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DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control

Nature Genetics volume 47, pages 1316–1325 (2015)Cite this article

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Abstract

Although Burkitt lymphomas and follicular lymphomas both have features of germinal center B cells, they are biologically and clinically quite distinct. Here we performed whole-genome bisulfite, genome and transcriptome sequencing in 13 IG-MYC translocation–positive Burkitt lymphoma, nine BCL2 translocation–positive follicular lymphoma and four normal germinal center B cell samples. Comparison of Burkitt and follicular lymphoma samples showed differential methylation of intragenic regions that strongly correlated with expression of associated genes, for example, genes active in germinal center dark-zone and light-zone B cells. Integrative pathway analyses of regions differentially methylated in Burkitt and follicular lymphomas implicated DNA methylation as cooperating with somatic mutation of sphingosine phosphate signaling, as well as the TCF3-ID3 and SWI/SNF complexes, in a large fraction of Burkitt lymphomas. Taken together, our results demonstrate a tight connection between somatic mutation, DNA methylation and transcriptional control in key B cell pathways deregulated differentially in Burkitt lymphoma and other germinal center B cell lymphomas.

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Figure 1: Loss of methylation in lymphoma.
Figure 2: Differentially methylated regions.
Figure 3: Sphingosine-1-phosphate signaling is affected by complementary DNA mutation and methylation in germinal center B lymphomas.
Figure 4: Enrichment of transcription factor binding sites in cDMRs.
Figure 5: SMARCA4 genome architecture and protein expression.

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Acknowledgements

This study has been supported by the German Ministry of Science and Education (BMBF) in the framework of the ICGC MMML-Seq project (01KU1002A-J) and the MMML-MYC-SYS project (036166B), the European Union in the framework of the BLUEPRINT Project (HEALTH-F5-2011-282510) and the KinderKrebsInitiative Buchholz/Holm-Seppensen and LIFE (Leipzig Research Center for Civilization Diseases), Leipzig University. LIFE is funded by the European Union, the European Regional Development Fund (ERDF), the European Social Fund (ESF) and the Free State of Saxony. WGBS was additionally supported by NGFNplus (BMBF, 01GS0883) and the DKFZ–Heidelberg Center for Personalized Oncology (DKFZ-HIPO). Former grant support of MMML by the Deutsche Krebshilfe (2003–2011) is gratefully acknowledged. J.R. is supported by the Dr. Werner Jackstädt Foundation in the framework of a Junior Excellence Research Group on 'Mechanisms of B-Cell Lymphomagenesis in the Senium as Basic Principle for the Development of Age-Adjusted Therapy Regimes' (S134-10.100).

Author information

Author notes

  1. Helene Kretzmer, Stephan H Bernhart, Wei Wang, Andrea Haake, Marc A Weniger and Anke K Bergmann: These authors contributed equally to this work.

  2. Ralf Küppers, Ole Ammerpohl, Peter Lichter, Reiner Siebert, Steve Hoffmann and Bernhard Radlwimmer: These authors jointly supervised this work.

Authors and Affiliations

  1. Transcriptome Bioinformatics, Research Center for Civilization Diseases (LIFE), University of Leipzig, Leipzig, Germany

    Helene Kretzmer, Stephan H Bernhart, Gero Doose, Frank Jühling, Christian Otto, Peter F Stadler & Steve Hoffmann

  2. Interdisciplinary Center for Bioinformatics, University of Leipzig, Leipzig, Germany

    Helene Kretzmer, Stephan H Bernhart, Gero Doose, Frank Jühling, Christian Otto, Peter F Stadler & Steve Hoffmann

  3. Department of Computer Science, Bioinformatics Group, University of Leipzig, Leipzig, Germany

    Helene Kretzmer, Stephan H Bernhart, Gero Doose, Frank Jühling, Christian Otto, Peter F Stadler & Steve Hoffmann

  4. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Wei Wang, Volker Hovestadt, Simone Picelli, Peter Lichter & Bernhard Radlwimmer

  5. Institute of Human Genetics, Christian Albrechts University, Kiel, Germany

    Andrea Haake, Anke K Bergmann, Jana Gutwein, Julia Richter, Julia Kolarova, Rabea Wagener, Cristina López, Inga Nagel, Inga Vater, Ole Ammerpohl & Reiner Siebert

  6. Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Kiel, Germany

    Marc A Weniger & Ralf Küppers

  7. Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

    Anke K Bergmann & Alexander Claviez

  8. Cell Networks, Bioquant, University of Heidelberg, Heidelberg, Germany

    Matthew J Betts, Qianhao Lu & Robert B Russell

  9. Structural Biology and BioComputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    Enrique Carrillo-de-Santa-Pau & Daniel Rico

  10. Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Bingding Huang, Roland Eils, Chris Lawerenz & Matthias Schlesner

  11. Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany

    Judith Arnolds

  12. Pediatric Hematology and Oncology, University Hospital Münster, Münster, Germany

    Birgit Burkhardt

  13. Leibniz Institut, German Collection of Microorganisms and Cell Cultures (DSMZ), Braunschweig, Germany

    Hans G Drexler, Sonja Eberth & Roderick A F MacLeod

  14. Department of Hematology and Oncology, Georg Augusts University of Göttingen, Göttingen, Germany

    Sonja Eberth & Lorenz Trümper

  15. Institute of Pharmacy and Molecular Biotechnology, Bioquant, University of Heidelberg, Heidelberg, Germany

    Roland Eils

  16. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, UK

    Paul Flicek

  17. Friedrich Ebert Hospital Neumünster, Clinics for Haematology, Oncology and Nephrology, Neumünster, Germany

    Siegfried Haas

  18. Institute of Pathology, Charité, University Medicine Berlin, Berlin, Germany

    Michael Hummel & Dido Lenze

  19. Department of Internal Medicine II, Hematology and Oncology, University Medical Centre, Campus Kiel, Kiel, Germany

    Dennis Karsch

  20. Department of Molecular Biology, Radboud University, Faculty of Science, Nijmegen, the Netherlands

    Hinrik H D Kerstens, Joost H A Martens, Marta Kulis, Monika Szczepanowski & Hendrik G Stunnenberg

  21. Hematopathology Section, Christian Albrechts University, Kiel, Germany

    Wolfram Klapper

  22. Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany

    Markus Kreuz, Markus Loeffler & Maciej Rosolowski

  23. Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    José Ignacio Martín-Subero

  24. Institute of Pathology, Medical Faculty of the Ulm University, Ulm, Germany

    Peter Möller

  25. Pediatric Hematology and Oncology, University Hospital Giessen, Giessen, Germany

    Marius Rohde

  26. Institute of Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany

    Philip Rosenstiel & Markus Schilhabel

  27. RNomics Group, Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany

    Peter F Stadler

  28. Santa Fe Institute, Santa Fe, New Mexico, USA

    Peter F Stadler

  29. Max Planck Institute for Mathematics in Sciences, Leipzig, Germany

    Peter F Stadler

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  1. Helene Kretzmer
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  2. Stephan H Bernhart
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  3. Wei Wang
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  4. Andrea Haake
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Consortia

ICGC MMML-Seq project

BLUEPRINT project

Contributions

A.H., O.A., R.K., P.L., R.S., S. Hoffmann and B.R. conceived and designed the experiments. W.W., A.H., A.K.B., J.G., J.R., J.K., R.W., S.E., H.H.D.K., W.K., D.L., C. López, S.P., I.V., P.R., M. Schilhabel, M. Szczepanowski, L.T. and R.K. performed the experiments. H.K., S.H.B., M.J.B., B.H., R.E., P.F., C. Lawerenz, J.H.A.M., M. Schlesner, P.F.S., H.G.S. and S. Hoffmann performed statistical analysis. H.K., S.H.B., G.D., V.H., D.R., F.J., C.O., M.H., M. Kreuz, M. Kulis, I.N., M. Rosolowski, R.B.R., M. Schlesner, S. Hoffmann and B.R. analyzed the data. H.K., M.A.W., M.J.B., E.C.-d.-S.-P., G.D., B.H., F.J., Q.L., C.O., J.A., B.B., A.C., H.G.D., S.E., R.E., P.F., S. Haas, D.K., H.H.D.K., W.K., M. Kreuz, C. Lawerenz, D.L., M.L., R.A.F.M., J.H.A.M., J.I.M.-S., P.M., M. Rohde, P.R., M. Schilhabel, M. Schlesner, L.T., H.G.S. and S. Hoffmann contributed reagents, materials and/or analysis tools. H.K., S.H.B., W.W., A.H., P.L., R.S., S. Hoffmann and B.R. wrote the manuscript.

Corresponding authors

Correspondence to Reiner Siebert, Steve Hoffmann or Bernhard Radlwimmer.

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Competing interests

The authors declare no competing financial interests.

Additional information

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–23 and Supplementary Tables 1–4, 6, 9–11, 13, 14 and 16–18. (PDF 4797 kb)

Supplementary Table 5

Statistics of whole-genome sequencing. (XLSX 15 kb)

Supplementary Table 7

Annotation of DMRs. (XLSX 7648 kb)

Supplementary Table 8

Correlating DMRs. (XLSX 990 kb)

Supplementary Table 12

Statistics of transcriptome arrays. (XLSX 29 kb)

Supplementary Table 15

SWI/SNF SNVs. (XLSX 14 kb)

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Kretzmer, H., Bernhart, S., Wang, W. et al. DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control. Nat Genet 47, 1316–1325 (2015). https://doi.org/10.1038/ng.3413

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