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

Nature Genetics volume 44, pages 1316–1320 (2012)Cite this article

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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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Figure 1: Spectrum of mutations in Burkitt lymphoma.
Figure 2: Mutual relationship of ID3 mutations with CCND3 (exon 5), TP53 (exons 4–10) and MYC box mutations in mBL samples without IGH-BCL2 translocation.
Figure 3: Cell cycle analysis of ID3-GFP–transfected cell lines by fluorescence-activated cell sorting (FACS).

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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

  1. Julia Richter, Matthias Schlesner, Steve Hoffmann, Markus Kreuz, Ellen Leich and Birgit Burkhardt: These authors contributed equally to this work.

  2. Michael Hummel, Wolfram Klapper, Philip Rosenstiel, Andreas Rosenwald, Benedikt Brors and Reiner Siebert: These authors jointly directed this work.

Authors and 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. Department of Computer Science and Interdisciplinary Center of Bioinformatics, Bioinformatics Group, University of Leipzig, Leipzig, Germany

    Peter F Stadler

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

    Roland Eils

Consortia

the ICGC MMML-Seq Project

  • Julia Richter
  • , Matthias Schlesner
  • , Steve Hoffmann
  • , Markus Kreuz
  • , Ellen Leich
  • , Birgit Burkhardt
  • , Maciej Rosolowski
  • , Ole Ammerpohl
  • , Rabea Wagener
  • , Stephan H Bernhart
  • , Dido Lenze
  • , Monika Szczepanowski
  • , Maren Paulsen
  • , Simone Lipinski
  • , Robert B Russell
  • , Sabine Adam-Klages
  • , Gordana Apic
  • , Alexander Claviez
  • , Dirk Hasenclever
  • , Volker Hovestadt
  • , Nadine Hornig
  • , Jan O Korbel
  • , Dieter Kube
  • , David Langenberger
  • , Chris Lawerenz
  • , Jasmin Lisfeld
  • , Katharina Meyer
  • , Simone Picelli
  • , Jordan Pischimarov
  • , Bernhard Radlwimmer
  • , Tobias Rausch
  • , Marius Rohde
  • , Markus Schilhabel
  • , René Scholtysik
  • , Rainer Spang
  • , Heiko Trautmann
  • , Thorsten Zenz
  • , Arndt Borkhardt
  • , Hans G Drexler
  • , Peter Möller
  • , Roderick A F MacLeod
  • , Christiane Pott
  • , Stefan Schreiber
  • , Lorenz Trümper
  • , Markus Loeffler
  • , Peter F Stadler
  • , Peter Lichter
  • , Roland Eils
  • , Ralf Küppers
  • , Michael Hummel
  • , Wolfram Klapper
  • , Philip Rosenstiel
  • , Andreas Rosenwald
  • , Benedikt Brors
  •  & Reiner Siebert

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.

Corresponding author

Correspondence to Reiner Siebert.

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Competing interests

The author declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Tables 1–4, 6–8, 10, 11 and 15–21 and Supplementary Figures 1–18 (PDF 2842 kb)

Supplementary Table 5

Somatic structural variants (XLSX 14 kb)

Supplementary Table 9

Potentially protein changing somatic mutations in the four index patients (XLSX 411 kb)

Supplementary Table 12

U133A gene expression data of the potentially protein changing somatic mutations (XLSX 169 kb)

Supplementary Table 13

450K DNA methylation pattern of the potentially protein changing somatic mutations (XLSX 426 kb)

Supplementary Table 14

Results of ID3 and CCND3 mutation analysis of primary lymphoma (XLSX 17 kb)

Supplementary Table 22

Primer sequences (XLSX 14 kb)

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the ICGC MMML-Seq Project. Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nat Genet 44, 1316–1320 (2012). https://doi.org/10.1038/ng.2469

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