T Nakamura1,2, K Tateishi1,2, T Niwa3, Y Matsushita4, K Tamura5, M Kinoshita6, K Tanaka7, S Fukushima1, H Takami1, H Arita4,6, A Kubo8, T Shuto9, M Ohno4, Y Miyakita4, S Kocialkowski10, T Sasayama7, N Hashimoto6, T Maehara5, S Shibui4, T Ushijima3, N Kawahara2, Y Narita4, K Ichimura1. 1. Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan. 2. Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan. 3. Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan. 4. Department of Neurosurgery and Neuro-oncology, National Cancer Center, Tokyo, Japan. 5. Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan. 6. Department of Neurosurgery, Graduate School of Medicine, Osaka University, Osaka, Japan. 7. Department of Neurosurgery, Graduate School of Medicine, Kobe University, Kobe, Japan. 8. Department of Neurosurgery, Yokosuka Kyosai Hospital, Yokosuka, Japan. 9. Department of Neurosurgery, Yokohama Rosai Hospital, Yokohama, Japan. 10. Department of Pathology, University of Cambridge, Cambridge, UK.
Abstract
AIMS: 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.
AIMS: 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: Christian Grommes; Alessandro Pastore; Nicolaos Palaskas; Sarah S Tang; Carl Campos; Derrek Schartz; Paolo Codega; Donna Nichol; Owen Clark; Wan-Ying Hsieh; Dan Rohle; Marc Rosenblum; Agnes Viale; Viviane S Tabar; Cameron W Brennan; Igor T Gavrilovic; Thomas J Kaley; Craig P Nolan; Antonio Omuro; Elena Pentsova; Alissa A Thomas; Elina Tsyvkin; Ariela Noy; M Lia Palomba; Paul Hamlin; Craig S Sauter; Craig H Moskowitz; Julia Wolfe; Ahmet Dogan; Minhee Won; Jon Glass; Scott Peak; Enrico C Lallana; Vaios Hatzoglou; Anne S Reiner; Philip H Gutin; Jason T Huse; Katherine S Panageas; Thomas G Graeber; Nikolaus Schultz; Lisa M DeAngelis; Ingo K Mellinghoff Journal: Cancer Discov Date: 2017-06-15 Impact factor: 39.397
Authors: Christian Grommes; Sarah S Tang; Julia Wolfe; Thomas J Kaley; Mariza Daras; Elena I Pentsova; Anna F Piotrowski; Jacqueline Stone; Andrew Lin; Craig P Nolan; Malbora Manne; Paolo Codega; Carl Campos; Agnes Viale; Alissa A Thomas; Michael F Berger; Vaios Hatzoglou; Anne S Reiner; Katherine S Panageas; Lisa M DeAngelis; Ingo K Mellinghoff Journal: Blood Date: 2018-12-19 Impact factor: 22.113
Authors: Christian Grommes; James L Rubenstein; Lisa M DeAngelis; Andres J M Ferreri; Tracy T Batchelor Journal: Neuro Oncol Date: 2019-02-19 Impact factor: 12.300
Authors: Ryan M Young; Tianyi Wu; Roland Schmitz; Moez Dawood; Wenming Xiao; James D Phelan; Weihong Xu; Laurence Menard; Eric Meffre; Wing-Chung C Chan; Elaine S Jaffe; Randy D Gascoyne; Elías Campo; Andreas Rosenwald; German Ott; Jan Delabie; Lisa M Rimsza; Louis M Staudt Journal: Proc Natl Acad Sci U S A Date: 2015-10-19 Impact factor: 11.205
Authors: Tarsheen K Sethi; Alexandra E Kovach; Natalie S Grover; Li-Ching Huang; Laura A Lee; Samuel M Rubinstein; Yang Wang; David S Morgan; John P Greer; Steven I Park; Mary Ann Thompson-Arildsen; Ashwini Yenamandra; Cindy L Vnencak-Jones; Nishitha M Reddy Journal: Leuk Lymphoma Date: 2019-06-11
Authors: M K Gandhi; T Hoang; S C Law; S Brosda; K O'Rourke; J W D Tobin; F Vari; V Murigneux; L Fink; J Gunawardana; C Gould; H Oey; K Bednarska; S Delecluse; R U Trappe; L Merida de Long; M B Sabdia; G Bhagat; G Hapgood; E Blyth; L Clancy; J Wight; E Hawkes; L M Rimsza; A Maguire; K Bojarczuk; B Chapuy; C Keane Journal: Blood Date: 2021-03-18 Impact factor: 22.113