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A Biologic Definition of Burkitt's Lymphoma from Transcriptional and Genomic Profiling

ABSTRACT: The distinction between the Burkitt lymphoma and diffuse large B-cell lymphoma is imprecise using current diagnostic criteria. We applied transcriptional and genomic profiling to molecularly define Burkitt lymphoma. Gene expression profiling employing Affymetrix GeneChips (U133A) was performed in 220 mature aggressive B-cell lymphomas, including a core group of eight Burkitt lymphomas, which fulfilled all diagnostic criteria of the WHO classification. A molecular signature of Burkitt lymphoma was generated. Chromosomal abnormalities were detected by interphase fluorescence in-situ hybridization and array comparative genomic hybridization. The molecular Burkitt lymphoma signature identified 44 cases. Fifteen of these cases lacked a morphology typical for Burkitt/Burkitt-like lymphoma. The vast majority (88%) of the 176 lymphomas without the molecular Burkitt lymphoma signature represented diffuse large B-cell lymphomas. In 20% of these cases a MYC break was detectable which was associated with complex chromosomal changes. Our molecular definition of Burkitt lymphoma sharpens and extends the spectrum of Burkitt lymphoma. In mature aggressive B-cell lymphomas without a Burkitt lymphoma signature, a chromosomal break in the MYC locus proved to be associated with adverse clinical outcome. Keywords: Gene expression

ORGANISM(S): Homo sapiens

PROVIDER: GSE4475 | GEO | 2006/06/07

SECONDARY ACCESSION(S): PRJNA94549

REPOSITORIES: GEO

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Project description:MYC translocations are the biologic hallmark of Burkitt lymphomas but also occur in other mature B-cell lymphomas. If accompanied by chromosomal breaks targeting the BCL2 and/or BCL6 oncogenes, these MYC translocation-positive (MYC+) lymphomas are called double-hit lymphomas (DHLs); otherwise, the term single-hit lymphoma (SHL) is applied. In order to characterize the biologic features of these MYC+ lymphomas other than Burkitt lymphomas, we explored, after exclusion of molecular Burkitt lymphoma (mBL) as defined by gene expression profiling (GEP), the molecular, pathological and clinical aspects of 80 MYC translocation (MYC+) lymphomas (31 SHL, 26 BCL2+/MYC+, 14 BCL6+/MYC+, 6 BCL2+/BCL6+/MYC+ and 3 MYC+ lymphomas with unknown BCL6 status). Comparison of SHL and DHL revealed no difference in frequency of MYC partner (IG/non-IG), genomic complexity or MYC expression and no differences in GEP. DHL showed a more frequent GCB-like GEP and higher IGH and MYC mutation rates. GEP revealed 130 differentially expressed genes between BCL6+/MYC+ and BCL2+/MYC+ DHL. BCL2+/MYC+ DHL showed a more frequent GCB-like GEP. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In contrast to mBL and lymphomas without MYC break, SHL and DHL patients had similar poor outcome. Our data suggest that after excluding mBL, MYC+ lymphomas could be biologically widely lumped without further need for subclassification. 32 diffuse large B-cell lymphoma samples were hybridized to HG-U133A Affymetrix GeneChips. In addition, this study contains 30 already published samples, which contribute to GSE4475 (Hummel et al. 2006 (PMID 16760442)), as well as 18 already published samples from GSE22470 (Salaverria et al. 2011 (PMID 21487109)). No re-normalisation of the published samples was performed. The complete dataset representing: (1) the 32 diffuse large B-cell lymphoma Samples, (2) the 30 Samples from GSE4475 and (3) the 18 Samples from GSE22470, is linked below as a supplementary file

Project description:Sporadic Burkitt lymphoma (sBL) can be delineated from diffuse large B-cell lymphoma (DLBCL) by a very homogeneous mRNA expression signature. However, it remained unclear whether all three BL variants – sBL, endemic BL (eBL) and immunodeficiency-associated BL (HIV-BL) – represent a uniform biological entity despite their differences in geographical occurrence, association with immunodeficiency and/or incidence of EBV infection. To address this issue, we generated micro RNA (miRNA) profiles from 18 eBL, 31 sBL and 15 HIV-BL cases. In addition, we analyzed the miRNA expression of 86 DLBCL to determine whether miRNA profiles recapitulate the molecular differences between BL and DLBCL evidenced by mRNA profiling. A signature of 38 miRNAs enriched in MYC regulated and NF-kB pathway associated miRNAs was obtained that differentiated BL from DLBCL. The miRNA profiles of sBL and eBL displayed only 6 differentially expressed miRNAs, whereas HIV and EBV infection had no impact on the miRNA profile of BL. In conclusion, miRNA profiling confirms that BL and DLBCL represent distinct lymphoma categories and demonstrates that the three BL variants are representatives of the same biological entity with only marginal miRNA expression differences between eBL and sBL. Archival tumor specimens of 86 diffuse large B-cell lymphoma (DLBCL) and 64 Burkitt lymphoma (BL) patients were obtained. The DLBCL samples have previously been reviewed by a panel of expert hematopathologists and their clinical data were published as part of the RiCOVER-60 trial. The diagnosis of all BL cases was confirmed by histopathology review according to the criteria of the WHO classification. Based on their geographical origin, 31 BL samples were designated as sporadic BL (sBL) and 18 samples as endemic BL (eBL). Fifteen BL cases were diagnosed as immunodeficiency-associated BL (HIV-BL). Of the 18 eBL 14 cases were EBV+ (87.5%), 2 samples were EBV- (12.5%) and for 2 eBL cases the EBV status was unknown. Of the sBL samples 26 were EBV- (86.7%), 4 cases were EBV+ (13.3%) and for 1 case the EBV status was not evaluable. Among the HIV-BL 5 (33.3%) were EBV+, whereas 10 (66.7%) were EBV-.

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A Biologic Definition of Burkitt's Lymphoma from Transcriptional and Genomic Profiling

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