Integrative Genomics Analyses Reveal Molecularly Distinct Subgroups of B-Cell Chronic Lymphocytic Leukemia Patients with 13q14 Deletion
Integrative Genomics Analyses Reveal Molecularly Distinct Subgroups of B-Cell Chronic Lymphocytic Leukemia Patients with 13q14 Deletion
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DOI：
10.1158/1078-0432.ccr-10-0151
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发表时间：
2010-12-01
影响因子：
11.5
通讯作者：
Neri, Antonino
中科院分区：
文献类型：
--
作者：
Mosca, Laura;Fabris, Sonia;Neri, Antonino
目的：染色体 13q14 缺失发生在大量慢性淋巴细胞白血病 (CLL) 患者中，并且被认为具有致病作用。由于其异质性和对相关基因的不精确了解，该病变涉及的确切机制尚未完全阐明。这项研究旨在进一步促进 CLL 病变的分子定义。实验设计：我们应用单核苷酸多态性 (SNP) 阵列技术和基因表达谱数据来研究 100 名未经治疗的早期 (Binet A) 患者中发生的 13q14 缺失，这些患者代表了该疾病的主要遗传学、分子和生物学特征。结果：与 FISH 分析一致，SNP 阵列识别出了 44 名患者del(13)(q14) 包括 11 个双等位基因缺失的病例。较短的单等位基因缺失长度为 635 kb。 miR-15a/16-1 簇的丢失发生在所有 del(13)(q14) 病例中，除了 2 名单等位基因缺失患者保留了两个拷贝之外。与 13q 正常病例相比，仅在 miRNA 簇双等位基因丢失的患者中，miR-15a/16 表达显着下调。最后，通过非负矩阵分解算法对 SNP 谱进行自然分组表明，患者可以分为 2 个独立的簇，主要特征是短/双等位基因与宽/单等位基因 13q14 缺失。对表达数据的监督分析表明，特定的转录谱与这 2 个基因组亚组相关。结论：总体而言，我们的数据强调了 13q14 缺失的 2 种不同分子类型的存在，这可能与 CLL 具有临床相关性。临床癌症研究； 16（23）； 5641-53。 (C)2010 AACR。
Purpose: Chromosome 13q14 deletion occurs in a substantial number of chronic lymphocytic leukemia (CLL) patients and it is believed to play a pathogenetic role. The exact mechanisms involved in this lesion have not yet been fully elucidated because of its heterogeneity and the imprecise knowledge of the implicated genes. This study was addressed to further contribute to the molecular definition of this lesion in CLL.Experimental Design: We applied single-nucleotide polymorphism (SNP)-array technology and gene expression profiling data to investigate the 13q14 deletion occurring in a panel of 100 untreated, early-stage (Binet A) patients representative of the major genetics, molecular, and biological features of the disease.Results: Concordantly with FISH analysis, SNP arrays identified 44 patients with del(13)(q14) including 11 cases with a biallelic deletion. The shorter monoallelic deletion was 635-kb long. The loss of the miR-15a/16-1 cluster occurred in all del(13)(q14) cases except in 2 patients with a monoallelic deletion, who retained both copies. MiR-15a/16 expression was significantly downregulated only in patients with the biallelic loss of the miRNA cluster compared to 13q normal cases. Finally, the natural grouping of SNP profiles by nonnegative matrix factorization algorithm showed that patients could be classified into 2 separate clusters, mainly characterized by short/biallelic versus wide/monoallelic 13q14 deletions. Supervised analyses of expression data showed that specific transcriptional profiles are correlated with these 2 genomic subgroups.Conclusions: Overall, our data highlight the presence of 2 distinct molecular types of 13q14 deletions, which may be of clinical relevance in CLL. Clin Cancer Res; 16(23); 5641-53. (C)2010 AACR.