PMID- 31039827
OWN - NLM
STAT- MEDLINE
DCOM- 20191227
LR  - 20231011
IS  - 1756-994X (Electronic)
IS  - 1756-994X (Linking)
VI  - 11
IP  - 1
DP  - 2019 Apr 30
TI  - A modular transcriptome map of mature B cell lymphomas.
PG  - 27
LID - 10.1186/s13073-019-0637-7 [doi]
LID - 27
AB  - 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.
FAU - Loeffler-Wirth, Henry
AU  - Loeffler-Wirth H
AUID- ORCID: 0000-0001-8239-440X
AD  - Interdisciplinary Centre for Bioinformatics, Universitat Leipzig, Hartelstr. 
      16-18, 04107, Leipzig, Germany. wirth@izbi.uni-leipzig.de.
FAU - Kreuz, Markus
AU  - Kreuz M
AD  - Institute for Medical Informatics, Statistics and Epidemiology, Universitat 
      Leipzig, Hartelstr. 16-18, 04107, Leipzig, Germany.
FAU - Hopp, Lydia
AU  - Hopp L
AD  - Interdisciplinary Centre for Bioinformatics, Universitat Leipzig, Hartelstr. 
      16-18, 04107, Leipzig, Germany.
FAU - Arakelyan, Arsen
AU  - Arakelyan A
AD  - Group of Bioinformatics, Institute of Molecular Biology, National Academy of 
      Sciences, 7 Hasratyan str, 0014, Yerevan, Armenia.
FAU - Haake, Andrea
AU  - Haake A
AD  - Institute of Human Genetics, University Hospital Schleswig-Holstein, 
      Arnold-Heller Str. 3, 24105, Kiel, Germany.
FAU - Cogliatti, Sergio B
AU  - Cogliatti SB
AD  - Institute of Pathology, Kantonal Hospital St. Gallen, Rorschacher Str. 95, 9007, 
      St. Gallen, Switzerland.
FAU - Feller, Alfred C
AU  - Feller AC
AD  - Hematopathology Lubeck, Maria-Goeppert-Str. 9a, 23562, Lubeck, Germany.
FAU - Hansmann, Martin-Leo
AU  - Hansmann ML
AD  - Institute of Pathology, University Hospital Frankfurt, Theodor-Stern-Kai 7, 
      60590, Frankfurt, Germany.
FAU - Lenze, Dido
AU  - Lenze D
AD  - AstraZeneca, Tinsdaler Weg 183, 22880, Wedel, Germany.
FAU - Moller, Peter
AU  - Moller P
AD  - Institute of Pathology, University Hospital of Ulm, Albert-Einstein-Allee 23, 
      89081, Ulm, Germany.
FAU - Muller-Hermelink, Hans Konrad
AU  - Muller-Hermelink HK
AD  - Institute of Pathology, University Hospital Wurzburg, Josef-Schneider-Str. 2, 
      97080, Wurzburg, Germany.
FAU - Fortenbacher, Erik
AU  - Fortenbacher E
AD  - Interdisciplinary Centre for Bioinformatics, Universitat Leipzig, Hartelstr. 
      16-18, 04107, Leipzig, Germany.
FAU - Willscher, Edith
AU  - Willscher E
AD  - Interdisciplinary Centre for Bioinformatics, Universitat Leipzig, Hartelstr. 
      16-18, 04107, Leipzig, Germany.
FAU - Ott, German
AU  - Ott G
AD  - Department of Pathology, Robert-Bosch-Hospital, Auerbachstr. 110, 70376, 
      Stuttgart, Germany.
FAU - Rosenwald, Andreas
AU  - Rosenwald A
AD  - Institute of Pathology, University Hospital Wurzburg, Josef-Schneider-Str. 2, 
      97080, Wurzburg, Germany.
FAU - Pott, Christiane
AU  - Pott C
AD  - Second Medical Department, University Hospital Schleswig-Holstein, Arnold-Heller 
      Str. 3, 24105, Kiel, Germany.
FAU - Schwaenen, Carsten
AU  - Schwaenen C
AD  - Ortenau Hospital Offenburg-Gengenbach, Ebertpl. 12, 77654, Offenburg, Germany.
AD  - Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 
      89081, Ulm, Germany.
FAU - Trautmann, Heiko
AU  - Trautmann H
AD  - Second Medical Department, University Hospital Schleswig-Holstein, Arnold-Heller 
      Str. 3, 24105, Kiel, Germany.
FAU - Wessendorf, Swen
AU  - Wessendorf S
AD  - Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, 
      89081, Ulm, Germany.
AD  - Hospital Esslingen, Hirschlandstr. 97, 73730, Esslingen a. N, Germany.
FAU - Stein, Harald
AU  - Stein H
AD  - Pathodiagnostik, Komturstr. 58-62, 12099, Berlin, Germany.
FAU - Szczepanowski, Monika
AU  - Szczepanowski M
AD  - Second Medical Department, University Hospital Schleswig-Holstein, Arnold-Heller 
      Str. 3, 24105, Kiel, Germany.
FAU - Trumper, Lorenz
AU  - Trumper L
AD  - Department of Hematology and Oncology, Georg-August University, Robert-Koch-Str. 
      42, 37077, Gottingen, Germany.
FAU - Hummel, Michael
AU  - Hummel M
AD  - Institute of Pathology, Charite Universitatsmedizin, Chariteplatz 1, 10117, 
      Berlin, Germany.
FAU - Klapper, Wolfram
AU  - Klapper W
AD  - Hematopathology Section, University Hospital Schleswig-Holstein, Arnold-Heller 
      Str. 3, 24105, Kiel, Germany.
FAU - Siebert, Reiner
AU  - Siebert R
AD  - Institute of Human Genetics, University Hospital Schleswig-Holstein, 
      Arnold-Heller Str. 3, 24105, Kiel, Germany.
AD  - Institute of Human Genetics, University Hospital of Ulm, Albert-Einstein-Allee 
      23, 89081, Ulm, Germany.
FAU - Loeffler, Markus
AU  - Loeffler M
AD  - Interdisciplinary Centre for Bioinformatics, Universitat Leipzig, Hartelstr. 
      16-18, 04107, Leipzig, Germany.
AD  - Institute for Medical Informatics, Statistics and Epidemiology, Universitat 
      Leipzig, Hartelstr. 16-18, 04107, Leipzig, Germany.
FAU - Binder, Hans
AU  - Binder H
AD  - Interdisciplinary Centre for Bioinformatics, Universitat Leipzig, Hartelstr. 
      16-18, 04107, Leipzig, Germany. binder@izbi.uni-leipzig.de.
CN  - German Cancer Aid consortium Molecular Mechanisms for Malignant Lymphoma
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190430
PL  - England
TA  - Genome Med
JT  - Genome medicine
JID - 101475844
SB  - IM
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Lymphoma, B-Cell/*genetics/metabolism/pathology
MH  - Machine Learning
MH  - *Transcriptome
PMC - PMC6492344
OTO - NOTNLM
OT  - B cell malignancies
OT  - Gene regulation
OT  - Machine learning
OT  - Molecular subtypes
OT  - Tumor heterogeneity
COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The study was performed as part of 
      the 'Molecular Mechanisms in Malignant Lymphomas' Network Project of the Deutsche 
      Krebshilfe for which central (University Hospital, Gottingen), and local ethics 
      approval was obtained. Informed consent was obtained in accordance with the 
      Declaration of Helsinki. CONSENT FOR PUBLICATION: Not applicable. COMPETING 
      INTERESTS: The authors declare that they have no competing interests. Dido Lenze 
      (now affiliated with AstraZeneca) contributed to the MMML consortium during her 
      employment at Charite Universitatsmedizin, Berlin. PUBLISHER'S NOTE: Springer 
      Nature remains neutral with regard to jurisdictional claims in published maps and 
      institutional affiliations.
EDAT- 2019/05/02 06:00
MHDA- 2019/12/28 06:00
PMCR- 2019/04/30
CRDT- 2019/05/02 06:00
PHST- 2018/11/09 00:00 [received]
PHST- 2019/04/04 00:00 [accepted]
PHST- 2019/05/02 06:00 [entrez]
PHST- 2019/05/02 06:00 [pubmed]
PHST- 2019/12/28 06:00 [medline]
PHST- 2019/04/30 00:00 [pmc-release]
AID - 10.1186/s13073-019-0637-7 [pii]
AID - 637 [pii]
AID - 10.1186/s13073-019-0637-7 [doi]
PST - epublish
SO  - Genome Med. 2019 Apr 30;11(1):27. doi: 10.1186/s13073-019-0637-7.