Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human purified plasma cells (PCs) obtained from 90 newly diagnosed multiple myeloma (MM) reveals a distinct transcriptional and genetic features associated with chromosome 13 deletion in multiple myeloma

ABSTRACT: Background and objective: The chromosome 13 deletion (del(13)) represents one of the most frequent chromosomal alterations in multiple myeloma (MM). del(13) is associated with an unfavorable prognosis, although there is an increasing agreement that its prognostic relevance has to be related to the ploidy status and the presence of different chromosomal translocations. This study is aimed at providing a comprehensive analysis of the transcriptional features of del(13) in MM. Design and methods: Highly purified plasma cells from 80 newly diagnosed MM patients were characterized by means of FISH and high-density oligonucleotide microarray for gene expression profiling and chromosomal alterations. Results: We identified 67 differentially expressed genes in the del(13)+ and del(13)- groups, all of which downregulated in the del(13)+ cases: 44 mapped along the whole chromosome 13, seven on chromosome 11 and three on chromosome 19. Functional analyses of the selected genes indicated their involvement in protein biosynthesis, ubiquitination and transcriptional regulation. An integrative genomic approach based on regional analyses of the gene expression data identified distinct chromosomal regions whose global expression modulation could differentiate del(13)+, in particular the upregulation of 1q21-1q42 and the downregulation of 19p and almost the entire chromosome 11. FISH analyses confirmed the close relationship between del(13)+ and the presence of extracopies of 1q21-1q42 (P=6x10-4) or the absence of chromosome 11 and 19 trisomy (P=5x10-4). Interpretation and conclusions: Our results indicate that distinct types of chromosomal aberrations are closely related to the transcriptional profiles of del(13)+, suggesting that the contribution of del(13) on the malignancy should be considered together with associated abnormalities. Experiment Overall Design: This series of microarray experiments contains the gene expression profiles of purified plasma cells (PCs) obtained from 90 newly diagnosed multiple myeloma (MM). PCs were purified from bone marrow specimens, after red blood cell lysis with 0.86% ammonium chloride, using CD138 immunomagnetic microbeads. The purity of the positively selected PCs was assessed by morphology and flow cytometry and was > 90% in all cases. 5 micrograms of total RNA was processed and, in accordance with the manufacturer's protocols, 15 micrograms of fragmented biotin-labelled cRNA were hybridized on GeneChip Human Genome U133A Arrays (Affymetrix Inc.). The arrays were scanned using the Agilent GeneChip Scanner G2500A. The images were acquired using Affymetrix MicroArray Suite (MAS) 5.0 software and the probe level data converted to expression values using the Bioconductor function for the Robust Multi-Array average (RMA) procedure (Irizarry et al, 2003), in which perfect match intensities are background adjusted and quantile-quantile normalised.

ORGANISM(S): Homo sapiens

SUBMITTER: Antonino Neri

PROVIDER: E-GEOD-6365 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Integrative genomic analysis reveals distinct transcriptional and genetic features associated with chromosome 13 deletion in multiple myeloma.

Agnelli Luca L Bicciato Silvio S Fabris Sonia S Baldini Luca L Morabito Fortunato F Intini Daniela D Verdelli Donata D Callegaro Andrea A Bertoni Francesco F Lambertenghi-Deliliers Giorgio G Lombardi Luigia L Neri Antonino A

Haematologica 20070101 1

<h4>Background and objectives</h4>The chromosome 13 deletion (Delta13) is one of the most frequent chromosomal alterations in multiple myeloma (MM). Delta13 is associated with an unfavorable prognosis, although there is increasing agreement that its prognostic relevance must be related to the ploidy status and the presence of different chromosomal translocations. The aim of this study was to provide a comprehensive analysis of the transcriptional features of Delta13 in MM.<h4>Design and methods< ...[more]

PMID: 17229636

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Project description:Multiple myeloma (MM) is a malignant plasma cell (PC) dyscrasia characterized by heterogeneous biological features and genetic alterations, resulting in a wide range of disease courses. Despite all the therapeutic strategies developed in the last three decades, MM is still incurable, and almost all patients will inevitably experience disease progression and eventually relapse. Among all the genetic abnormalities, the amplification of the 1q21 region is one of the most frequent lesions occurring in malignant PCs and it has become a new prognostic factor in MM patients. Furthermore, the incidence of gain and/or amplification of the 1q21 locus (1q21+) increases with disease progression. It can be detected in around 30-45% of patients with smoldering MM (SMM) and newly diagnosed MM (NDMM), and in around 70% of relapsed/refractory MM patients. Moreover, the impact of 1q21 on disease progression at an early stage has not been widely investigated. Few studies have suggested that the acquisition of extra 1q21 copies may play a role in disease progression. In fact, SMM patients with 1q21+ may be more likely to progress to MM than patients without 1q21+. Recent studies have demonstrated that the 1q21 copy number has a different impact on the responsiveness to MM treatments, especially proteasome inhibitors (PIs). Throughout the years, the implementation of PIs drugs as part of standard MM therapy has continued to improve the quality of life and clinical outcomes of MM patients. However, innate and acquired resistance to PIs limits their long-term clinical utility. Furthermore, additional copies of 1q21 have been associated with PI resistance and recurrence of the disease in patients with 1q21+. Several genes are known to be deregulated upon the amplification of the 1q21 locus, however, the pathogenic mechanism of how those genes drive disease progression and contribute to the poor outcome in patients with 1q21+ and their possible role as druggable targets is not fully understood. In this study, we analyzed purified CD138+ bone marrow PCs from 11 SMM and 18 NDMM patients to identify genes whose expressions are deregulated in patients with 1q21+ in correlation with the number of copies and their putative role in drug response.

Project description:Multiple myeloma (MM) is characterized by marked genomic instability. Beyond structural rearrangements, a relevant role in its biology is represented by allelic imbalances leading to significant variations in ploidy status. To better elucidate the genomic complexity of MM, we analyzed a panel of 45 patients using combined FISH and microarray approaches. Using a self-developed procedure to infer exact local copy numbers for each sample, we identified a significant fraction of patients showing marked aneuploidy. A conventional clustering analysis showed that aneuploidy, chromosome 1 alterations, hyperdiploidy and recursive deletions at 1p and chromosomes 13, 14 and 22 were the main aberrations driving samples grouping. Then, we integrated mapping information with gene and microRNAs expression profiles: a multiclass analysis of the identified clusters showed a marked gene-dosage effect, particularly concerning 1q transcripts, also confirmed by correlating gene expression levels and local copy number alterations. A wide dosage effect affected also microRNAs, indicating that structural abnormalities in MM closely reflect in their expression imbalances. Finally, we identified several loci in which genes and microRNAs expression correlated with loss-of-heterozygosity occurrence. Our results provide insights into the composite network linking genome structure and gene/microRNA transcriptional features in MM. Experiment Overall Design: This series of microarray experiments contains the gene expression profiles of purified plasma cells (PCs) obtained from 4 normal donor (N), 11 monoclonal gammopathy of undetermined significance (MGUS), 133 multiple myeloma (MM) and 9 plasma cell leukemia (PCL) at diagnosis. PCs were purified from bone marrow specimens, after red blood cell lysis with 0.86% ammonium chloride, using CD138 immunomagnetic microbeads. The purity of the positively selected PCs was assessed by morphology and flow cytometry and was > 90% in all cases. 5 micrograms of total RNA was processed and, in accordance with the manufacturer's protocols, 15 micrograms of fragmented biotin-labelled cRNA were hybridized on GeneChip Human Genome U133A Arrays (Affymetrix Inc.). The arrays were scanned using the Agilent GeneChip Scanner G2500A. The images were acquired using Affymetrix MicroArray Suite (MAS) 5.0 software and the probe level data converted to expression values using the Bioconductor function for the Robust Multi-Array average (RMA) procedure (Irizarry et al, 2003), in which perfect match intensities are background adjusted, quantile-quantile normalised and log2 transformed.

Project description:Karyotypic instability, including numerical and structural chromosomal aberrations, represents a distinct feature of multiple myeloma (MM). 40-50% of patients displayed hyperdiploidy, defined by recurrent trisomies of non-random chromosomes. To characterize hyperdiploid (H) and nonhyperdiploid (NH) MM molecularly, we analyzed the gene expression profiles of 66 primary tumors, and used FISH to investigate the major chromosomal alterations. The differential expression of 225 genes mainly involved in protein biosynthesis, transcriptional machinery and oxidative phosphorylation distinguished the 28 H-MM from the 38 NH-MM cases. The 204 upregulated genes in H-MM mapped mainly to the chromosomes involved in hyperdiploidy, and the29% up-regulated genes in NH-MM mapped to 16q. The identified transcriptional fingerprint was robustly validated on a publicly available gene expression dataset of 64 MM cases; and the global expression modulation of regions on the chromosomes involved in hyperdiploidy was verified using a self-developed non-parametric statistical method. We showed that H-MM could be further divided into two distinct molecular and transcriptional entities, characterized by the presence of trisomy 11 and 1q-extracopies/chromosome 13 deletion, respectively. Our data reinforce the importance of combining molecular cytogenetics and gene expression profiling to define a genomic framework for the study of MM pathogenesis and clinical management. Experiment Overall Design: This series of microarray experiments contains the gene expression profiles of purified plasma cells (PCs) obtained from 102 newly diagnosed multiple myeloma (MM). PCs were purified from bone marrow specimens, after red blood cell lysis with 0.86% ammonium chloride, using CD138 immunomagnetic microbeads. The purity of the positively selected PCs was assessed by morphology and flow cytometry and was > 90% in all cases. 5 micrograms of total RNA was processed and, in accordance with the manufacturer's protocols, 15 micrograms of fragmented biotin-labelled cRNA were hybridized on GeneChip Human Genome U133A Arrays (Affymetrix Inc.). The arrays were scanned using the Agilent GeneChip Scanner G2500A. The images were acquired using Affymetrix MicroArray Suite (MAS) 5.0 software and the probe level data converted to expression values using the Bioconductor function for the Robust Multi-Array average (RMA) procedure (Irizarry et al, 2003), in which perfect match intensities are background adjusted and quantile-quantile normalised.

Project description:PURPOSE. The deregulation of CCND1, CCND2 and CCND3 genes represents a common event in multiple myeloma (MM). The recently proposed TC classification grouped MM patients into five classes on the basis of their cyclins D expression profiles and the presence of the main translocations involving the immunoglobulin heavy-chain locus (IGH) at 14q32. In this study, we provide a molecular characterization of the identified TC groups. MATERIALS AND METHODS. The gene expression profiles of purified plasma cells from 50 MM cases were used to stratify the samples into the five TC classes and identify their transcriptional fingerprints. The cyclin D expression data were validated by means of real-time quantitative PCR analysis; fluorescence in-situ hybridization was used to investigate the cyclin D loci arrangements, and to detect the main IGH translocations and the chromosome 13q deletion. RESULTS. Class-prediction analysis identified 112 probe sets as characterizing the TC1, TC2, TC4 and TC5 groups, whereas the TC3 samples showed heterogeneous phenotypes and no marker genes. The TC2 group, which showed extra copies of the CCND1 locus and no IGH translocations or the chromosome 13q deletion, was characterized by the overexpression of genes involved in protein biosynthesis at translational level. A meta-analysis of published datasets validated the identified gene expression signatures. CONCLUSIONS. Our data contribute to the understanding of the molecular and biological features of distinct MM subtypes. The identification of a distinctive gene expression pattern in TC2 patients may improve risk stratification and indicate novel therapeutic targets. Experiment Overall Design: This series of microarray experiments contains the gene expression profiles of purified plasma cells (PCs) obtained from 50 newly diagnosed multiple myeloma (MM). PCs were purified from bone marrow specimens, after red blood cell lysis with 0.86% ammonium chloride, using CD138 immunomagnetic microbeads. The purity of the positively selected PCs was assessed by morphology and flow cytometry and was > 90% in all cases. 5 micrograms of total RNA was processed and hybridized to the Affymetrix HG-U133A chip following the manufacturer's instructions.

Dataset Information

Transcription profiling of human purified plasma cells (PCs) obtained from 90 newly diagnosed multiple myeloma (MM) reveals a distinct transcriptional and genetic features associated with chromosome 13 deletion in multiple myeloma

Publications

Integrative genomic analysis reveals distinct transcriptional and genetic features associated with chromosome 13 deletion in multiple myeloma.

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