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Genomic characterization of primary central nervous system lymphoma

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Abstract

Primary central nervous system lymphoma (PCNSL) is a rare malignancy confined to the central nervous system (CNS), and majority of PCNSL is pathologically classified as diffuse large B-cell lymphoma (DLBCL). We have now performed whole-exome sequencing for 41 tumor tissues of DLBCL-type PCNSL and paired normal specimens and also RNA-sequencing for 30 tumors, revealing a very high frequency of nonsynonymous somatic mutations in PIM1 (100 %), BTG2 (92.7 %), and MYD88 (85.4 %). Many genes in the NF-κB pathway are concurrently mutated within the same tumors. Further, focal deletion or somatic mutations in the HLA genes are associated with poor prognosis. Copy number amplification and overexpression of genes at chromosome 7q35 were both found to predict short progression-free survival as well. Oncogenic mutations in GRB2 were also detected, the effects of which in cultured cells were attenuated by inhibitors of the downstream kinases MAP2K1 and MAP2K2. Individuals with tumors positive for MYD88 mutations also harbored the same mutations at a low frequency in peripheral blood mononuclear cells, suggesting that MYD88 mutation-positive precancerous cells originate outside of the CNS and develop into lymphoma after additional genetic hits that confer adaptation to the CNS environment.

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Acknowledgments

This study was supported in part by a grant for Applied Research for Innovative Treatment of Cancer from the Ministry of Health, Labor, and Welfare of Japan, by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by a Research Grant from Princess Takamatsu Cancer Research Fund. We thank J. Shibahara, K. Suzuki, M. Tamura, and A. Maruyama for technical assistance. Raw sequencing data for exome and RNA-seq analyses have been deposited at the Japanese Genotype–Phenotype Archive (JGA, http://trace.ddbj.nig.ac.jp/jga), which is hosted by DDBJ, under the accession number JGAS00000000021.

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Authors and Affiliations

  1. Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

    Kazutaka Fukumura, Shinya Kojima, Toshihide Ueno, Manabu Soda, Takahiko Yasuda, Hiroyuki Yamaguchi & Hiroyuki Mano

  2. Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan

    Masahito Kawazu & Eirin Sai

  3. Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan

    Hiroki Ueda & Hiroyuki Aburatani

  4. Department of Neurosurgery, School of Medicine, Kyorin University Faculty of Medicine, Tokyo, 181-8611, Japan

    Jeunghun Lee & Motoo Nagane

  5. Department of Pathology, School of Medicine, Kyorin University Faculty of Medicine, Tokyo, 181-8611, Japan

    Yukiko Shishido-Hara

  6. Department of Neurosurgery, Sassa General Hospital, Tokyo, 188-0011, Japan

    Jeunghun Lee

  7. Department of Pathology, Saitama International Medical Center, Saitama Medical University, Saitama, 350-1298, Japan

    Atsushi Sasaki

  8. Department of Neuro-Oncology/Neurosurgery, Saitama International Medical Center, Saitama Medical University, Saitama, 350-1298, Japan

    Mitsuaki Shirahata, Kazuhiko Mishima & Ryo Nishikawa

  9. Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, 104-0045, Japan

    Koichi Ichimura

  10. Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan

    Akitake Mukasa & Nobuhito Saito

  11. Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, 104-0045, Japan

    Yoshitaka Narita

  12. Strategic Basic Research Program, Japan Science and Technology Agency, Saitama, 332-0012, Japan

    Hiroyuki Mano

Authors
  1. Kazutaka Fukumura
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  2. Masahito Kawazu
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Correspondence to Hiroyuki Mano.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments.

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Fukumura, K., Kawazu, M., Kojima, S. et al. Genomic characterization of primary central nervous system lymphoma. Acta Neuropathol 131, 865–875 (2016). https://doi.org/10.1007/s00401-016-1536-2

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  • DOI: https://doi.org/10.1007/s00401-016-1536-2

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