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Lymphoma

The mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing

Leukemia volume 29, pages 677–685 (2015)Cite this article

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Abstract

To decipher the mutational pattern of primary CNS lymphoma (PCNSL), we performed whole-exome sequencing to a median coverage of 103 × followed by mutation verification in 9 PCNSL and validation using Sanger sequencing in 22 PCNSL. We identified a median of 202 (range: 139–251) potentially somatic single nucleotide variants (SNV) and 14 small indels (range: 7–22) with potentially protein-changing features per PCNSL. Mutations affected the B-cell receptor, toll-like receptor, and NF-κB and genes involved in chromatin structure and modifications, cell-cycle regulation, and immune recognition. A median of 22.2% (range: 20.0–24.7%) of somatic SNVs in 9 PCNSL overlaps with the RGYW motif targeted by somatic hypermutation (SHM); a median of 7.9% (range: 6.2–12.6%) affects its hotspot position suggesting a major impact of SHM on PCNSL pathogenesis. In addition to the well-known targets of aberrant SHM (aSHM) (PIM1), our data suggest new targets of aSHM (KLHL14, OSBPL10, and SUSD2). Among the four most frequently mutated genes was ODZ4 showing protein-changing mutations in 4/9 PCNSL. Together with mutations affecting CSMD2, CSMD3, and PTPRD, these findings may suggest that alterations in genes having a role in CNS development may facilitate diffuse large B-cell lymphoma manifestation in the CNS. This may point to intriguing mechanisms of CNS tropism in PCNSL.

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Acknowledgements

We thank all our technicians. This study has been supported by the Deutsche Krebshilfe (grant nos. 109471, 109472), ICGC MMML-Seq project/German Ministry for Education and Science (BMBF Grant no. 01KU1002 A-J), and the Jackstädt foundation.

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Author notes

  1. I Vater, M Montesinos-Rongen and M Schlesner: These authors contributed equally to this work.

  2. M Deckert and R Siebert: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

    I Vater, A Haake, I Nagel, J Gutwein, J Richter & R Siebert

  2. Institute of Neuropathology, University of Cologne, Cologne, Germany

    M Montesinos-Rongen, F Purschke, R Sprute, N Mettenmeyer, I Nazzal & M Deckert

  3. Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany

    M Schlesner, I Buchhalter & R Eils

  4. Cell Networks, University of Heidelberg, Heidelberg, Germany

    R B Russell

  5. BioQuant, Heidelberg University, Heidelberg, Germany

    R B Russell & R Eils

  6. German Cancer Research Center (DKFZ), Heidelberg, Germany

    O D Wiestler

  7. Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB), Heidelberg University, Heidelberg, Germany

    R Eils

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Correspondence to M Deckert.

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Vater, I., Montesinos-Rongen, M., Schlesner, M. et al. The mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing. Leukemia 29, 677–685 (2015). https://doi.org/10.1038/leu.2014.264

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