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。该病的诊断和分期由临床和实验室结果决定。该疾病的临床病程变化很大，治疗和预后变量也在不断改进。识别最具侵袭性CLL亚型的生物标志物是研究的重点，因为这些患者在CLL死亡率中所占的比例不成比例。在目前已知的生物标志物中，只有相对罕见的del17p（占诊断时所有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，del17p的鉴定在CLL疾病管理中具有重要意义，并导致了CLL风险适应治疗方法的发展。与核型变化在治疗选择中起主导作用的急性髓性白血病不同，CLL基于遗传病变的治疗和咨询仍在发展和完善中。由于CLL细胞在体外不能很好地生长，因此很难全面研究CLL的基因组变化。因此，一项重大的技术突破是将间期荧光原位杂交技术应用于CLL基因组的研究，该技术描绘了五种具有预后意义的染色体畸变：del13q14（约50%）、del11q22-q23（约10%）、12三体（约15-20%）、del17p13（约5-7%）和del6q21。间期FISH现在用于临床实践中对CLL患者进行风险分层，del17p或del11q的存在已经确定了对标准治疗反应时间较差的CLL患者亚组。尽管FISH检测在CLL中很重要，但该技术存在显著缺陷。最突出的警告之一是对基因组的有偏见的评估，因此无法可靠地检测多染色体异常的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，我们和其他人使用snp阵列来高分辨率表征CLL基因组。该分析的一个结果是发现并初步表征了CLL患者亚组（约15-40%）具有多个亚染色体丢失和获得（高基因组复杂性），其疾病进展非常快，对标准治疗的反应时间很短。在本提案中，我们希望扩展我们对高基因组复杂性的CLL患者的初步观察，以充分探索这一观察的临床意义，并初步了解这一现象的分子机制。我们预计，通过这些研究，具有高基因组复杂性的CLL患者将被确认为早期需要治疗的高风险患者，并且对常规治疗反应不佳导致过早死亡，从而确定一个非常高风险的CLL患者亚群，应该针对这些患者开发新药，并应用精细的咨询。

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.