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Acta Neuropathologica

, Volume 131, Issue 6, pp 865–875 | Cite as

Genomic characterization of primary central nervous system lymphoma

  • Kazutaka Fukumura
  • Masahito Kawazu
  • Shinya Kojima
  • Toshihide Ueno
  • Eirin Sai
  • Manabu Soda
  • Hiroki Ueda
  • Takahiko Yasuda
  • Hiroyuki Yamaguchi
  • Jeunghun Lee
  • Yukiko Shishido-Hara
  • Atsushi Sasaki
  • Mitsuaki Shirahata
  • Kazuhiko Mishima
  • Koichi Ichimura
  • Akitake Mukasa
  • Yoshitaka Narita
  • Nobuhito Saito
  • Hiroyuki Aburatani
  • Ryo Nishikawa
  • Motoo Nagane
  • Hiroyuki Mano
Original Paper

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.

Keywords

Primary central nervous system lymphoma Oncogene Genomics MYD88 

Notes

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.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

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.

Supplementary material

401_2016_1536_MOESM1_ESM.docx (5.1 mb)
Supplementary material 1 (DOCX 5223 kb)
401_2016_1536_MOESM2_ESM.xlsx (98 kb)
Supplementary material 2 (XLSX 97 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Kazutaka Fukumura
    • 1
  • Masahito Kawazu
    • 2
  • Shinya Kojima
    • 1
  • Toshihide Ueno
    • 1
  • Eirin Sai
    • 2
  • Manabu Soda
    • 1
  • Hiroki Ueda
    • 3
  • Takahiko Yasuda
    • 1
  • Hiroyuki Yamaguchi
    • 1
  • Jeunghun Lee
    • 4
    • 6
  • Yukiko Shishido-Hara
    • 5
  • Atsushi Sasaki
    • 7
  • Mitsuaki Shirahata
    • 8
  • Kazuhiko Mishima
    • 8
  • Koichi Ichimura
    • 9
  • Akitake Mukasa
    • 10
  • Yoshitaka Narita
    • 11
  • Nobuhito Saito
    • 10
  • Hiroyuki Aburatani
    • 3
  • Ryo Nishikawa
    • 8
  • Motoo Nagane
    • 4
  • Hiroyuki Mano
    • 1
    • 12
  1. 1.Department of Cellular Signaling, Graduate School of MedicineThe University of TokyoTokyoJapan
  2. 2.Department of Medical Genomics, Graduate School of MedicineThe University of TokyoTokyoJapan
  3. 3.Genome Science Division, Research Center for Advanced Science and TechnologyThe University of TokyoTokyoJapan
  4. 4.Department of Neurosurgery, School of MedicineKyorin University Faculty of MedicineTokyoJapan
  5. 5.Department of Pathology, School of MedicineKyorin University Faculty of MedicineTokyoJapan
  6. 6.Department of NeurosurgerySassa General HospitalTokyoJapan
  7. 7.Department of Pathology, Saitama International Medical CenterSaitama Medical UniversitySaitamaJapan
  8. 8.Department of Neuro-Oncology/Neurosurgery, Saitama International Medical CenterSaitama Medical UniversitySaitamaJapan
  9. 9.Division of Brain Tumor Translational ResearchNational Cancer Center Research InstituteTokyoJapan
  10. 10.Department of Neurosurgery, Graduate School of MedicineThe University of TokyoTokyoJapan
  11. 11.Department of Neurosurgery and Neuro-OncologyNational Cancer Center HospitalTokyoJapan
  12. 12.Strategic Basic Research ProgramJapan Science and Technology AgencySaitamaJapan

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