Genomic Profiling and clinical Outcome in Chronic Lymphocytic Leukemia

描述(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，估计在美国每年有10,000-15,000例新病例发生。在急性髓系白血病中，核型分析现在是预后和临床决策的主要分子标记，而在慢性淋巴细胞性白血病中，核型分析充满了技术困难。这一建议试图使用无偏见的全基因组基因组图谱来描述CLL中新的遗传损伤以及已知遗传损伤的亚型。这项研究的CLL样本和成对的正常口腔DNA样本来自密歇根大学一项前瞻性翻译研究试验的患者，该试验计划连续购买样本10年，并进行连续20年的随访。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丢失(LOH)和拷贝数变化的分析。在确定LOH、复制中性LOH或复制丢失或复制获得的区域的特征后，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。将进行进行多变量分析的生物学测量，包括通过流式细胞仪评估ZAP70的表达和免疫球蛋白可变基因突变状态。这些数据将在需要时得到补充，并对选定的基因(如p53)进行有针对性的外显子重新测序。最终，该数据集将指导CLL临床风险适应试验的开发或改进，包括实验性药物疗法和异基因干细胞移植。分析CLL基因组变化的另一个好处是以高分辨率描绘可能包含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，估计在美国每年新发病例10,000-15,000例。仅用化疗仍无法治愈慢性淋巴细胞性白血病，其临床病程多种多样。使用改进的、无偏见的基因测试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，从而增加改善患者结局的可能性。慢性淋巴细胞白血病(CLL)是西方世界最常见的白血病，据估计，美国每年新增病例10,000-15,000例。仅用化疗仍无法治愈慢性淋巴细胞性白血病，其临床病程多种多样。使用无偏见的基因测试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治疗方案。

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.