Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors
Por:
Sievers P, Henneken SC, Blume C, Sill M, Schrimpf D, Stichel D, Okonechnikov K, Reuss DE, Benzel J, Maaß KK, Kool M, Sturm D, Zheng T, Ghasemi DR, Kohlhof-Meinecke P, Cruz-Martínez O, Suñol M, Lavarino C, Ruf V, Boldt HB, Pagès M, Pouget C, Schweizer L, Kranendonk MEG, Akhtar N, Bunkowski S, Stadelmann C, Schüller U, Mueller WC, Dohmen H, Acker T, Harter PN, Mawrin C, Beschorner R, Brandner S, Snuderl M, Abdullaev Z, Aldape K, Gilbert MR, Armstrong TS, Ellison DW, Capper D, Ichimura K, Reifenberger G, Grundy RG, Jabado N, Krskova L, Zapotocky M, Vicha A, Varlet P, Wesseling P, Rutkowski S, Korshunov A, Wick W, Pfister SM, Jones DTW, von Deimling A, Pajtler KW and Sahm F
Publicada:
1 nov 2021
Ahead of Print:
1 ago 2021
Resumen:
Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
Filiaciones:
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
Henneken SC:
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Blume C:
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
Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), Heidelberg, Germany
Sill M:
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Schrimpf 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
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
Okonechnikov K:
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Reuss DE:
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
Benzel J:
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Maaß KK:
Hopp Children's Cancer Center Heidelberg (KiTZ), 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
Kool M:
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Sturm D:
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, University Hospital Heidelberg, Heidelberg, Germany
Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
Zheng T:
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Faculty of Biosciences, Heidelberg University, 69117, Heidelberg, Germany
Ghasemi DR:
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Kohlhof-Meinecke P:
Department of Pathology, Klinikum Stuttgart, Stuttgart, Germany
Cruz-Martínez O:
Department of Pediatric Oncology, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Suñol M:
Department of Pathology, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Lavarino C:
Laboratory of Molecular Oncology, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Ruf V:
Institute of Neuropathology, Ludwig-Maximilian University, Munich, Germany
Boldt HB:
Department of Pathology, Odense University Hospital, Odense, Denmark
Department of Clinical Research, University of Southern Denmark, Odense, Denmark
Pagès M:
Department of Neuropathology, GHU Paris Psychiatry and Neurosciences, Sainte-Anne Hospital, Paris, France
Laboratory of Translational Research in Pediatric Oncology, SIREDO, INSERM U830, Institut Curie, Paris Sciences Lettres University, Paris, France
Pouget C:
Department of Pathology, CHRU, Nancy, France
Schweizer L:
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Neuropathology, Berlin, Germany
German Cancer Consortium (DKTK), partner site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
Kranendonk MEG:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
Akhtar N:
Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, UK
Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan
Bunkowski S:
Institute for Neuropathology, University Medical Centre Göttingen, Göttingen, Germany
Stadelmann C:
Institute for Neuropathology, University Medical Centre Göttingen, Göttingen, 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
Mueller WC:
Paul-Flechsig Institute of Neuropathology, University Hospital and Faculty of Medicine, Leipzig, Germany
Dohmen H:
Institute of Neuropathology, University of Giessen, Giessen, Germany
Acker T:
Institute of Neuropathology, University of Giessen, Giessen, Germany
Harter PN:
Frankfurt Cancer Institute (FCI), University Hospital, Goethe University Frankfurt am Main, Frankfurt am Main, Germany
Institute of Neurology (Edinger-Institute), University Hospital, Goethe University Frankfurt am Main, Frankfurt am Main, Germany
German Cancer Consortium (DKTK), Partner site Frankfurt/Mainz, Frankfurt am Main, Germany
German Cancer Research Center (DKFZ), Heidelberg, Germany
Mawrin C:
Department of Neuropathology, Otto-Von-Guericke University, Magdeburg, Germany
Beschorner R:
Department of Neuropathology, University of Tübingen, Tübingen, Germany
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
Snuderl M:
Department of Pathology, NYU Langone Medical Center, New York, NY, USA
Abdullaev Z:
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Aldape K:
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Gilbert MR:
Neuro-Oncology Branch, National Cancer Institute, Bethesda, MD, USA
Armstrong TS:
Neuro-Oncology Branch, National Cancer Institute, Bethesda, MD, USA
Ellison DW:
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
Capper D:
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Neuropathology, Berlin, Germany
German Cancer Consortium (DKTK), partner site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
Ichimura K:
Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
Reifenberger G:
Institute of Neuropathology, Heinrich Heine University, Düsseldorf, Germany
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen/Düsseldorf, Germany
Grundy RG:
Children's Brain Tumour Research Centre, University of Nottingham, Nottingham, UK
Jabado N:
Department of Human Genetics, McGill University, Montreal, QC, H3A 1B1, Canada
Department of Pediatrics, McGill University, Montreal, QC, H4A 3J1, Canada
The Research Institute of the McGill University Health Center, Montreal, QC, H4A 3J1, Canada
Krskova L:
Prague Brain Tumor Research Group, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
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
Vicha A:
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
Varlet P:
Department of Neuropathology, GHU Paris Psychiatry and Neurosciences, Sainte-Anne Hospital, Paris, France
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
Rutkowski S:
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Korshunov 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
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Wick W:
Clinical Cooperation Unit Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany
Pfister SM:
Hopp Children's Cancer Center Heidelberg (KiTZ), 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
Jones DTW:
Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), 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
Pajtler KW:
Hopp Children's Cancer Center Heidelberg (KiTZ), 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:
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.
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