Letter | Published:

Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing

Nature Genetics volume 44, pages 13161320 (2012) | Download Citation

Abstract

Burkitt lymphoma is a mature aggressive B-cell lymphoma derived from germinal center B cells1. Its cytogenetic hallmark is the Burkitt translocation t(8;14)(q24;q32) and its variants, which juxtapose the MYC oncogene with one of the three immunoglobulin loci2. Consequently, MYC is deregulated, resulting in massive perturbation of gene expression3. Nevertheless, MYC deregulation alone seems not to be sufficient to drive Burkitt lymphomagenesis. By whole-genome, whole-exome and transcriptome sequencing of four prototypical Burkitt lymphomas with immunoglobulin gene (IG)-MYC translocation, we identified seven recurrently mutated genes. One of these genes, ID3, mapped to a region of focal homozygous loss in Burkitt lymphoma4. In an extended cohort, 36 of 53 molecularly defined Burkitt lymphomas (68%) carried potentially damaging mutations of ID3. These were strongly enriched at somatic hypermutation motifs. Only 6 of 47 other B-cell lymphomas with the IG-MYC translocation (13%) carried ID3 mutations. These findings suggest that cooperation between ID3 inactivation and IG-MYC translocation is a hallmark of Burkitt lymphomagenesis.

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Acknowledgements

This manuscript is dedicated to the memory of Karl Lennert, the founder of the Kiel classification of lymphoma, who died during the preparation of the manuscript. The authors thank O. Batic, C. Becher, C. Botz-von Drathen, A. Dietsch, J. Eils, M. Friskovec, K. Göbel, T. Grieb, S. Hengst, U. Jacobsen, T. Kaacksteen, H. Lammert, C. von der Lancken, H.-H. Müller, S. Radomski, J. Schieferstein, M. Schlapkohl, D. Schuster, S. Ölmez and L. Valles for their excellent technical support. We are grateful to G. Richter for excellent work in the coordination of the ICGC MMML-Seq Consortium and to the members of the MMML Consortium for providing extensive data of the sample analyzed within that project. We are also very grateful to all individuals who participate in this study. The project was funded by the Federal Ministry of Education and Research in Germany (BMBF) within the Program for Medical Genome Research (01KU1002A to 01KU1002J). The authors are responsible for the content of this publication. The MMML Consortium was funded by the Deutsche Krebshilfe from 2003 to 2011. Support of sequencing infrastructure by the Deutsche Forschungsgemeinschaft (DFG) and the KinderKrebsInitiative Buchholz/Holm-Seppensen is gratefully acknowledged. R.W. is the recipient of a Christoph-Schubert-Award from the KinderKrebsInitiative Buchholz/Holm-Seppensen.

Author information

Author notes

    • Julia Richter
    • , Matthias Schlesner
    • , Steve Hoffmann
    • , Markus Kreuz
    • , Ellen Leich
    •  & Birgit Burkhardt

    These authors contributed equally to this work.

    • Michael Hummel
    • , Wolfram Klapper
    • , Philip Rosenstiel
    • , Andreas Rosenwald
    • , Benedikt Brors
    •  & Reiner Siebert

    These authors jointly directed this work.

Affiliations

  1. Institute of Human Genetics, Christian-Albrechts-University, Kiel, Germany.

    • Julia Richter
    • , Ole Ammerpohl
    • , Rabea Wagener
    • , Nadine Hornig
    •  & Reiner Siebert
  2. Division of Theoretical Bioinformatics, Deutsches Krebsforschungszentrum Heidelberg (DKFZ), Heidelberg, Germany.

    • Matthias Schlesner
    • , Chris Lawerenz
    • , Roland Eils
    •  & Benedikt Brors
  3. Transcriptome Bioinformatics, LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.

    • Steve Hoffmann
    • , Stephan H Bernhart
    •  & David Langenberger
  4. Institute for Medical Informatics Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.

    • Markus Kreuz
    • , Maciej Rosolowski
    • , Dirk Hasenclever
    •  & Markus Loeffler
  5. Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany.

    • Ellen Leich
    • , Jordan Pischimarov
    •  & Andreas Rosenwald
  6. Pediatric Hematology and Oncology, University Hospital Muenster, Muenster, Germany.

    • Birgit Burkhardt
  7. Pediatric Hematology and Oncology, University Hospital Giessen, Giessen, Germany.

    • Birgit Burkhardt
    • , Jasmin Lisfeld
    •  & Marius Rohde
  8. Institute of Pathology, Charité–University Medicine Berlin, Berlin, Germany.

    • Dido Lenze
    •  & Michael Hummel
  9. Hematopathology Section, Christian-Albrechts-University, Kiel, Germany.

    • Monika Szczepanowski
    •  & Wolfram Klapper
  10. Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.

    • Maren Paulsen
    • , Simone Lipinski
    • , Markus Schilhabel
    •  & Philip Rosenstiel
  11. Cell Networks, Bioquant, University of Heidelberg, Heidelberg, Germany.

    • Robert B Russell
    •  & Gordana Apic
  12. Institute of Immunology, Christian-Albrechts-University, Kiel, Germany.

    • Sabine Adam-Klages
  13. Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

    • Alexander Claviez
  14. Division of Molecular Genetics, DKFZ, Heidelberg, Germany.

    • Volker Hovestadt
    • , Simone Picelli
    • , Bernhard Radlwimmer
    •  & Peter Lichter
  15. Genome Biology Research Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.

    • Jan O Korbel
    •  & Tobias Rausch
  16. Department of Hematology and Oncology, Georg-Augusts-University of Göttingen, Göttingen, Germany.

    • Dieter Kube
    •  & Lorenz Trümper
  17. Institute of Functional Genomics, University of Regensburg, Regensburg, Germany.

    • Katharina Meyer
    •  & Rainer Spang
  18. Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Duisburg-Essen, Medical School, Essen, Germany.

    • René Scholtysik
    •  & Ralf Küppers
  19. Department of Internal Medicine II, Hematology and Oncology, University Medical Centre, Campus Kiel, Kiel, Germany.

    • Heiko Trautmann
    •  & Christiane Pott
  20. Department of Medicine V, University of Heidelberg, Heidelberg, Germany.

    • Thorsten Zenz
  21. Department of Translational Oncology, National Center for Tumor Diseases (NCT) and DKFZ, Heidelberg, Germany.

    • Thorsten Zenz
  22. Department of Medicine III, Ulm University, Ulm, Germany.

    • Thorsten Zenz
  23. Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany.

    • Arndt Borkhardt
  24. Department of Human and Animal Cell Cultures, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.

    • Hans G Drexler
    •  & Roderick A F MacLeod
  25. Institute of Pathology, Medical Faculty of the Ulm University, Ulm, Germany.

    • Peter Möller
  26. Department of General Internal Medicine, Christian-Albrechts-University, Kiel, Germany.

    • Stefan Schreiber
  27. Bioinformatics Group, Department of Computer Science and Interdisciplinary Center of Bioinformatics, University of Leipzig, Leipzig, Germany.

    • Peter F Stadler
  28. Institute of Pharmacy and Molecular Biotechnology, Bioquant, University of Heidelberg, Heidelberg, Germany.

    • Roland Eils

Consortia

  1. the ICGC MMML-Seq Project

Authors

    Contributions

    B. Burkhardt, A.C., A.B., M. Rohde, J.L. and N.H. provided subject samples and clinical data. W.K., M.H. and P.M. coordinated and performed pathology review. D. Lenze, M. Szczepanowski, M.H. and W.K. stained and reviewed cryomaterial, prepared analytes and performed analyte quality control. D. Lenze and M.H. performed and interpreted immunoglobulin gene PCR. R.A.F.M. and H.G.D. characterized and provided cell lines. E.L., M. Schilhabel, V.H., S.P. and B.R. performed next-generation sequencing analyses, and A.R., P.R., P.L. and S.S. supervised next-generation sequencing analysis and interpreted data. C.L. coordinated transfer and data management of the sequences. M. Schlesner, B. Brors, S.H., S.H.B., P.F.S., D. Langenberger, V.H., J.O.K., T.R. and J.P. performed analysis of next-generation sequencing data, and B. Brors and R.E. conceived the statistical analysis. J.R., E.L., O.A., S.A.-K., M.P., S.L., R.B.R. and G.A. performed validation analyses. J.R. and R.W. were responsible for ID3 mutation and expression analyses. M.K., M. Rosolowski, M.L., H.T., C.P., R. Spang, K.M., R.K., R. Scholtysik, T.Z., D.K., L.T., D.H. and R. Siebert provided and analyzed data from the MMML cohort. M.K. and M. Rosolowski performed correlative and biometric analyses of the MMML cohort. J.R., M. Schlesner, M.K., S.H., R.E. and R. Siebert interpreted data and wrote the manuscript. R.E., M.H., W.K., P.R., A.R., B. Brors, O.A. and R. Siebert designed the study and coordinated the project. All authors read and approved the final manuscript.

    Competing interests

    The author declare no competing financial interests.

    Corresponding author

    Correspondence to Reiner Siebert.

    Supplementary information

    PDF files

    1. 1.

      Supplementary Text and Figures

      Supplementary Note, Supplementary Tables 1–4, 6–8, 10, 11 and 15–21 and Supplementary Figures 1–18

    Excel files

    1. 1.

      Supplementary Table 5

      Somatic structural variants

    2. 2.

      Supplementary Table 9

      Potentially protein changing somatic mutations in the four index patients

    3. 3.

      Supplementary Table 12

      U133A gene expression data of the potentially protein changing somatic mutations

    4. 4.

      Supplementary Table 13

      450K DNA methylation pattern of the potentially protein changing somatic mutations

    5. 5.

      Supplementary Table 14

      Results of ID3 and CCND3 mutation analysis of primary lymphoma

    6. 6.

      Supplementary Table 22

      Primer sequences

    About this article

    Publication history

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    DOI

    https://doi.org/10.1038/ng.2469

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