Genomic Profiling and clinical Outcome in Chronic Lymphocytic Leukemia

慢性淋巴细胞白血病的基因组分析和临床结果

基本信息

批准号：
7303648
负责人：
Sami Nimer Malek
金额：
$ 18.24万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7303648
关键词：
11q22-q23 13q14 14q 17p13 18p 18q 6q21 Algorithms Allogenic Anatomy Biological Biological Markers Biology Caring Cataloging Catalogs Cells Chromosomal translocation Chromosome abnormality Chronic Lymphocytic Leukemia Classification Clinical Clinical Course of Disease Complex Computer software Counseling DNA DNA Microarray Chip DNA Resequencing Data Data Set Decision Making Development Diagnosis Disease Enrollment Epithelial Cells Exons Fluorescent in Situ Hybridization Gene Expression Profile Gene Mutation Genes Genetic Genetic screening method Genome Genomics Genotype Immunoglobulin Genes Immunoglobulins Incidence Individual Interphase Karyotype Knowledge Laboratories Laboratory Finding Lesion Loss of Heterozygosity Malignant Neoplasms Maps Measurement Michigan MicroRNAs Multivariate Analysis Mutate Mutation Numbers Outcome Pathogenesis Patients Persons Pharmacotherapy Play Prognostic Marker Protein Tyrosine Kinase Recurrence Research Resolution Risk Risk Assessment Role Sampling Sampling Studies Specimen Staging Stem cell transplant TP53 gene Techniques Testing Time Translational Research Transplantation Trisomy 12 United States Universities Western World abstracting base cancer genetics chemotherapy chromosome 16 loss chromosome 7 loss clinical Diagnosis cohort comparative density follow-up improved leukemia novel outcome forecast prognostic programs prospective

项目摘要

DESCRIPTION (provided by applicant): Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, with an estimated incidence of 10,000-15,000 new cases per year in the United States. Unlike AML, where karyotypic analysis is now the dominant molecular marker for outcome and clinical decision making, in CLL, karyotypic analysis is fraught with technical difficulties. This proposal attempts the characterization of novel genetic lesions as well as subtypes of known genetic lesions in CLL using unbiased genome-wide genomic profiling. CLL samples and paired normal buccal DNA samples for this study are from patients that are enrolled in a prospective translational research trial at the University of Michigan with planned serial specimen procurement for ten years and serial follow-up for twenty years. Analysis for loss of heterozygosity (LOH) and copy number changes is performed using the 50K SNP-chip platform developed by Affymetrix and software programs developed in the PI's laboratory and elsewhere. Upon characterization of regions of LOH, copy-neutral LOH or copy losses or gains, we will use uni- and multivariate analysis to determine the prognostic utility of individual lesions. Biological measurements to conduct the multivariate analysis, including assessment of the expression of ZAP70 by FACS and immunoglobulin variable gene mutation status, will be performed. This data will be supplemented, where needed, with targeted exon resequencing efforts of selected genes, such as p53. Ultimately, this data set will guide development or refinement of clinical risk-adapted trials in CLL, including experimental drug therapies and allogeneic stem cell transplantation. An additional benefit of the analysis of changes in the CLL genome is the delineation at high resolution of lesions that may harbor important genes in CLL biology and pathogenesis. Lay person abstract: Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world with an estimated incidence of 10,000-15,000 new cases per year in the United States. CLL remains incurable with chemotherapy alone and has a varied clinical course. An accurate risk assessment for individual patients using improved, unbiased genetic testing may prove helpful in recommending appropriate therapies, thereby increasing the possibility of improved patient outcome. Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world with an estimated incidence of 10,000-15,000 new cases per year in the United States. CLL remains incurable with chemotherapy alone and has a varied clinical course. An accurate risk assessment for individual patients using unbiased genetic testing may prove helpful in recommending appropriate therapies including transplantation.

描述（由申请人提供）：慢性淋巴细胞白血病 (CLL) 是西方世界最常见的白血病，估计美国每年新发病例为 10,000-15,000 例。与 AML 不同，在 AML 中，核型分析现在是结果和临床决策的主要分子标记，而在 CLL 中，核型分析充满了技术困难。该提案尝试使用无偏见的全基因组基因组分析来表征 CLL 中新的遗传病变以及已知遗传病变的亚型。本研究的 CLL 样本和配对正常口腔 DNA 样本来自密歇根大学参加一项前瞻性转化研究试验的患者，计划进行十年的连续标本采集和二十年的连续随访。使用 Affymetrix 开发的 50K SNP 芯片平台以及 PI 实验室和其他地方开发的软件程序对杂合性丢失 (LOH) 和拷贝数变化进行分析。根据 LOH、复制中性 LOH 或复制丢失或增益区域的特征，我们将使用单变量和多变量分析来确定单个病变的预后效用。将进行生物学测量以进行多变量分析，包括通过 FACS 评估 ZAP70 的表达和免疫球蛋白可变基因突变状态。如果需要，将通过对选定基因（例如 p53）进行有针对性的外显子重测序工作来补充这些数据。最终，该数据集将指导 CLL 临床风险适应试验的开发或完善，包括实验药物疗法和同种异体干细胞移植。分析 CLL 基因组变化的另一个好处是以高分辨率描绘可能含有 CLL 生物学和发病机制重要基因的病变。非专业人士摘要：慢性淋巴细胞白血病 (CLL) 是西方世界最常见的白血病，估计美国每年新发病例为 10,000-15,000 例。仅靠化疗仍无法治愈 CLL，并且具有不同的临床病程。使用改进的、公正的基因检测对个体患者进行准确的风险评估可能有助于推荐适当的治疗方法，从而增加改善患者治疗结果的可能性。慢性淋巴细胞白血病 (CLL) 是西方世界最常见的白血病，估计美国每年新发病例为 10,000-15,000 例。仅靠化疗仍无法治愈 CLL，并且具有不同的临床病程。使用公正的基因检测对个体患者进行准确的风险评估可能有助于推荐包括移植在内的适当疗法。