Integrative Genomics Analyses Reveal Molecularly Distinct Subgroups of B-Cell Chronic Lymphocytic Leukemia Patients with 13q14 Deletion

Abstract

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. Ó2010 AACR.

microRNAome Expression in Chronic Lymphocytic Leukemia: Comparison with Normal B-cell Subsets and Correlations with Prognostic and Clinical Parameters

“…Specifically reduced miR16 expression was significantly associated with biallelic and monoallelic 13q deletion, in accordance with the notion of a gene dosage effect for the expression of this miRNA (15). The downregulation of miR34a was closely related to the presence of 17p deletion (14,23).…”

“…S5) because the downregulation of miR34a in the 17pÀ CLL cases (13,14) and the downregulation of miR16 in the 13qÀ cases had already been confirmed by earlier reports (15).…”

Genome‐wide analysis of primary plasma cell leukemia identifies recurrent imbalances associated with changes in transcriptional profiles

“…Genotyping Console (GC) was used to extract raw DNA copy number (CN) and loss-of-heterozygosity (LOH) probability from CEL files according to Affymetrix guidelines. CN was then estimated using circular binary segmentation and normalized on FISH data using DNAcopy and FBN packages in R software, respectively, as previously described [10,15]. LOH was defined by applying a 1 Mb smoothing window on the GC-derived value with a probability higher than 0.95 for the detection of a monoallelic polymorphism.…”

Chromosome 2p gain in monoclonal B‐cell lymphocytosis and in early stage chronic lymphocytic leukemia

“…The FISH study was performed using the protocol provided by the manufacturer of the multicolor probes LSI D13S25/LSI 13q34, LSIp53/CEP17, LSI ATM/CEP11, and CEP12 (Vysis Inc., Downers Grove, IL) as previously described [33], for the detection of 13q14, 17p13, and 11q22-q23 deletions and trisomy 12, respectively. On the basis of single nucleotide polymorphism (SNP) arrays data previously reported by us [34], specific BAC clones RP11-606L8 (BCL11A; 2p16.1) and RP11-368O18 (2p24.1), selected from the University of California Santa Cruz (UCSC) Genome Browser Database (http://genome.ucsc.edu/), were used for the identification of 2p gain. FISH analyses were performed according to previously described protocols [35].…”