scholarly journals Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study

Leukemia ◽  
2012 ◽  
Vol 26 (9) ◽  
pp. 2103-2113 ◽  
Author(s):  
C Visco ◽  
Y Li ◽  
Z Y Xu-Monette ◽  
R N Miranda ◽  
T M Green ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
Molecular Subtype ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Immunohistochemical Studies ◽  
Large B Cell

Cell-of-Origin in Diffuse Large B-Cell Lymphoma: Are the Assays Ready for the Clinic?

2015 ◽  
pp. e458-e466 ◽  
Author(s):  
David W. Scott
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Practical Implementation ◽  
Cell Of Origin ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma worldwide and consists of a heterogeneous group of cancers classified together on the basis of shared morphology, immunophenotype, and aggressive clinical behavior. It is now recognized that this malignancy comprises at least two distinct molecular subtypes identified by gene expression profiling: the activated B-cell-like (ABC) and the germinal center B-cell-like (GCB) groups—the cell-of-origin (COO) classification. These two groups have different genetic mutation landscapes, pathobiology, and outcomes following treatment. Evidence is accumulating that novel agents have selective activity in one or the other COO group, making COO a predictive biomarker. Thus, there is now a pressing need for accurate and robust methods to assign COO, to support clinical trials, and ultimately guide treatment decisions for patients. The “gold standard” methods for COO are based on gene expression profiling (GEP) of RNA from fresh frozen tissue using microarray technology, which is an impractical solution when formalin-fixed paraffin-embedded tissue (FFPET) biopsies are the standard diagnostic material. This review outlines the history of the COO classification before examining the practical implementation of COO assays applicable to FFPET biopsies. The immunohistochemistry (IHC)-based algorithms and gene expression–based assays suitable for the highly degraded RNA from FFPET are discussed. Finally, the technical and practical challenges that still need to be addressed are outlined before robust gene expression–based assays are used in the routine management of patients with DLBCL.

scholarly journals Constitutive Nuclear Factor κB Activity Is Required for Survival of Activated B Cell–like Diffuse Large B Cell Lymphoma Cells

2001 ◽  
Vol 194 (12) ◽  
pp. 1861-1874 ◽  
Author(s):  
R. Eric Davis ◽  
Keith D. Brown ◽  
Ulrich Siebenlist ◽  
Louis M. Staudt
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Nuclear Factor ◽  
Large B Cell Lymphoma ◽  
Dlbcl Subtype ◽  
Large B Cell

Gene expression profiling has revealed that diffuse large B cell lymphoma (DLBCL) consists of at least two distinct diseases. Patients with one DLBCL subtype, termed activated B cell–like (ABC) DLBCL, have a distinctly inferior prognosis. An untapped potential of gene expression profiling is its ability to identify pathogenic signaling pathways in cancer that are amenable to therapeutic attack. The gene expression profiles of ABC DLBCLs were notable for the high expression of target genes of the nuclear factor (NF)-κB transcription factors, raising the possibility that constitutive activity of the NF-κB pathway may contribute to the poor prognosis of these patients. Two cell line models of ABC DLBCL had high nuclear NF-κB DNA binding activity, constitutive IκB kinase (IKK) activity, and rapid IκBα degradation that was not seen in cell lines representing the other DLBCL subtype, germinal center B-like (GCB) DLBCL. Retroviral transduction of a super-repressor form of IκBα or dominant negative forms of IKKβ was toxic to ABC DLBCL cells but not GCB DLBCL cells. DNA content analysis showed that NF-κB inhibition caused both cell death and G1-phase growth arrest. These findings establish the NF-κB pathway as a new molecular target for drug development in the most clinically intractable subtype of DLBCL and demonstrate that the two DLBCL subtypes defined by gene expression profiling utilize distinct pathogenetic mechanisms.

Gene Expression Profiling of Diffuse Large B-Cell Lymphomas Supervised by CD5 Expression

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4164-4164
Author(s):  
Kana Miyazaki ◽  
Motoko Yamaguchi ◽  
Hiroshi Imai ◽  
Satoshi Tamaru ◽  
Tohru Kobayashi ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Gene Set ◽  
Large B Cell Lymphoma ◽  
The Difference ◽  
Large B Cell

Abstract Abstract 4164 Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and is composed of heterogeneous groups of lymphoma with pathophysiological, genetic and clinical features. Gene expression profiling identified two distinct forms of DLBCL: activated B cell-like (ABC) and germinal center B-cell-like (GCB) types. ABC DLBCL shows more activated phenotype characterized with high activity of the NF-kappa B pathway and worse prognosis than GCB DLBCL. CD5-positive (CD5+) DLBCL comprises 5 to 10% of DLBCL and is one of the immunohistochemical subgroups in the 2008 WHO classification. It shows many distinct clinical characteristics with elderly onset, advanced stage at diagnosis, high serum lactate dehydrogenase level and frequent involvement of extranodal sites. Despite the use of rituximab, CD5+ DLBCL shows a poor prognosis and high incidence of central nervous system (CNS) relapse. More than 80% of patients with CD5+ DLBCL are classified as non-GCB subgroup by Hans' method; however, few molecular studies have been reported. To clarify the difference between CD5+ DLBCL and CD5-negative (CD5-) DLBCL in the gene expression profile, total RNA from 90 patients with de novo DLBCL including 33 CD5+ DLBCLs and 57 CD5- DLBCLs was examined using Agilent 44K human oligo-microarrays (Agilent 4112F). The expression of CD5 in tumor cells was confirmed by means of immunohistochemistry using frozen sections. Cases of primary mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma and primary DLBCL of the CNS were excluded from the present study. Supervised hierarchical clustering of the expression data could separate the DLBCL cases into the two groups, CD5+ DLBCL and CD5- DLBCL. A signature gene set supervised by CD5 expression included some of the same genes (SH3BP5, CCND2, LMO2) in the predictor gene set to discriminate between GCB and ABC DLBCLs. To classify the difference between CD5+ ABC DLBCL and CD5- ABC DLBCL in the gene expression profile, the 90 DLBCLs were analyzed by the Rosenwald's gene set (NEJM, 2002). Those cases were separated with 78 ABC DLBCLs and 12 GCB DLBCLs. Incidence of CD5+ cases was 42% (33/78) in ABC DLBCLs and 0% in GCB DLBCLs. A classifier based on gene expression at supervised analysis also correctly identified CD5 expression in ABC DLBCL. Signature genes to distinguish between CD5+ ABC DLBCL and CD5- ABC DLBCL were as follows: SNAP25, SYCP3, CCNA1, MAPK4, CCNA1, LMO3, NLGN3, GRIN2A, AQP4, FGFR2, NEUROD1, KL, FGF1, SYT5, etc., were overexpressed in CD5+ ABC DLBCL, and CYP4Z1, MDM2, IL7R, GRLF1, TNFRSF9, CD1A etc., were overexpressed in CD5- ABC DLBCL. Enriched Gene Ontology (GO) categories in CD5+ ABC DLBCL were synapse, multicellular organismal process, fibroblast growth factor receptor signaling pathway, cell projection, alcohol dehydrogenase activity and glucuronosyltransferase activity. Among them, synapse was the top GO category (P=6.1E-05). In conclusion, our current study confirmed that most of CD5+ DLBCLs are classified as ABC DLBCL by gene expression profiling. Our results suggest that neurological component- and function-related genes in the CD5+ ABC DLBCL signature gene set may be related to the high frequency of CNS relapse in CD5+ DLBCL. Disclosures: No relevant conflicts of interest to declare.

Diffuse Large B-Cell Lymphoma

2008 ◽  
Vol 132 (1) ◽  
pp. 118-124 ◽  
Author(s):  
Kristin E. Hunt ◽  
Kaaren K. Reichard
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Germinal Center ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Chemotherapeutic Regimen ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Diffuse large B-cell lymphoma is the most common lymphoma worldwide. Both morphologically and prognostically it represents a diverse spectrum of disease. Traditional morphologic subclassification often results in poor interobserver reproducibility and has not been particularly helpful in predicting outcome. Recent gene expression profiling studies have classified diffuse large B-cell lymphoma into 2 main subtypes, germinal center B-cell and activated B-cell, with the germinal center type showing an overall better survival. Validation of these subtypes has become possible for the practicing pathologist with the use of surrogate immunohistochemical markers. Importantly however, these prognostic studies were performed on material from the pre-rituximab treatment era. With the now well-accepted addition of rituximab (anti-CD20 antibody) to the typical large B-cell lymphoma chemotherapeutic regimen, a revalidation of any survival differences between the large B-cell lymphoma subgroups is necessary. This short review covers the current clinical, morphologic, immunophenotypic, genetic, gene expression profiling, and prognostic (studies before and after the addition of rituximab) features of de novo diffuse large B-cell lymphoma.

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