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Diffuse large B-cell lymphoma

ABSTRACT: Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumors. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumors of DLBCL patients, apparently reflecting the variation in tumor proliferation rate, host response and differentiation state of the tumor. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal center B cells ('germinal center B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal center B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumors on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer. This study is described more fully in Alizadeh AA et al.(2000) Nature 403:503-11 Keywords: other

ORGANISM(S): Homo sapiens

PROVIDER: GSE60 | GEO | 2002/06/27

SECONDARY ACCESSION(S): PRJNA85395

REPOSITORIES: GEO

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Project description:A better understanding of the pathogenesis of diffuse large B-cell lymphoma (DLBCL) has clarified its relationship to normal B-cells, pointed to distinct mechanisms of cell transformation, and facilitated the design of novel treatments. However, these data derive from mRNA genes studies, whereas genome-wide integrative investigations of the role of microRNAs (miRNAs) in DLBCL are still unavailable. We used array-CGH and microarray-based expression analyses to map the abnormalities targeting miRNAs in DLBCLs (n=86). Using training and validation DLBCL cohorts, we defined a collection of miRNAs that robustly segregates these tumors in three unique subsets. This miRNA-driven substructure appears to influence disease outcome, is independent of other mRNA-based DLBCL classifications, and stems from copy number changes targeting the miRNA genome, MYC activity, and the miRNA fingerprints of mature normal B-cells. Our data have uncovered clinically relevant additional molecular complexity in DLBCL and have established a blueprint for the detailed characterizations of miRNAs that are pertinent to B-cell lymphoma biology. Fifty-nine primary DLBCL samples obtained from our Cancer Center tumor bank and 27 cell lines (26 DLBCL and 1 mediastinal B-cell lymphoma) were included in this study for copy number analysis. The clinical and pathological features of this collection are described in the paper. All tumors were reviewed for diagnostic accuracy by a hematopathologist (R.R.) and the categorization in germinal center B-cell-like (GCB) or non-germinal center B-cell-like (non-GCB) was performed according to the algorithm described by Hans et al. The extent of normal cells infiltration in the DLBCL was determined by semi-quantitative measurement of CD3 (T-cells) and CD68 (macrophages) staining. Four normal control hybridizations are also included. Even though we started off with 90 samples total, we inspected the sample quality visually according the log2 ratio curves and excluded 13 samples with noisy or very low signals throughout the genome. The 77 remaining samples were used in the following analyses.

Project description:Diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adulthood, comprises multiple biologically and clinically distinct subtypes including germinal center B cell-like (GCB) and activated B cell like (ABC) DLBCL. Gene expression profile studies have shown that its most aggressive subtype, ABC-DLBCL, is associated with constitutive activation of the NF-kB transcription complex. However, except for a small fraction of cases, it remains unclear whether NF-kB activation in these tumors represents an intrinsic program of the tumor cell of origin or a pathogenetic event. Here we show that >50% of ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations at multiple genes, including negative (TNFAIP3/A20) and positive (CARD11, TRAF2, TRAF5, MAP3K7/TAK1 and TNFRSF11A/RANK) regulators of NF-kB. Of these, the A20 gene, which encodes for a ubiquitin-modifying enzyme involved in termination of NF-kB responses, is the most commonly affected one, with ~30% of the patients displaying biallelic inactivation by mutations and/or deletions, suggesting a tumor suppressor role. Less frequently, missense mutations of TRAF2 and CARD11 produce molecules with significantly enhanced ability to activate NF-kB. Thus, our results demonstrate that NF-kB activation in DLBCL is caused by genetic lesions affecting multiple genes, whose loss or activation may promote lymphomagenesis by leading to abnormally prolonged NF-kB responses. We show that most ABC-DLBCL and a smaller fraction of GCB-DLBCL display genetic lesions affecting multiple NFkB pathway genes, with A20 representing the most frequently mutated gene Experiment Overall Design: DLBCL biopsies from 73 patients were collected from the archives of the Departments of Pathology at Columbia University and Weill Cornell Medical College. Total RNA was extracted from frozen tumor biopsies and processed according to Affymetrix standard protocols. Purified tonsillar geminal center cells (centroblasts and centrocytes, 5 samples each from different individuals) were purified by magnetic cell separation as described in Klein et al, PNAS 2003.

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Diffuse large B-cell lymphoma

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