Germinal Center B Cell-Like (GCB) and Activated B Cell-Like (ABC) Type of Diffuse Large B Cell Lymphoma (DLBCL): Analysis of Molecular Predictors, Signatures, Cell Cycle State and Patient Survival

Blenk, Steffen; Engelmann, Julia Cathérine; Weniger, Markus; Schultz, Jörg; Dittrich, Marcus; Rosenwald, A.; Müller‐Hermelink, Hans Konrad; Müller, Tobias; Dandekar, Thomas

doi:10.1177/117693510700300004

Cited by 53 publications

(43 citation statements)

References 29 publications

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“…The lymphoid-restricted membrane protein (LRMP), is an endoplasmic reticulum-associated protein. We found higher mRNA levels of LRMP in the GCB- compared to the non-GCB-subtype of DLBCL, which demonstrated that it predicted and supported the aggressive behavior of the non-GCB subtype of DLBCL [23, 25]. In this study, we discovered that NONHSAG026900 was clustered with these three protein-coding genes into one functional module for cell cycle regulation by gene co-expression network analysis.…”

Section: Discussionsupporting

confidence: 57%

The long non-coding RNA NONHSAG026900 predicts prognosis as a favorable biomarker in patients with diffuse large B-cell lymphoma

et al. 2017

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Long non-coding RNAs are known to be involved in cancer progression, but their biological functions and prognostic values are still largely unexplored in diffuse large B-cell lymphoma. In this study, long non-coding RNAs expression was characterized in 1,403 samples including normal and diffuse large B-cell lymphoma by repurposing 7 microarray datasets. Compared with any stage of normal B cells, NONHSAG026900 expression was significantly decreased in tumor samples. And in germinal center B-cell subtype, the significantly higher expression of NONHSAG026900 indicated it was a favorable prognosis biomarker. Then the prognostic power of NONHSAG026900 was validated with another independent dataset and NONHSAG026900 improved the predictive power of International Prognostic Index as an independent factor. Moreover, functional prediction and validation demonstrated that NONHSAG026900 could inhibit cell cycle activity to restrain tumor proliferation. These findings identified NONHSAG026900 as a novel prognostic biomarker and offered a new therapeutic target for diffuse large B-cell lymphoma patients.

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Section: Discussionsupporting

confidence: 57%

The long non-coding RNA NONHSAG026900 predicts prognosis as a favorable biomarker in patients with diffuse large B-cell lymphoma

et al. 2017

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“…SH3BP5 has been included in a signature gene set for ABC DLBCL [18,28], and it has been shown to inhibit the autophosphorylation and transphosphorylation activities of BTK in normal B cells [26,29]. A selective BTK inhibitor, ibrutinib, has been shown to be effective in treating several types of B-cell lymphomas, such as chronic lymphocytic leukemia, mantle cell lymphoma, and ABC DLBCL [30].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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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. Enriched GO categories in the CD5(+) ABC DLBCL signature gene set included multicellular organismal signaling, transmission of nerve impulse, and synaptic transmission. The 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.

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“…1). For COO segmentation, multiple predictors have been described in the literature (4,13,19). By combining unique predictors from these studies, a list of 51 distinct genes was obtained (Fig.…”

Section: Definition Of Nanostring and Rt-pcr Gene Lists For Dlbcl Segmentioning

confidence: 99%

Reproducible, Quantitative, and Flexible Molecular Subtyping of Clinical DLBCL Samples Using the NanoString nCounter System

Veldman-Jones

Lai

Wappett

et al. 2015

Clinical Cancer Research

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Purpose: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with distinct molecular subtypes. The most established subtyping approach, the "Cell of Origin" (COO) algorithm, categorizes DLBCL into activated B-cell (ABC) and germinal center B-cell (GCB)-like subgroups through gene expression profiling. Recently developed immunohistochemical (IHC) techniques and other established methodologies can deliver discordant results and have various technical limitations. We evaluated the NanoString nCounter gene expression system to address issues with current platforms.Experimental Design: We devised a scoring system using 145 genes from published datasets to categorize DLBCL samples. After cell line validation, clinical tissue segmentation was tested using commercially available diagnostic DLBCL samples. Finally, we profiled biopsies from patients with relapsed/refractory DLBCL enrolled in the fostamatinib phase IIb clinical trial using three independent RNA expression platforms: NanoString, Affymetrix, and qNPA.Results: Diagnostic samples showed a typical spread of subtypes with consistent gene expression profiles across matched fresh, frozen, and formalin-fixed paraffin-embedded tissues. Results from biopsy samples across platforms were remarkably consistent, in contrast to published IHC data. Interestingly, COO segmentation of longitudinal fostamatinib biopsies taken at initial diagnosis and then again at primary relapse showed 88% concordance (15/17), suggesting that COO designation remains stable over the course of disease progression.Conclusions: DLBCL segmentation of patient tumor samples is possible using a number of expression platforms. However, we found that NanoString offers the most flexibility and fewest limitations in regards to robust clinical tissue subtype characterization. These subtype distinctions should help guide disease prognosis and treatment options within DLBCL clinical practice.

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Germinal Center B Cell-Like (GCB) and Activated B Cell-Like (ABC) Type of Diffuse Large B Cell Lymphoma (DLBCL): Analysis of Molecular Predictors, Signatures, Cell Cycle State and Patient Survival

Cited by 53 publications

References 29 publications

The long non-coding RNA NONHSAG026900 predicts prognosis as a favorable biomarker in patients with diffuse large B-cell lymphoma

The long non-coding RNA NONHSAG026900 predicts prognosis as a favorable biomarker in patients with diffuse large B-cell lymphoma

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

Reproducible, Quantitative, and Flexible Molecular Subtyping of Clinical DLBCL Samples Using the NanoString nCounter System

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