Genomic Complexity and Clinical Outcome in Chronic Lymphocytic Leukemia

慢性淋巴细胞白血病的基因组复杂性和临床结果

• 批准号: 8253756
• 负责人: Sami Nimer Malek
• 金额: $ 30.85万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8253756
• 关键词: Acute Myelocytic Leukemia; Aftercare; Allogenic; Anatomy; Apoptotic; Biological; Biological Factors; Biological Markers; Blood; Bone Marrow Transplantation; Cells; Cessation of life; Chromosomal Gain; Chromosomal Loss; Chromosome abnormality; Chronic Lymphocytic Leukemia; Clinical; Clinical Course of Disease; Complex; Counseling; Cytotoxic Chemotherapy; DNA Double Strand Break; DNA Repair; DNA Sequence Analysis; Data; Data Analyses; Defect; Development; Diagnosis; Disease; Disease Management; Disease Progression; Enrollment; Fluorescent in Situ Hybridization; Foundations; Gene Mutation; Genes; Genetic; Genome; Genomic Instability; Genomics; Health; Individual; Interphase; Investigational Therapies; Karyotype determination procedure; Laboratories; Laboratory Finding; Lesion; Malignant Neoplasms; Maps; Marrow; Measurement; Measures; Molecular; Multivariate Analysis; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Prognostic Factor; Prognostic Marker; Progressive Disease; Recurrence; Reporting; Research Priority; Resolution; Risk; Role; Sampling; Staging; Subgroup; Surrogate Markers; Techniques; Technology; Testing; Time; Trisomy 12; Variant; Western World; base; chemotherapy; clinical practice; clinically significant; cohort; conventional therapy; density; drug development; ds-DNA; functional status; gene therapy; high risk; insight; leukemia; mortality; new technology; novel; prognostic; repaired; response

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.

描述（由申请人提供）：CLL是西方世界上最常见的白血病。疾病的诊断和分期是由临床和实验室发现进行的。该疾病的临床过程高度可变，治疗和预后变量正在不断完善。鉴定鉴定最具侵略性CLL亚型的生物标志物是研究的重点，因为这些患者在CLL死亡率负担中占不变的份额。在当前已知的生物标志物中，只有相对罕见的DEL17P（诊断为所有CLL病例的5％-7％）可以确定诊断年几年内死亡高风险的患者。因此，DEL17P的鉴定在CLL疾病管理中至关重要，并导致了适应风险的CLL方法的发展。与急性粒细胞性白血病不同，核型变化在适当的治疗选择中起主要作用，在基于遗传病变的CLL，治疗和咨询中仍在开发和完善。 CLL的基因组变化很难全面研究，因为CLL细胞在体内生长不佳。因此，主要的技术突破是将相互荧光原位杂交在CLL基因组研究中的应用，该研究描绘了五个预后具有重要意义的染色体畸变：DEL13Q14（约50％），Del11q222-Q23（〜10％），Trisomy 12（〜15-20％）（〜15-20％），DEL6 Q.5-17％，〜5-17p13（〜5-5-17p1）（〜5-17p1）。现在，中间鱼类用于临床实践中，以使CLL患者风险划分，并且存在DEL17P或DEL11Q的存在已确定对标准疗法反应持续时间较差的CLL患者亚组。尽管在CLL中进行鱼类测试的重要性，但该技术仍存在重大缺点。最突出的警告之一是对基因组的偏见评估，因此无法可靠地检测出具有多种染色体异常（具有复杂核型的CLL）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阵列来表征高分辨率的CLL基因组。该分析的一个结果是发现和初步表征CLL患者的亚组（〜15-40％），具有多个亚染色体损失和增长（高基因组复杂性），这些疾病进展非常快，对标准疗法的反应持续时间很差。在此提案中，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，以充分探索该观察结果的临床意义，并获得对该现象的分子机制的初步见解。我们预计，通过这些研究，将证实具有高基因组复杂性的CLL患者对早期需要治疗和对常规治疗的反应不佳，导致过早死亡具有高风险，从而确定应对新药物发育的非常高风险的CLL患者的实质性亚群，并应采用精致的咨询。