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Gene expression profiling of diffuse large B-cell lymphomas supervised by CD5 expression

ABSTRACT: CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) has a poor prognosis and high incidence of central nervous system (CNS) relapse, even in the rituximab era. To determine the gene expression profile of CD5+ DLBCL, total RNA from 90 patients with DLBCL, including 33 CD5+ DLBCL and 57 CD5-negative (CD5-) DLBCL patients, was examined using Agilent human oligo microarrays. These cases were separated into 78 activated B-cell-like (ABC) DLBCLs and 12 germinal center B-cell-like (GCB) DLBCLs. All cases of CD5+ DLBCL were classified as ABC DLBCLs. The classifier based on gene expression used in a supervised analysis correctly identified CD5 expression in the DLBCL and ABC DLBCL samples. The gene most relevant to CD5 expression was SH3BP5. The enriched GO categories in the CD5+ ABC DLBCL signature gene set were multicellular organismal signaling, transmission of nerve impulse, and synaptic transmission. This present study, which includes the largest reported number of patients with CD5+ DLBCL, confirmed that most CD5+ DLBCLs are ABC DLBCLs, suggesting that therapeutic strategies for ABC DLBCL may be effective for the treatment of CD5+ DLBCL. Our CD5+ ABC DLBCL signature gene set may provide insights into the cause of the high frequency of CNS relapse in CD5+ DLBCL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE66770 | GEO | 2015/05/19

SECONDARY ACCESSION(S): PRJNA277914

REPOSITORIES: GEO

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Gene expression profiling of diffuse large B-cell lymphomas supervised by CD5 expression

Project description:CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) has a poor prognosis and high incidence of central nervous system (CNS) relapse, even in the rituximab era. To determine the gene expression profile of CD5+ DLBCL, total RNA from 90 patients with DLBCL, including 33 CD5+ DLBCL and 57 CD5-negative (CD5-) DLBCL patients, was examined using Agilent human oligo microarrays. These cases were separated into 78 activated B-cell-like (ABC) DLBCLs and 12 germinal center B-cell-like (GCB) DLBCLs. All cases of CD5+ DLBCL were classified as ABC DLBCLs. The classifier based on gene expression used in a supervised analysis correctly identified CD5 expression in the DLBCL and ABC DLBCL samples. The gene most relevant to CD5 expression was SH3BP5. The enriched GO categories in the CD5+ ABC DLBCL signature gene set were multicellular organismal signaling, transmission of nerve impulse, and synaptic transmission. This present study, which includes the largest reported number of patients with CD5+ DLBCL, confirmed that most CD5+ DLBCLs are ABC DLBCLs, suggesting that therapeutic strategies for ABC DLBCL may be effective for the treatment of CD5+ DLBCL. Our CD5+ ABC DLBCL signature gene set may provide insights into the cause of the high frequency of CNS relapse in CD5+ DLBCL. This present study involved 90 cases (33 patients with CD5+ DLBCL and 57 with CD5- DLBCL) of de novo consecutive DLBCL diagnosed at Mie University Hospital with available frozen biopsy specimens and total RNA samples. Lymphoma tissue RNA from 90 patients was extracted for target preparation and hybridization onto Agilent microarrays. The expression of CD5 in tumor cells was confirmed by means of immunohistochemistry using frozen sections.

2015-05-19 | E-GEOD-66770 | biostudies-arrayexpress

Expression defined classification of subtypes of diffuse large B cell lymphoma

Project description:Diffuse large B-cell lymphoma (DLBCL) comprises molecularly distinct subgroups such as activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCLs. We previously reported that CD5(+) and CD5(-)CD10(+) DLBCL constitute clinically relevant subgroups. To determine whether these 2 subgroups are related to ABC and GCB DLBCLs, we analyzed the genomic imbalance of 99 cases (36 CD5(+), 19 CD5(-)CD10(+), and 44 CD5(-)CD10(-)) using array-based comparative genomic hybridization (CGH). Forty-six of these cases (22 CD5(+), 9 CD5(-)CD10(+), 1 CD5 (-), and 14 CD5(-)CD10(-)) were subsequently subjected to gene-expression profiling, resulting in their division into 28 ABC (19 CD5(+) and 9 CD5(-)CD10(-)) and 18 GCB (3 CD5(+), 7 CD5(-)CD10(+), and 8 CD5(-)CD10(-)) types. A comparison of genome profiles of distinct subgroups of DLBCL demonstrated that (1) ABC DLBCL is characterized by gain of 3q, 18q, and 19q and loss of 6q and 9p21, and GCB DLBCL is characterized by gain of 1q, 2p, 7q, and 12q; (2) the genomic imbalances characteristic of the CD5(+) and CD5(-)CD10(+) groups were similar to those of the ABC and GCB types, respectively. These findings suggest that CD5(+) and CD5(-)CD10(+) subgroups are included, respectively, in the ABC and GCB types. Finally, when searching for genomic imbalances that affect patients' prognosis, we found that 9p21 loss (p16(INK4a) locus) marks the most aggressive type of DLBCL. Expression profiles in 46 patients with DLBCL and 8 for normal lymph node biopsy samples.

2009-07-10 | E-GEOD-16920 | biostudies-arrayexpress

Expression defined classification of subtypes of diffuse large B cell lymphoma

2009-07-10 | GSE16920 | GEO

Longitudinal gene expression profiling identifies a poor risk subset of patients with ABC-type Diffuse Large B Cell Lymphoma

Project description:Despite the effectiveness of immuno-chemotherapy, 40% of patients with diffuse large B-cell lymphoma (DLBCL) experience relapse or refractory disease. Longitudinal studies have previously focused on the mutational landscape of relapse but falling short of providing a consistent relapse-specific genetic signature. In our study, we have focussed attention on the changes in gene expression profile accompanying DLBCL relapse using archival paired diagnostic/relapse specimens from 38 de novo DLBCL patients. Cell of origin remained stable from diagnosis to relapse in 80% of patients, with only a single patient showing COO switching from ABC to GCB. Analysis of the transcriptomic changes that occur following relapse suggest ABC and GCB relapses are mediated via different mechanisms. We developed a 30-gene discriminator for ABC-DLBCLs derived from relapse-associated genes, that defined clinically distinct high and low risk subgroups in ABC-DLBCLs at diagnosis in datasets comprising both population-based and clinical trial cohorts. This signature also identified a population of <60-year-old patients with superior PFS and OS treated with Ibrutinib-R-CHOP as part of the PHOENIX trial. Altogether this new signature adds to the existing toolkit of putative genetic predictors now available in DLBCL that can be readily assessed as part of prospective clinical trials.

2023-03-08 | GSE193566 | GEO

DNA methylation signatures define molecular subtypes of Diffuse Large B Cell Lymphoma

Project description:We performed DNA methylation (HELP) and gene expression profiling in 69 samples of diffuse large B cell lymphoma (DLBCL). First, by gene expression, two molecular subtypes of DLBCL termed as germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL were assigned to the 69 DLBCL cases. Then, we performed supervised analysis using HELP data and defined DNA methylation signature differentiating 2 subgroups of DLBCLs. Keywords: DNA methylation profiling

2010-09-03 | GSE23967 | GEO

DNA methylation signatures define molecular subtypes of Diffuse Large B Cell Lymphoma

2010-09-03 | E-GEOD-23967 | biostudies-arrayexpress

MCL1 is deregulated in subgroups of diffuse large B-cell lymphoma

Project description:MCL1 is an anti-apoptotic member of the BCL2 family that is deregulated in various solid and hematological malignancies. However, its role in the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL) is unclear. We analyzed gene expression profiling data from 350 DLBCL patient samples and detected that activated B-cell-like (ABC) DLBCLs express MCL1 at significantly higher levels compared to germinal center B-cell-like (GCB) DLBCL patient samples (p=2.7 x 10(-10)) [PMID 23257783]. Immunohistochemistry confirmed high MCL1 protein expression predominantly in ABC DLBCL in an independent patient cohort (n=249; p=0.001). To elucidate molecular mechanisms leading to aberrant MCL1 expression, we analyzed array comparative genomic hybridization (aCGH) data of 203 DLBCL samples [GSE11318] and identified recurrent chromosomal gains/amplifications of the MCL1 locus that occurred in 26% of ABC DLBCLs. In addition, aberrant STAT3 signaling contributed to high MCL1 expression in this subtype. Knockdown of MCL1 as well as treatment with the BH3-mimetic obatoclax induced apoptotic cell death in MCL1 positive DLBCL cell lines. In summary, MCL1 is deregulated in a significant fraction of ABC DLBCLs and contributes to therapy resistance. These data suggest that specific inhibition of MCL1 might be utilized therapeutically in a subset of DLBCLs.

2013-01-04 | GSE43272 | GEO

MCL1 is deregulated in subgroups of diffuse large B-cell lymphoma

2013-01-04 | E-GEOD-43272 | biostudies-arrayexpress

Combinatorial treatment rescues tumour-microenvironment-mediated attenuation of MALT1 inhibitors in B-cell lymphomas

Project description:Activated B cell-like diffuse large B cell lymphomas (ABC-DLBCLs) arise from B cell follicles of secondary lymphoid organs and are among the most aggressive DLBCLs. ABC-DLBCLs are characterized by constitutive activation of NF-ĸB driven by activation of the B cell receptor (BCR) and toll-like receptor (TLR) pathways, often due to activating mutations. The goal of the current RNA Sequencing study was to understand the role of select bioadhesive extracellular matrix ligands and cell-based ligands in regulating the gene expression in ABC-DLBCL cells.

2023-01-12 | GSE209551 | GEO

Whole Exome Sequencing of Diffuse Large B-Cell Lymphoma

Project description:<p>Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogenous disease that is further classified into transcriptionally defined activated B-cell (ABC) and germinal center B-cell (GCB) subtypes. Here, we describe a comprehensive genetic analysis of DLBCLs that identifies low-frequency alterations, captures recurrent mutations, copy number alterations (CNAs) and structural variants (SVs) and characterizes coordinate genetic signatures in 304 primary DLBCLs with available outcome data. We integrated these genetic drivers using consensus clustering and identified 5 robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; 2 distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss and associated genomic instability. The genetic features of the newly identified subsets, their mutational signatures and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, these studies provide a roadmap for an actionable DLBCL classification. </p>

| phs000450 | dbGaP

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