Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification.

Autor: Keck MK; Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Division of Pediatric Glioma Research (B360), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Sill M; Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Wittmann A; Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Division of Pediatric Glioma Research (B360), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Joshi P; Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Stichel D; Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Beck P; Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany., Okonechnikow K; Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Sievers P; Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Wefers AK; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Roncaroli F; Geoffrey Jefferson Brain Research Centre, Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK., Avula S; Department of Radiology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK., McCabe MG; Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK., Hayden JT; Department of Pediatric Hematology and Oncology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK., Wesseling P; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.; Department of Pathology, Amsterdam University Medical Centers, Location VUmc and Brain Tumor Center Amsterdam, Amsterdam, The Netherlands., Øra I; Department of Pediatric Oncology and Hematology, Skåne University Hospital, Lund University, Lund, Sweden., Nistér M; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Kranendonk MEG; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., Tops BBJ; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., Zapotocky M; Prague Brain Tumor Research Group, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.; Department of Pediatric Haematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic., Zamecnik J; Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic., Vasiljevic A; Institut de Pathologie Multisite-Site Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France., Fenouil T; Institut de Pathologie Multisite-Site Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France., Meyronet D; Institut de Pathologie Multisite-Site Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France., von Hoff K; Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany., Schüller U; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Research Institute Children's Cancer Center Hamburg, Hamburg, Germany., Loiseau H; University of Bordeaux, Bordeaux Institute of Oncology (BRIC)-INSERM U1312 Université de Bordeaux, 146 rue Leo Saignat, Case 76, 33076, Bordeaux, France., Figarella-Branger D; Aix-Marseille Univ, APHM, CNRS, INP, Inst Neurophysiopathol, CHU Timone, Service d'Anatomie Pathologique et de Neuropathologie, Marseille, France., Kramm CM; Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany., Sturm D; Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Division of Pediatric Glioma Research (B360), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, University Hospital Heidelberg, Heidelberg, Germany., Scheie D; Department of Pathology, Rigshospitalet, Copenhagen, Denmark., Rauramaa T; Department of Clinical Pathology, Kuopio University Hospital and Unit of Pathology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland., Pesola J; Department of Pediatrics, Pediatric Hematology and Oncology Ward, Kuopio University Hospital and Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland., Gojo J; Department of Pediatrics and Adolescent Medicine, Comprehensive Cancer Center and Comprehensive Center for Pediatrics, Medical University of Vienna, 1090, Vienna, Austria., Haberler C; Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria., Brandner S; Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London, UK.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London, UK., Jacques T; Department of Developmental Biology and Cancer, UCL GOS Institute of Child Health, University College London, London, UK., Sexton Oates A; Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia., Saffery R; Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia., Koscielniak E; Department of Pediatric Oncology/Hematology/Immunology, Olgahospital, Klinikum Stuttgart, Stuttgart, Germany., Baker SJ; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA., Yip S; Department of Pathology and Laboratory Medicine, The University of British Colombia, Vancouver, Canada., Snuderl M; Department of Pathology, NYU Langone Medical Center, New York, NY, USA., Ud Din N; Department of Pathology and Laboratory Medicine, The Aga Khan University, Karachi, Pakistan., Samuel D; Department of Pediatric Hematology-Oncology, Valley Children's Hospital, Madera, CA, USA., Schramm K; Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Division of Pediatric Glioma Research (B360), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Blattner-Johnson M; Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Division of Pediatric Glioma Research (B360), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany., Selt F; Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Clinical Cooperation Unit Pediatric Oncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.; KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany., Ecker J; Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Clinical Cooperation Unit Pediatric Oncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.; KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany., Milde T; Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Clinical Cooperation Unit Pediatric Oncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.; KiTZ Clinical Trial Unit (ZIPO), Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany., von Deimling A; Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Korshunov A; Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Perry A; Division of Neuropathology, Department of Pathology, University of California San Francisco (UCSF), 513 Parnassus Ave, Health Sciences West 451, San Francisco, CA, 94143, USA., Pfister SM; Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, University Hospital Heidelberg, Heidelberg, Germany., Sahm F; Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.; Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.; Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Solomon DA; Division of Neuropathology, Department of Pathology, University of California San Francisco (UCSF), 513 Parnassus Ave, Health Sciences West 451, San Francisco, CA, 94143, USA. david.solomon@ucsf.edu., Jones DTW; Hopp Children's Cancer Center Heidelberg (KiTZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. david.jones@kitz-heidelberg.de.; Division of Pediatric Glioma Research (B360), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. david.jones@kitz-heidelberg.de.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2023 Jan; Vol. 145 (1), pp. 49-69. Date of Electronic Publication: 2022 Nov 27.
DOI: 10.1007/s00401-022-02516-2
Abstrakt: Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.
(© 2022. The Author(s).)
Databáze: MEDLINE
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