Genomic Complexity and Clinical Outcome in Chronic Lymphocytic Leukemia

描述（由申请人提供）：CLL是西方世界最常见的白血病。疾病的诊断和分期是通过临床和实验室检查结果进行的。该疾病的临床过程是高度可变的，治疗和预后变量正在不断完善。识别最具侵袭性的CLL亚型的生物标志物的鉴定是研究的优先事项，因为正是这些患者承担了不成比例的CLL死亡率负担。在目前已知的生物标志物中，只有相对罕见的del 17 p（诊断时所有CLL病例的5%-7%）可识别诊断后数年内死亡风险高的患者。因此，del 17 p的鉴定在CLL疾病管理中具有实质性的重要性，并且已经导致CLL的风险适应性治疗方法的发展。与核型变化在适当选择治疗中起主导作用的急性髓性白血病不同，在CLL中，基于遗传病变的治疗和咨询仍在开发和完善中。CLL的基因组变化一直难以全面研究，因为CLL细胞离体生长不好。因此，一项重大的技术突破是间期荧光原位杂交技术应用于CLL基因组的研究，该技术描绘了五种在临床上显著的染色体畸变：del 13 q14（约50%）、del 11 q22-q23（约10%）、12三体（约15-20%）、del 17 p13（约5-7%）和del 6 q21。间期FISH现在用于临床实践中对CLL患者进行风险分层，del 17 p或del 11 q的存在已经确定了对标准治疗反应持续时间较差的CLL患者亚组。尽管FISH检测在CLL中很重要，但该技术存在显着缺陷。最突出的警告之一是对基因组的偏倚评估，因此无法可靠地检测具有多个染色体异常的CLL（具有复杂核型的CLL）。为了克服CLL基因组分析中的这些困难，我们和其他人已经采用SNP阵列以高分辨率表征CLL基因组。该分析的一个结果是发现并初步表征了一个CLL患者亚组（约15-40%），该亚组具有多个亚染色体丢失和获得（高基因组复杂性），显示出非常快速的疾病进展和对标准疗法的不良反应持续时间。在这项提案中，我们希望扩展我们对具有高基因组复杂性的CLL患者的初步观察，以充分探索这一观察的临床意义，并获得对这一现象的分子机制的初步见解。我们预计，通过这些研究，具有高基因组复杂性的CLL患者将被证实具有早期治疗需求和对常规治疗反应不良导致过早死亡的高风险，从而确定了大量极高风险CLL患者亚群，应针对其进行新药开发，并应对其进行精细咨询。公共卫生相关性：慢性淋巴细胞性白血病（CLL）是西方世界最常见的白血病，临床病程具有高度可变性。鉴定预测患者临床结果的生物标志物仍然是研究的优先事项。我们的研究旨在通过使用能够以公正的方式测量这些变化的新技术来确定CLL基因组变化在CLL结局预测中的作用。

DESCRIPTION (provided by applicant): CLL is the most common leukemia in the Western world. Diagnosis and staging of the disease is made by clinical and laboratory findings. The clinical course of the disease is highly variable, and treatment and prognostic variables are continuously being refined. Identification of biomarkers that identify the most aggressive CLL subtypes is a research priority as it is these patients that carry a disproportional share of the burden of CLL mortality. Of the currently known biomarkers, only the relatively rare del17p (5%-7% of all CLL cases at diagnosis) identifies patients with high risk for death within years of diagnosis. Identification of del17p is therefore of substantial importance in CLL disease management and has resulted in the development of risk-adapted therapy approaches to CLL. Unlike acute myelogenous leukemia, where karyotypic changes play a dominant role in the appropriate selection of therapy, in CLL, therapy and counseling based on genetic lesions are still being developed and refined. Genomic changes in CLL have been difficult to study comprehensively, as CLL cells do not grow well ex vivo. A major technical breakthrough, therefore, has been the application of interphase fluorescent in situ hybridization to the study of CLL genomes, which delineated five prognostically significant chromosomal aberrations: del13q14 (about 50%), del11q22-q23 (~10%), trisomy 12 (~15-20%), del17p13 (~5-7%) and del6q21. Interphase FISH is now used in clinical practice to risk-stratify CLL patients and presence of del17p or del11q has identified a subgroup of CLL patients with poor response duration to standard therapy. Despite the importance of FISH testing in CLL, this technique has significant shortcomings. One of the most prominent caveats is the biased assessment of the genome and consequently the inability to reliably detect CLL with multiple chromosomal abnormalities (CLL with complex karyotypes). To overcome these difficulties in CLL genome analysis, we and others have employed SNP-arrays to characterize the CLL genome at high resolution. One outcome of this analysis has been the discovery and initial characterization of a subgroup of CLL patients (~15-40%) with multiple sub-chromosomal losses and gains (high genomic complexity) that display very rapid disease progression and poor response duration to standard therapies. In this proposal, we wish to extend our initial observation on CLL patients with high genomic complexity to fully explore the clinical significance of this observation and to derive initial insights into the molecular mechanisms of this phenomenon. We anticipate that through these studies, CLL patients with high genomic complexity will be confirmed to be of high risk for early need of therapy and for poor response to conventional therapy resulting in untimely death, thus identifying a substantial subpopulation of very high risk CLL patients towards which new drug development should be targeted and to which refined counseling should be applied. PUBLIC HEALTH RELEVANCE: Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and has a highly variable clinical course. Identification of biomarkers that predict the clinical outcome of patients remains a research priority. Our studies aim at defining the role of CLL genomic changes in outcome prognostication in CLL through use of novel technologies able to measure these changes in an unbiased fashion.