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A modular transcriptome map of mature B cell lymphomas

BACKGROUND: Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecu...

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Autores principales: Loeffler-Wirth, Henry, Kreuz, Markus, Hopp, Lydia, Arakelyan, Arsen, Haake, Andrea, Cogliatti, Sergio B., Feller, Alfred C., Hansmann, Martin-Leo, Lenze, Dido, Möller, Peter, Müller-Hermelink, Hans Konrad, Fortenbacher, Erik, Willscher, Edith, Ott, German, Rosenwald, Andreas, Pott, Christiane, Schwaenen, Carsten, Trautmann, Heiko, Wessendorf, Swen, Stein, Harald, Szczepanowski, Monika, Trümper, Lorenz, Hummel, Michael, Klapper, Wolfram, Siebert, Reiner, Loeffler, Markus, Binder, Hans
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492344/
https://www.ncbi.nlm.nih.gov/pubmed/31039827
http://dx.doi.org/10.1186/s13073-019-0637-7
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author Loeffler-Wirth, Henry
Kreuz, Markus
Hopp, Lydia
Arakelyan, Arsen
Haake, Andrea
Cogliatti, Sergio B.
Feller, Alfred C.
Hansmann, Martin-Leo
Lenze, Dido
Möller, Peter
Müller-Hermelink, Hans Konrad
Fortenbacher, Erik
Willscher, Edith
Ott, German
Rosenwald, Andreas
Pott, Christiane
Schwaenen, Carsten
Trautmann, Heiko
Wessendorf, Swen
Stein, Harald
Szczepanowski, Monika
Trümper, Lorenz
Hummel, Michael
Klapper, Wolfram
Siebert, Reiner
Loeffler, Markus
Binder, Hans
author_facet Loeffler-Wirth, Henry
Kreuz, Markus
Hopp, Lydia
Arakelyan, Arsen
Haake, Andrea
Cogliatti, Sergio B.
Feller, Alfred C.
Hansmann, Martin-Leo
Lenze, Dido
Möller, Peter
Müller-Hermelink, Hans Konrad
Fortenbacher, Erik
Willscher, Edith
Ott, German
Rosenwald, Andreas
Pott, Christiane
Schwaenen, Carsten
Trautmann, Heiko
Wessendorf, Swen
Stein, Harald
Szczepanowski, Monika
Trümper, Lorenz
Hummel, Michael
Klapper, Wolfram
Siebert, Reiner
Loeffler, Markus
Binder, Hans
author_sort Loeffler-Wirth, Henry
collection PubMed
description BACKGROUND: Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt’s lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. METHODS: We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. RESULTS: We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt’s lymphoma and particularly on ‘double-hit’ MYC and BCL2 transformed lymphomas. CONCLUSIONS: The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13073-019-0637-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-64923442019-05-06 A modular transcriptome map of mature B cell lymphomas Loeffler-Wirth, Henry Kreuz, Markus Hopp, Lydia Arakelyan, Arsen Haake, Andrea Cogliatti, Sergio B. Feller, Alfred C. Hansmann, Martin-Leo Lenze, Dido Möller, Peter Müller-Hermelink, Hans Konrad Fortenbacher, Erik Willscher, Edith Ott, German Rosenwald, Andreas Pott, Christiane Schwaenen, Carsten Trautmann, Heiko Wessendorf, Swen Stein, Harald Szczepanowski, Monika Trümper, Lorenz Hummel, Michael Klapper, Wolfram Siebert, Reiner Loeffler, Markus Binder, Hans Genome Med Research BACKGROUND: Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt’s lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. METHODS: We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. RESULTS: We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt’s lymphoma and particularly on ‘double-hit’ MYC and BCL2 transformed lymphomas. CONCLUSIONS: The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13073-019-0637-7) contains supplementary material, which is available to authorized users. BioMed Central 2019-04-30 /pmc/articles/PMC6492344/ /pubmed/31039827 http://dx.doi.org/10.1186/s13073-019-0637-7 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Loeffler-Wirth, Henry
Kreuz, Markus
Hopp, Lydia
Arakelyan, Arsen
Haake, Andrea
Cogliatti, Sergio B.
Feller, Alfred C.
Hansmann, Martin-Leo
Lenze, Dido
Möller, Peter
Müller-Hermelink, Hans Konrad
Fortenbacher, Erik
Willscher, Edith
Ott, German
Rosenwald, Andreas
Pott, Christiane
Schwaenen, Carsten
Trautmann, Heiko
Wessendorf, Swen
Stein, Harald
Szczepanowski, Monika
Trümper, Lorenz
Hummel, Michael
Klapper, Wolfram
Siebert, Reiner
Loeffler, Markus
Binder, Hans
A modular transcriptome map of mature B cell lymphomas
title A modular transcriptome map of mature B cell lymphomas
title_full A modular transcriptome map of mature B cell lymphomas
title_fullStr A modular transcriptome map of mature B cell lymphomas
title_full_unstemmed A modular transcriptome map of mature B cell lymphomas
title_short A modular transcriptome map of mature B cell lymphomas
title_sort modular transcriptome map of mature b cell lymphomas
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492344/
https://www.ncbi.nlm.nih.gov/pubmed/31039827
http://dx.doi.org/10.1186/s13073-019-0637-7
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