IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v576y2019i7786d10.1038_s41586-019-1815-x.html
   My bibliography  Save this article

The molecular landscape of ETMR at diagnosis and relapse

Author

Listed:
  • Sander Lambo

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ))

  • Susanne N. Gröbner

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ))

  • Tobias Rausch

    (Genome Biology Unit)

  • Sebastian M. Waszak

    (Genome Biology Unit)

  • Christin Schmidt

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ))

  • Aparna Gorthi

    (University of Texas Health at San Antonio
    University of Texas Health at San Antonio)

  • July Carolina Romero

    (University of Texas Health at San Antonio
    University of Texas Health at San Antonio)

  • Monika Mauermann

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ))

  • Sebastian Brabetz

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ))

  • Sonja Krausert

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ))

  • Ivo Buchhalter

    (German Cancer Research Center (DKFZ))

  • Jan Koster

    (Academic Medical Center)

  • Danny A. Zwijnenburg

    (Academic Medical Center)

  • Martin Sill

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ))

  • Jens-Martin Hübner

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ))

  • Norman Mack

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ))

  • Benjamin Schwalm

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ))

  • Marina Ryzhova

    (NN Burdenko Neurosurgical Institute)

  • Volker Hovestadt

    (German Cancer Research Center (DKFZ))

  • Simon Papillon-Cavanagh

    (McGill University Health Center, McGill University)

  • Jennifer A. Chan

    (University of Calgary)

  • Pablo Landgraf

    (Faculty of Medicine and University Hospital Cologne, University of Cologne)

  • Ben Ho

    (The Hospital for Sick Children)

  • Till Milde

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ)
    Heidelberg University Hospital)

  • Olaf Witt

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ)
    Heidelberg University Hospital)

  • Jonas Ecker

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    Heidelberg University Hospital)

  • Felix Sahm

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • David Sumerauer

    (University Hospital Motol)

  • David W. Ellison

    (St Jude Children’s Research Hospital)

  • Brent A. Orr

    (St Jude Children’s Research Hospital)

  • Anna Darabi

    (Lund University)

  • Christine Haberler

    (Medical University of Vienna)

  • Dominique Figarella-Branger

    (Aix-Marseille University, Neurophysiopathology Institute (INP), CNRS
    APHM)

  • Pieter Wesseling

    (Princess Máxima Center for Pediatric Oncology
    Amsterdam University Medical Centers/location VUmc)

  • Jens Schittenhelm

    (University Hospital of Tübingen
    University Hospital of Tübingen)

  • Marc Remke

    (German Cancer Research Center (DKFZ)
    University Hospital Düsseldorf
    University of Toronto)

  • Michael D. Taylor

    (University of Toronto)

  • Maria J. Gil-da-Costa

    (University Hospital São João Alameda Hernani Monteiro)

  • Maria Łastowska

    (Children’s Memorial Health Institute)

  • Wiesława Grajkowska

    (Children’s Memorial Health Institute)

  • Martin Hasselblatt

    (University Hospital Münster)

  • Peter Hauser

    (Semmelweis University)

  • Torsten Pietsch

    (University of Bonn Medical Center)

  • Emmanuelle Uro-Coste

    (Toulouse University Hospital
    INSERM U1037, Cancer Research Center of Toulouse (CRCT))

  • Franck Bourdeaut

    (INSERM U830, Laboratory of Translational Research in Pediatric Oncology, SIREDO Pediatric Oncology Center, Paris Sciences Lettres Research University, Curie Institute)

  • Julien Masliah-Planchon

    (Curie Institute
    Paris Sciences et Lettres Research University, Institut Curie Hospital, Laboratory of Somatic Genetics)

  • Valérie Rigau

    (Montpellier University Medical Center
    INSERM U1051, Montpellier University Hospital)

  • Sanda Alexandrescu

    (Harvard Medical School)

  • Stephan Wolf

    (German Cancer Research Center (DKFZ))

  • Xiao-Nan Li

    (Baylor College of Medicine
    Ann & Robert H. Lurie Children’s Hospital of Chicago
    Northwestern University Feinberg School of Medicine)

  • Ulrich Schüller

    (University Medical Center, Hamburg-Eppendorf
    Research Institute Children’s Cancer Center
    University Medical Center, Hamburg-Eppendorf)

  • Matija Snuderl

    (NYU Langone Health)

  • Matthias A. Karajannis

    (The Stephen D. Hassenfeld Children’s Center for Cancer and Blood Disorders)

  • Felice Giangaspero

    (Sapienza University of Rome
    IRCCS Neuromed-Mediterranean Neurological Institute)

  • Nada Jabado

    (McGill University Health Center, McGill University)

  • Andreas Deimling

    (Hopp Children’s Cancer Center (KiTZ)
    Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • David T. W. Jones

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ))

  • Jan O. Korbel

    (Genome Biology Unit)

  • Katja Hoff

    (Charité University Medicine
    University Hospital Hamburg-Eppendorf)

  • Peter Lichter

    (German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ))

  • Annie Huang

    (The Hospital for Sick Children
    University of Toronto)

  • Alexander J. R. Bishop

    (University of Texas Health at San Antonio
    University of Texas Health at San Antonio
    University of Texas Health at San Antonio)

  • Stefan M. Pfister

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ)
    Heidelberg University Hospital)

  • Andrey Korshunov

    (Heidelberg University Hospital
    German Cancer Research Center (DKFZ))

  • Marcel Kool

    (Hopp Children’s Cancer Center (KiTZ)
    German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ))

Abstract

Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis1. 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 C19MC2–4 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.

Suggested Citation

  • Sander Lambo & Susanne N. Gröbner & Tobias Rausch & Sebastian M. Waszak & Christin Schmidt & Aparna Gorthi & July Carolina Romero & Monika Mauermann & Sebastian Brabetz & Sonja Krausert & Ivo Buchhalt, 2019. "The molecular landscape of ETMR at diagnosis and relapse," Nature, Nature, vol. 576(7786), pages 274-280, December.
  • Handle: RePEc:nat:nature:v:576:y:2019:i:7786:d:10.1038_s41586-019-1815-x
    DOI: 10.1038/s41586-019-1815-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-019-1815-x
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/s41586-019-1815-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Felix K. F. Kommoss & Anne-Sophie Chong & Anne-Laure Chong & Elke Pfaff & David T. W. Jones & Laura S. Hiemcke-Jiwa & Lennart A. Kester & Uta Flucke & Manfred Gessler & Daniel Schrimpf & Felix Sahm & , 2023. "Genomic characterization of DICER1-associated neoplasms uncovers molecular classes," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:576:y:2019:i:7786:d:10.1038_s41586-019-1815-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.