Molecular characterization of chronic lymphocytic leukemia patients with a high number of losses in 13q14.
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ABSTRACT: Background
Patients with chronic lymphocytic leukemia and 13q deletion as their only FISH abnormality could have a different outcome depending on the number of cells displaying this aberration. Thus, cases with a high number of 13q- cells (13q-H) had both shorter overall survival and time to first therapy. The goal of the study was to analyze the genetic profile of 13q-H patients.Design and methods
A total of 102 samples were studied, 32 of which served as a validation cohort and five were healthy donors.Results
Chronic lymphocytic leukemia patients with higher percentages of 13q- cells (>80%) showed a different level of gene expression as compared to patients with lower percentages (<80%, 13q-L). This deregulation affected genes involved in apoptosis and proliferation (BCR and NFkB signaling), leading to increased proliferation and decreased apoptosis in 13q-H patients. Deregulation of several microRNAs, such as miR-15a, miR-155, miR-29a and miR-223, was also observed in these patients. In addition, our study also suggests that the gene expression pattern of 13q-H cases could be similar to the patients with 11q- or 17p-.Conclusions
This study provides new evidence regarding the heterogeneity of 13q deletion in chronic lymphocytic leukemia patients, showing that apoptosis, proliferation as well as miRNA regulation are involved in cases with higher percentages of 13q- cells.
SUBMITTER: Rodriguez AE
PROVIDER: S-EPMC3496725 | biostudies-literature | 2012
REPOSITORIES: biostudies-literature
Publications
Molecular characterization of chronic lymphocytic leukemia patients with a high number of losses in 13q14.
Rodríguez Ana Eugenia AE Hernández Jose Ángel JÁ Benito Rocío R Gutiérrez Norma C NC García Juan Luis JL Hernández-Sánchez María M Risueño Alberto A Sarasquete M Eugenia ME Fermiñán Encarna E Fisac Rosa R de Coca Alfonso García AG Martín-Núñez Guillermo G de Las Heras Natalia N Recio Isabel I Gutiérrez Oliver O De Las Rivas Javier J González Marcos M Hernández-Rivas Jesús M JM Hernández-Rivas Jesús M JM
PloS one 20121113 11
<h4>Background</h4>Patients with chronic lymphocytic leukemia and 13q deletion as their only FISH abnormality could have a different outcome depending on the number of cells displaying this aberration. Thus, cases with a high number of 13q- cells (13q-H) had both shorter overall survival and time to first therapy. The goal of the study was to analyze the genetic profile of 13q-H patients.<h4>Design and methods</h4>A total of 102 samples were studied, 32 of which served as a validation cohort and ...[more]
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Project description:PurposeTo further our understanding of the biology and prognostic significance of various chromosomal 13q14 deletions in chronic lymphocytic leukemia (CLL).Experimental designWe analyzed data from SNP 6.0 arrays to define the anatomy of various 13q14 deletions in a cohort of 255 CLL patients and have correlated two subsets of 13q14 deletions (type I exclusive of RB1 and type II inclusive of RB1) with patient survival. Furthermore, we measured the expression of the 13q14-resident microRNAs by quantitative PCR (Q-PCR) in 242 CLL patients and subsequently assessed their prognostic significance. We sequenced all coding exons of RB1 in patients with monoallelic RB1 deletion and have sequenced the 13q14-resident miR locus in all patients.ResultsLarge 13q14 (type II) deletions were detected in approximately 20% of all CLL patients and were associated with shortened survival. A strong association between 13q14 type II deletions and elevated genomic complexity, as measured through CLL-FISH or SNP 6.0 array profiling, was identified, suggesting that these lesions may contribute to CLL disease evolution through genomic destabilization. Sequence and copy number analysis of the RB1 gene identified a small CLL subset that is RB1 null. Finally, neither the expression levels of the 13q14-resident microRNAs nor the degree of 13q14 deletion, as measured through SNP 6.0 array-based copy number analysis, had significant prognostic importance.ConclusionsOur data suggest that the clinical course of CLL is accelerated in patients with large (type II) 13q14 deletions that span the RB1 gene, therefore justifying routine identification of 13q14 subtypes in CLL management.
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Project description:Deletions of chromosome 13q14 are common in chronic lymphocytic leukemia and other cancers, demonstrating the importance of this region in tumorigenesis. We report the use of two single-nucleotide polymorphism (SNP)-based techniques to determine 13q loss of heterozygosity (LOH) status in 15 patients with CLL: (i) digital SNP (dSNP), where analysis of heterozygous SNPs detects allelic imbalances, and (ii) DNA sequencing, where LOH is identified by comparison of allelic peak heights in normal and neoplastic cells. The SNP-based techniques were compared with established molecular techniques, fluorescence in situ hybridization and multiplex ligation-dependent probe amplification, to determine their utility and relative sensitivity. dSNP proved to be the most sensitive technique, identifying 13q14 LOH in 11 of 13 (85%) patients (95% CI: 55%, 98%) without the need for neoplastic cell enrichment. Three cases showed evidence of LOH by dSNP that was not apparent by other techniques. In 8 of 13 (62%) cases, partial or interstitial patterns of LOH were observed by dSNP. Our findings demonstrate that dSNP represents a useful, sensitive technique for the analysis of chromosomal aberrations that result in LOH. It may have applications for the analysis of other malignancies that are difficult to assess by conventional molecular techniques.
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Project description:B-cell chronic lymphocytic leukemia (B-CLL) is characterized by a highly variable clinical course that reflects its heterogeneous genomic pattern. To better define molecular subtypes of the disease, we performed SNP and gene expression profiling microarray analyses in a panel of early stage (Binet A) patients. A clustering analysis of genomic profiles identified four significant groups mainly driven by del(13)(q14) and trisomy 12. Notably, patients with del(13)(q14) were grouped in two separate clusters based on the presence of a biallelic loss and the extension of the deletion. The shorter monoallelic deleted 13q14 region was found to be 635 kb in length, not encompassing the mir-15a/16-1 locus. Interestingly, the mir-15a and mir-16 expression was found to be significantly down-regulated only in patients with biallelic loss. Furthermore, a multiclass supervised analysis identified a different transcriptional signatures in the two genomic subgroups with del(13)(q14). Finally, an integrative approach identified 93 transcripts, mainly mapped to chromosome 12 and 13q12-q14.3, whose expression was significantly correlated with the DNA copy number. Overall, our data further support the notion that transcription deregulation in B-CLL could be mostly due to a gene dosage effect and underscore the presence of two distinct molecular types of 13q14 deleted patients with potential clinical relevance.
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