Zhang Linsheng, Znoyko Iya, Costa Luciano J, Conlin Laura K, Daber Robert D, Self Sally E, Wolff Daynna J
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, USA.
Cancer Genet. 2011 Dec;204(12):654-65. doi: 10.1016/j.cancergen.2011.10.012.
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease. The methods currently used for monitoring CLL and determining conditions for treatment are limited in their ability to predict disease progression, patient survival, and response to therapy. Although clonal diversity and the acquisition of new chromosomal abnormalities during the disease course (clonal evolution) have been associated with disease progression, their prognostic potential has been underappreciated because cytogenetic and fluorescence in situ hybridization (FISH) studies have a restricted ability to detect genomic abnormalities and clonal evolution. We hypothesized that whole genome analysis using high resolution single nucleotide polymorphism (SNP) microarrays would be useful to detect diversity and infer clonal evolution to offer prognostic information. In this study, we used the Infinium Omni1 BeadChip (Illumina, San Diego, CA) array for the analysis of genetic variation and percent mosaicism in 25 non-selected CLL patients to explore the prognostic value of the assessment of clonal diversity in patients with CLL. We calculated the percentage of mosaicism for each abnormality by applying a mathematical algorithm to the genotype frequency data and by manual determination using the Simulated DNA Copy Number (SiDCoN) tool, which was developed from a computer model of mosaicism. At least one genetic abnormality was identified in each case, and the SNP data was 98% concordant with FISH results. Clonal diversity, defined as the presence of two or more genetic abnormalities with differing percentages of mosaicism, was observed in 12 patients (48%), and the diversity correlated with the disease stage. Clonal diversity was present in most cases of advanced disease (Rai stages III and IV) or those with previous treatment, whereas 9 of 13 patients without detected clonal diversity were asymptomatic or clinically stable. In conclusion, SNP microarray studies with simultaneous evaluation of genomic alterations and mosaic distribution of clones can be used to assess apparent clonal evolution via analysis of clonal diversity. Since clonal evolution in CLL is strongly correlated with disease progression, whole genome SNP microarray analysis provides a new comprehensive and reliable prognostic tool for CLL patients.
慢性淋巴细胞白血病（CLL）是一种临床异质性疾病。目前用于监测CLL和确定治疗条件的方法在预测疾病进展、患者生存及对治疗的反应方面能力有限。尽管在疾病进程中克隆多样性和新染色体异常的获得（克隆进化）与疾病进展相关，但其预后潜力一直未得到充分重视，因为细胞遗传学和荧光原位杂交（FISH）研究检测基因组异常和克隆进化的能力有限。我们推测，使用高分辨率单核苷酸多态性（SNP）微阵列进行全基因组分析有助于检测多样性并推断克隆进化，从而提供预后信息。在本研究中，我们使用Infinium Omni1 BeadChip（Illumina，圣地亚哥，加利福尼亚州）阵列分析25例未经选择的CLL患者的基因变异和嵌合百分比，以探讨评估CLL患者克隆多样性的预后价值。我们通过对基因型频率数据应用数学算法并使用从嵌合计算机模型开发的模拟DNA拷贝数（SiDCoN）工具进行手动测定，计算每种异常的嵌合百分比。每例均至少鉴定出一种基因异常，SNP数据与FISH结果的一致性为98%。在12例患者（48%）中观察到克隆多样性，定义为存在两种或更多种具有不同嵌合百分比的基因异常，且这种多样性与疾病分期相关。大多数晚期疾病（Rai分期III和IV）或既往接受过治疗的病例存在克隆多样性，而13例未检测到克隆多样性的患者中有9例无症状或临床稳定。总之，同时评估基因组改变和克隆嵌合分布的SNP微阵列研究可用于通过分析克隆多样性来评估明显的克隆进化。由于CLL中的克隆进化与疾病进展密切相关，全基因组SNP微阵列分析为CLL患者提供了一种新的全面且可靠的预后工具。
