿瘤（如套细胞）之间的比较基因组分析 淋巴瘤、边缘区淋巴瘤和瓦尔登斯特伦巨球蛋白血症。套细胞淋巴瘤，像MM， 细胞周期蛋白D上调（通常是D1，但偶尔也有D2和D3）作为病原体，例如 边缘区淋巴瘤和Waldenstrom巨球蛋白血症共享NF-κ B激活 所有这些肿瘤对硼替佐米的反应性增强。