Genomic Profiling and clinical Outcome in Chronic Lymphocytic Leukemia

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，在美国估计每年有10,000-15,000例新病例。与AML不同，核型分析现在是结果和临床决策的主要分子标记，在CLL中，核型分析充满了技术困难。本研究试图利用无偏倚的全基因组图谱来表征CLL中新的遗传病变以及已知遗传病变的亚型。本研究的CLL样本和配对的正常颊DNA样本来自于密歇根大学一项前瞻性转化研究试验的患者，该试验计划进行10年的连续标本采集和20年的连续随访。使用Affymetrix开发的50K snp芯片平台和PI实验室和其他地方开发的软件程序进行杂合性损失（LOH）和拷贝数变化的分析。根据LOH区域、拷贝中性LOH或拷贝丢失或获得的特征，我们将使用单因素和多因素分析来确定单个病变的预后效用。进行多变量分析的生物学测量，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。这些数据将补充，在需要的地方，有针对性的外显子重测序工作选定的基因，如p53。最终，该数据集将指导CLL临床风险适应试验的发展或改进，包括实验性药物治疗和同种异体干细胞移植。CLL基因组变化分析的另一个好处是可以高分辨率地描绘出可能在CLL生物学和发病机制中含有重要基因的病变。

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.