title: Genomic characterization of primary central nervous system lymphoma.
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.
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Fukumura
authors.affiliation: Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Kawazu
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Kojima
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
authors.forename: Eirin
authors.initials: E
authors.lastname: Sai
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Soda
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ueda
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yasuda
authors.affiliation: Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamaguchi
authors.affiliation: Department of Neurosurgery, School of Medicine, Kyorin University Faculty of Medicine, Tokyo, 181-8611, Japan.|Department of Neurosurgery, Sassa General Hospital, Tokyo, 188-0011, Japan.
authors.forename: Jeunghun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pathology, School of Medicine, Kyorin University Faculty of Medicine, Tokyo, 181-8611, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Shishido-Hara
authors.affiliation: Department of Pathology, Saitama International Medical Center, Saitama Medical University, Saitama, 350-1298, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sasaki
authors.affiliation: Department of Neuro-Oncology/Neurosurgery, Saitama International Medical Center, Saitama Medical University, Saitama, 350-1298, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Shirahata
authors.affiliation: Department of Neuro-Oncology/Neurosurgery, Saitama International Medical Center, Saitama Medical University, Saitama, 350-1298, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Mishima
authors.affiliation: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, 104-0045, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ichimura
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
authors.forename: Akitake
authors.initials: A
authors.lastname: Mukasa
authors.affiliation: Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, 104-0045, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Narita
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Saito
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, 153-8904, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Department of Neuro-Oncology/Neurosurgery, Saitama International Medical Center, Saitama Medical University, Saitama, 350-1298, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Nishikawa
authors.affiliation: Department of Neurosurgery, School of Medicine, Kyorin University Faculty of Medicine, Tokyo, 181-8611, Japan.
authors.forename: Motoo
authors.initials: M
authors.lastname: Nagane
authors.affiliation: 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.|Strategic Basic Research Program, Japan Science and Technology Agency, Saitama, 332-0012, Japan. hmano@m.u-tokyo.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mano
mesh_terms: D016543:Central Nervous System Neoplasms / Q000235:genetics*; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D023281:Genomics / Q000379:methods; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics; D009420:Nervous System / Q000473:pathology
chemical_list: D016328:NF-kappa B
keywords: Genomics; MYD88; Oncogene; Primary central nervous system lymphoma