title: Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas.
abstract: OBJECTIVE
  Primary central nervous system lymphoma (PCNSL) manifest aggressive clinical behaviour and have poor prognosis. Although constitutive activation of the nuclear factor-κB (NF-κB) pathway has been documented, knowledge about the genetic alterations leading to the impairment of the NF-κB pathway in PCNSLs is still limited. This study was aimed to unravel the underlying genetic profiles of PCNSL.
  
  
  METHODS
  We conducted the systematic sequencing of 21 genes relevant to the NF-κB signalling network for 71 PCNSLs as well as the pyrosequencing of CD79B and MYD88 mutation hotspots in a further 35 PCNSLs and 46 glioblastomas (GBMs) for validation.
  
  
  RESULTS
  The results showed that 68 out of 71 PCNSLs had mutations in the NF-κB gene network, most commonly affecting CD79B (83%), MYD88 (76%), TBL1XR1 (23%), PRDM1 (20%) and CREBBP1 (20%). These mutations, particularly CD79B and MYD88, frequently coincided within each tumour in various combinations, simultaneously affecting diverse pathways within the network. No GBMs had hotspot mutation of CD79B Y196 and MYD88 L265.
  
  
  CONCLUSIONS
  The prevalence of CD79B and MYD88 mutations in PCNSLs was considerably higher than reported in systemic diffuse large B-cell lymphomas. This observation could reflect the paucity of antigen stimuli from the immune system in the central nervous system (CNS) and the necessity to substitute them by the constitutive activation of CD79B and MYD88 that would initiate the signalling cascades. These hotspot mutations may serve as a genetic hallmark for PCNSL serving as a genetic marker for diagnose and potential targets for molecular therapy.
authors.affiliation: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.|Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.|Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tateishi
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Niwa
authors.affiliation: Department of Neurosurgery and Neuro-oncology, National Cancer Center, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Matsushita
authors.affiliation: Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kinoshita
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, Kobe University, Kobe, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Fukushima
authors.affiliation: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Takami
authors.affiliation: Department of Neurosurgery and Neuro-oncology, National Cancer Center, Tokyo, Japan.|Department of Neurosurgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Arita
authors.affiliation: Department of Neurosurgery, Yokosuka Kyosai Hospital, Yokosuka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kubo
authors.affiliation: Department of Neurosurgery, Yokohama Rosai Hospital, Yokohama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shuto
authors.affiliation: Department of Neurosurgery and Neuro-oncology, National Cancer Center, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ohno
authors.affiliation: Department of Neurosurgery and Neuro-oncology, National Cancer Center, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Miyakita
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: S
authors.initials: S
authors.lastname: Kocialkowski
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, Kobe University, Kobe, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sasayama
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Hashimoto
authors.affiliation: Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Maehara
authors.affiliation: Department of Neurosurgery and Neuro-oncology, National Cancer Center, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Shibui
authors.affiliation: Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ushijima
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kawahara
authors.affiliation: Department of Neurosurgery and Neuro-oncology, National Cancer Center, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Narita
authors.affiliation: Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ichimura
mesh_terms: D000368:Aged; D051925:CD79 Antigens / Q000235:genetics*; D016543:Central Nervous System Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D016133:Polymerase Chain Reaction
chemical_list: D051925:CD79 Antigens; C497883:CD79B protein, human; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88
keywords: B-cell receptor signalling; CD79B; MYD88; NF-κB; PCNSL