title: Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas.
abstract: Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p.Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.
authors.affiliation: 1] Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. [2].
authors.forename: Liwei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 1] Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA. [2].
authors.forename: Lee H
authors.initials: LH
authors.lastname: Chen
authors.affiliation: 1] Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. [2].
authors.forename: Hong
authors.initials: H
authors.lastname: Wan
authors.affiliation: 1] Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA. [2].
authors.forename: Rui
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Feng
authors.affiliation: 1] Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. [2] Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. [3] Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Yang
authors.affiliation: Personal Genome Diagnostics, Inc., Baltimore, Maryland, USA.
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.affiliation: Beijing Pangenomics Technology, Co Ltd., Beijing, China.
authors.forename: Sizhen
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA.
authors.forename: Weixin
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA.
authors.forename: Huishan
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Killela
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Junting
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
authors.forename: Guilin
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Hao
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Webb
authors.affiliation: Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA.
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
authors.affiliation: Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA.
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.affiliation: Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA.
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.affiliation: Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA.
authors.forename: Yiping
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA.
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Reitman
authors.affiliation: Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA.
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.affiliation: Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
mesh_terms: D020295:Brain Stem Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D059472:Exome / Q000235:genetics*; D020869:Gene Expression Profiling; D005910:Glioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D009154:Mutation / Q000235:genetics*; D010749:Phosphoprotein Phosphatases / Q000235:genetics*; D011379:Prognosis; D000071636:Protein Phosphatase 2C; D015996:Survival Rate; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C468783:H2AX protein, human; D006657:Histones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C