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，在美国每年估计有10，000 - 15，000例新发病例。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。该建议尝试使用无偏的全基因组基因组分析来表征CLL中的新型遗传病变以及已知遗传病变的亚型。用于本研究的CLL样品和配对的正常口腔DNA样品来自于在密歇根大学参加前瞻性转化研究试验的患者，该试验计划连续采集标本10年，连续随访20年。杂合性缺失（洛）和拷贝数变化的分析使用由Affytechnology开发的50 K SNP芯片平台和PI实验室和其他地方开发的软件程序进行。在表征区域的洛，拷贝中性洛或拷贝丢失或增益，我们将使用单因素和多因素分析，以确定预后效用的个别病变。将进行生物学测量以进行多变量分析，包括通过FACS评估ZAP 70的表达和免疫球蛋白可变基因突变状态。在需要时，将通过选定基因（如p53）的靶向外显子重测序工作对该数据进行补充。最终，该数据集将指导CLL临床风险适应性试验的开发或完善，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益处是以高分辨率描绘可能含有CLL生物学和发病机制中重要基因的病变。 外行人摘要：慢性淋巴细胞白血病（CLL）是西方世界最常见的白血病，在美国每年估计有10，000 - 15，000例新发病例。CLL仍然无法单独使用化疗治愈，并且具有不同的临床病程。使用改进的、无偏见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，从而增加改善患者预后的可能性。慢性淋巴细胞白血病（CLL）是西方世界最常见的白血病，在美国每年估计有10，000 - 15，000例新发病例。CLL仍然无法单独使用化疗治愈，并且具有不同的临床病程。使用无偏见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，包括移植。

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.