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    Nature. 2019 Dec 4. doi: 10.1038/s41586-019-1815-x. pii: 10.1038/s41586-019-1815-x
    The molecular landscape of ETMR at diagnosis and relapse.
    Lambo S1,  Gröbner SN2,  Rausch T3,  Waszak SM4,  Schmidt C5,  Gorthi A6,  Romero JC7,  Mauermann M8,  Brabetz S9,  Krausert S10,  Buchhalter I11,  Koster J12,  Zwijnenburg DA13,  Sill M14,  Hübner JM15,  Mack N16,  Schwalm B17,  Ryzhova M18,  Hovestadt V19,  Papillon-Cavanagh S20,  Chan JA21,  Landgraf P22,  Ho B23,  Milde T24,  Witt O25,  Ecker J26,  Sahm F27,  Sumerauer D28,  Ellison DW29,  Orr BA30,  Darabi A31,  Haberler C32,  Figarella-Branger D33,  Wesseling P34,  Schittenhelm J35,  Remke M36,  Taylor MD37,  Gil-da-Costa MJ38,  Łastowska M39,  Grajkowska W40,  Hasselblatt M41,  Hauser P42,  Pietsch T43,  Uro-Coste E44,  Bourdeaut F45,  Masliah-Planchon J46,  Rigau V47,  Alexandrescu S48,  Wolf S49,  Li XN50,  Schüller U51,  Snuderl M52,  Karajannis MA53,  Giangaspero F54,  Jabado N55,  von Deimling A56,  Jones DTW57,  Korbel JO58,  von Hoff K59,  Lichter P60,  Huang A61,  Bishop AJR62,  Pfister SM63,  Korshunov A64,  Kool M65
    Author information
    1Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    2Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    3European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
    4European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
    5Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    6Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, USA.
    7Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, USA.
    8Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    9Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    10Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    11Omics IT and Data Management Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    12Department of Oncogenomics, Academic Medical Center, Amsterdam, The Netherlands.
    13Department of Oncogenomics, Academic Medical Center, Amsterdam, The Netherlands.
    14Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    15Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    16Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    17Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    18Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow, Russia.
    19Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    20Department of Pediatrics, McGill University Health Center, McGill University, Montreal, Quebec, Canada.
    21Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
    22Department of Pediatrics, Pediatric Oncology and Hematology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
    23Division of Hematology/Oncology Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
    24Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    25Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    26Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    27Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    28Department of Pediatric Hematology and Oncology, University Hospital Motol, Prague, Czech Republic.
    29Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
    30Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
    31Department of Clinical Sciences Lund, Section of Neurosurgery, Faculty of Medicine, Lund University, Lund, Sweden.
    32Institute of Neurology, Medical University of Vienna, Vienna, Austria.
    33Aix-Marseille University, Neurophysiopathology Institute (INP), CNRS, Marseille, France.
    34Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
    35Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tübingen, Tübingen, Germany.
    36German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
    37Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
    38Pediatric Hematology and Oncology Division, University Hospital São João Alameda Hernani Monteiro, Porto, Portugal.
    39Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland.
    40Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland.
    41Institute of Neuropathology, University Hospital Münster, Münster, Germany.
    422nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
    43Institute of Neuropathology, Brain Tumor Reference Center of the German Society of Neuropathology and Neuroanatomy, University of Bonn Medical Center, Bonn, Germany.
    44Department of Pathology, Toulouse University Hospital, Toulouse, France.
    45INSERM U830, Laboratory of Translational Research in Pediatric Oncology, SIREDO Pediatric Oncology Center, Paris Sciences Lettres Research University, Curie Institute, Paris, France.
    46Pediatric Oncology Department, SIREDO Pediatric Oncology Centre, Curie Institute, Paris, France.
    47Department of Pathology, Montpellier University Medical Center, Montpellier, France.
    48Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
    49Genomics and Proteomics Core Facility, High Throughput Sequencing Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    50Brain Tumor Program, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
    51Institute of Neuropathology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
    52Department of Pathology, NYU Langone Health, New York, NY, USA.
    53Division of Pediatric Hematology/Oncology, NYU Langone Medical Center, The Stephen D. Hassenfeld Children's Center for Cancer and Blood Disorders, New York, NY, USA.
    54Department of Radiological, Oncological and Anatomopathological Sciences, Sapienza University of Rome, Rome, Italy.
    55Department of Pediatrics, McGill University Health Center, McGill University, Montreal, Quebec, Canada.
    56Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    57Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    58European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
    59Department of Pediatric Oncology/Hematology, Charité University Medicine, Berlin, Germany.
    60German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
    61Division of Hematology/Oncology Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
    62Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, USA.
    63Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
    64Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.
    65Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany. m.kool@dkfz.de.
    Abstract

    Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis. Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.


    Publikations ID: 31802000
    Quelle: öffnen
     
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