Dataset Information

Molecular classification of MYC-driven B-cell lymphomas by targeted gene expression profiling of fixed biopsy specimens.

ABSTRACT: Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are aggressive tumors of mature B cells that are distinguished by a combination of histomorphological, phenotypic, and genetic features. A subset of B-cell lymphomas, however, has one or more characteristics that overlap BL and DLBCL, and are categorized as B-cell lymphoma unclassifiable, with features intermediate between BL and DLBCL (BCL-U). Molecular analyses support the concept that there is a biological continuum between BL and DLBCL that includes variable activity of MYC, an oncoprotein once thought to be only associated with BL, but now recognized as a major predictor of survival among patients with DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). We tested whether a targeted expression profiling panel could be used to categorize tumors as BL and DLBCL, resolve the molecular heterogeneity of BCL-U, and capture MYC activity using RNA from formalin-fixed, paraffin-embedded biopsy specimens. A diagnostic molecular classifier accurately predicted pathological diagnoses of BL and DLBCL, and provided more objective subclassification for a subset of BCL-U and genetic double-hit lymphomas as molecular BL or DLBCL. A molecular classifier of MYC activity correlated with MYC IHC and stratified patients with primary DLBCL treated with R-CHOP into high- and low-risk groups. These results establish a framework for classifying and stratifying MYC-driven, aggressive, B-cell lymphomas on the basis of quantitative molecular profiling that is applicable to fixed biopsy specimens.

SUBMITTER: Carey CD

PROVIDER: S-EPMC4279427 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Molecular classification of MYC-driven B-cell lymphomas by targeted gene expression profiling of fixed biopsy specimens.

Carey Christopher D CD Gusenleitner Daniel D Chapuy Bjoern B Kovach Alexandra E AE Kluk Michael J MJ Sun Heather H HH Crossland Rachel E RE Bacon Chris M CM Rand Vikki V Dal Cin Paola P Le Long P LP Neuberg Donna D Sohani Aliyah R AR Shipp Margaret A MA Monti Stefano S Rodig Scott J SJ

The Journal of molecular diagnostics : JMD 20141107 1

Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are aggressive tumors of mature B cells that are distinguished by a combination of histomorphological, phenotypic, and genetic features. A subset of B-cell lymphomas, however, has one or more characteristics that overlap BL and DLBCL, and are categorized as B-cell lymphoma unclassifiable, with features intermediate between BL and DLBCL (BCL-U). Molecular analyses support the concept that there is a biological continuum between BL an ...[more]

PMID: 25468432

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Project description:The most frequent mature aggressive B-cell lymphomas are diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Patients suffering from molecularly defined BL (mBL) but treated with a regimen developed for DLBCL show an unfavorable outcome compared to mBL treated with chemotherapy regimens for BL. Distinguishing BL from DLBCL by conventional histopathology is challenging in lymphomas that have features common to both diseases (aggressive B-cell lymphoma unclassifiable with features of DLBCL and BL [intermediates]). Moreover, DLBCL are a heterogeneous group of lymphomas comprising distinct molecular subtypes: the activated B-cell (ABC)-like, the germinal center B-cell-like (GCB) and the unclassifyable subtype as defined by gene expression profiling (GEP). Attempts to replace GEP with techniques applicable to formalin-fixed paraffin-embedded (FFPE) tissue led to algorithms for immunohistochemical stainings (IHS). Disappointingly, the algorithms yielded conflicting results with respect to their prognostic potential, raising concerns about their validity. Furthermore, IHS algorithms did not provide a fully resolved classification: They did not identify mBL; nor did they separate ABC from unclassified DLBCL. We used digital multiplexed gene expression (DMGE) with FFPE derived RNA to classify agressive B-cell lymphomas. Our assay comprised only 30 genes (10 for the detection of mBL and 20 for the detection of ABC and GCB). We chose these genes by reanalysis of the microarray data reported in a previous study. 39 samples from mature aggressive B-cell lymphomas were analyzed using DMGE (nCounter, NanoString Technologies Inc., Seattle, WA, USA) of FFPE- and fresh-frozen derived RNA. All cases were previously characterized by the Molecular Mechanisms of Malignant Lymphoma (MMML) consortium using the Affymetrix GeneChip technology (gold standard of classification). 29 diffuse large B-Cell lymphoma samples were hybridized to HGU133A Affymetrix GeneChips. In addition, this study contains 22 already published samples whereas 11 of them contribute to GSE22470, 6 contribute to GSE10172, 3 to GSE44164 and 2 to GSE4475. No re-normalisation of published samples was performed. The dataset representing: (1) 11 samples from GSE22470, (2) 6 samples from GSE10172, (3) 3 samples from GSE44164 and (4) 2 samples from GSE4475 is linked below as a supplementary file.

Project description:The most frequent mature aggressive B-cell lymphomas are diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Patients suffering from molecularly defined BL (mBL) but treated with a regimen developed for DLBCL show an unfavorable outcome compared to mBL treated with chemotherapy regimens for BL. Distinguishing BL from DLBCL by conventional histopathology is challenging in lymphomas that have features common to both diseases (aggressive B-cell lymphoma unclassifiable with features of DLBCL and BL [intermediates]). Moreover, DLBCL are a heterogeneous group of lymphomas comprising distinct molecular subtypes: the activated B-cell (ABC)-like, the germinal center B-cell-like (GCB) and the unclassifyable subtype as defined by gene expression profiling (GEP). Attempts to replace GEP with techniques applicable to formalin-fixed paraffin-embedded (FFPE) tissue led to algorithms for immunohistochemical stainings (IHS). Disappointingly, the algorithms yielded conflicting results with respect to their prognostic potential, raising concerns about their validity. Furthermore, IHS algorithms did not provide a fully resolved classification: They did not identify mBL; nor did they separate ABC from unclassified DLBCL. 29 diffuse large B-Cell lymphoma samples were hybridized to HGU133A Affymetrix GeneChips. In addition, this study contains 22 already published samples whereas 11 of them contribute to GSE22470, 6 contribute to GSE10172, 3 to GSE44164 and 2 to GSE4475. No re-normalisation of published samples was performed. We used digital multiplexed gene expression (DMGE) with FFPE derived RNA to classify agressive B-cell lymphomas. Our assay comprised only 30 genes (10 for the detection of mBL and 20 for the detection of ABC and GCB). We chose these genes by reanalysis of the microarray data reported in a previous study. 39 samples from mature aggressive B-cell lymphomas were analyzed using DMGE (nCounter, NanoString Technologies Inc., Seattle, WA, USA) of FFPE- and fresh-frozen derived RNA. All cases were previously characterized by the Molecular Mechanisms of Malignant Lymphoma (MMML) consortium using the Affymetrix GeneChip technology (gold standard of classification). Please note that there are total 40 FFPE-derived and 50 fresh-frozen derived samples, with 39 samples derived from both materials (allowing direct comparison).

Dataset Information

Molecular classification of MYC-driven B-cell lymphomas by targeted gene expression profiling of fixed biopsy specimens.

Publications

Molecular classification of MYC-driven B-cell lymphomas by targeted gene expression profiling of fixed biopsy specimens.

Similar Datasets

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