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Acta Neuropathol. 2016 Jun;131(6):865-75. doi: 10.1007/s00401-016-1536-2. Epub 2016 Jan 12.

Genomic characterization of primary central nervous system lymphoma.

Author information

1
Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
2
Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
3
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan.
4
Department of Neurosurgery, School of Medicine, Kyorin University Faculty of Medicine, Tokyo, 181-8611, Japan.
5
Department of Neurosurgery, Sassa General Hospital, Tokyo, 188-0011, Japan.
6
Department of Pathology, School of Medicine, Kyorin University Faculty of Medicine, Tokyo, 181-8611, Japan.
7
Department of Pathology, Saitama International Medical Center, Saitama Medical University, Saitama, 350-1298, Japan.
8
Department of Neuro-Oncology/Neurosurgery, Saitama International Medical Center, Saitama Medical University, Saitama, 350-1298, Japan.
9
Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, 104-0045, Japan.
10
Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
11
Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, 104-0045, Japan.
12
Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. hmano@m.u-tokyo.ac.jp.
13
Strategic Basic Research Program, Japan Science and Technology Agency, Saitama, 332-0012, Japan. hmano@m.u-tokyo.ac.jp.

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:

Genomics; MYD88; Oncogene; Primary central nervous system lymphoma

PMID:
26757737
DOI:
10.1007/s00401-016-1536-2
[Indexed for MEDLINE]

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