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Nature
12, 2019;576 (7786): 274-280.

The molecular landscape of ETMR at diagnosis and relapse.

Sander Lambo, Susanne N Gröbner, Tobias Rausch, Sebastian M Waszak, Christin Schmidt, Aparna Gorthi, July Carolina Romero, Monika Mauermann, Sebastian Brabetz, Sonja Krausert, Ivo Buchhalter, Jan Koster, Danny A Zwijnenburg, Martin Sill, Jens-Martin Hübner, Norman Mack, Benjamin Schwalm, Marina Ryzhova, Volker Hovestadt, Simon Papillon-Cavanagh, Jennifer A Chan, Pablo Landgraf, Ben Ho, Till Milde, Olaf Witt, Jonas Ecker, Felix Sahm, David Sumerauer, David W Ellison, Brent A Orr, Anna Darabi, Christine Haberler, Dominique Figarella-Branger, Pieter Wesseling, Jens Schittenhelm, Marc Remke, Michael D Taylor, Maria J Gil-da-Costa, Maria Łastowska, Wiesława Grajkowska, Martin Hasselblatt, Peter Hauser, Torsten Pietsch, Emmanuelle Uro-Coste, Franck Bourdeaut, Julien Masliah-Planchon, Valérie Rigau, Sanda Alexandrescu, Stephan Wolf, Xiao-Nan Li, Ulrich Schüller, Matija Snuderl, Matthias A Karajannis, Felice Giangaspero, Nada Jabado, Andreas von Deimling, David T W Jones, Jan O Korbel, Katja von Hoff, Peter Lichter, Annie Huang, Alexander J R Bishop, Stefan M Pfister, Andrey Korshunov, Marcel Kool
Author Information
  1. Sander Lambo: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  2. Susanne N Gröbner: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  3. Tobias Rausch: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
  4. Sebastian M Waszak: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
  5. Christin Schmidt: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  6. Aparna Gorthi: Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, USA.
  7. July Carolina Romero: Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, USA.
  8. Monika Mauermann: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  9. Sebastian Brabetz: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  10. Sonja Krausert: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  11. Ivo Buchhalter: Omics IT and Data Management Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  12. Jan Koster: Department of Oncogenomics, Academic Medical Center, Amsterdam, The Netherlands.
  13. Danny A Zwijnenburg: Department of Oncogenomics, Academic Medical Center, Amsterdam, The Netherlands.
  14. Martin Sill: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  15. Jens-Martin Hübner: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  16. Norman Mack: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  17. Benjamin Schwalm: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  18. Marina Ryzhova: Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow, Russia.
  19. Volker Hovestadt: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  20. Simon Papillon-Cavanagh: Department of Pediatrics, McGill University Health Center, McGill University, Montreal, Quebec, Canada.
  21. Jennifer A Chan: Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
  22. Pablo Landgraf: Department of Pediatrics, Pediatric Oncology and Hematology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  23. Ben Ho: Division of Hematology/Oncology Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
  24. Till Milde: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  25. Olaf Witt: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  26. Jonas Ecker: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  27. Felix Sahm: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  28. David Sumerauer: Department of Pediatric Hematology and Oncology, University Hospital Motol, Prague, Czech Republic.
  29. David W Ellison: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
  30. Brent A Orr: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
  31. Anna Darabi: Department of Clinical Sciences Lund, Section of Neurosurgery, Faculty of Medicine, Lund University, Lund, Sweden.
  32. Christine Haberler: Institute of Neurology, Medical University of Vienna, Vienna, Austria.
  33. Dominique Figarella-Branger: Aix-Marseille University, Neurophysiopathology Institute (INP), CNRS, Marseille, France.
  34. Pieter Wesseling: Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
  35. Jens Schittenhelm: Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tübingen, Tübingen, Germany.
  36. Marc Remke: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  37. Michael D Taylor: Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  38. Maria J Gil-da-Costa: Pediatric Hematology and Oncology Division, University Hospital São João Alameda Hernani Monteiro, Porto, Portugal.
  39. Maria Łastowska: Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland.
  40. Wiesława Grajkowska: Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland.
  41. Martin Hasselblatt: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
  42. Peter Hauser: 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
  43. Torsten Pietsch: Institute of Neuropathology, Brain Tumor Reference Center of the German Society of Neuropathology and Neuroanatomy, University of Bonn Medical Center, Bonn, Germany.
  44. Emmanuelle Uro-Coste: Department of Pathology, Toulouse University Hospital, Toulouse, France.
  45. Franck Bourdeaut: INSERM U830, Laboratory of Translational Research in Pediatric Oncology, SIREDO Pediatric Oncology Center, Paris Sciences Lettres Research University, Curie Institute, Paris, France.
  46. Julien Masliah-Planchon: Pediatric Oncology Department, SIREDO Pediatric Oncology Centre, Curie Institute, Paris, France.
  47. Valérie Rigau: Department of Pathology, Montpellier University Medical Center, Montpellier, France.
  48. Sanda Alexandrescu: Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  49. Stephan Wolf: Genomics and Proteomics Core Facility, High Throughput Sequencing Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  50. Xiao-Nan Li: Brain Tumor Program, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
  51. Ulrich Schüller: Institute of Neuropathology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
  52. Matija Snuderl: Department of Pathology, NYU Langone Health, New York, NY, USA.
  53. Matthias A Karajannis: Division of Pediatric Hematology/Oncology, NYU Langone Medical Center, The Stephen D. Hassenfeld Children's Center for Cancer and Blood Disorders, New York, NY, USA.
  54. Felice Giangaspero: Department of Radiological, Oncological and Anatomopathological Sciences, Sapienza University of Rome, Rome, Italy.
  55. Nada Jabado: Department of Pediatrics, McGill University Health Center, McGill University, Montreal, Quebec, Canada.
  56. Andreas von Deimling: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  57. David T W Jones: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  58. Jan O Korbel: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
  59. Katja von Hoff: Department of Pediatric Oncology/Hematology, Charité University Medicine, Berlin, Germany.
  60. Peter Lichter: German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  61. Annie Huang: Division of Hematology/Oncology Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
  62. Alexander J R Bishop: Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, USA.
  63. Stefan M Pfister: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  64. Andrey Korshunov: Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.
  65. Marcel Kool: Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany. m.kool@dkfz.de.
PMID: 31802000 DOI: 10.1038/s41586-019-1815-x

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.

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Grants

  1. R15 ES019128/NIEHS NIH HHS
  2. TL1 TR002647/NCATS NIH HHS
  3. T32 CA148724/NCI NIH HHS
  4. P30 CA054174/NCI NIH HHS
  5. K22 ES012264/NIEHS NIH HHS
  6. R01 CA152063/NCI NIH HHS

MeSH Term

DEAD-box RNA Helicases
DNA Topoisomerases, Type I
Humans
MicroRNAs
Mutation
Neoplasms, Germ Cell and Embryonal
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases
Polymorphism, Single Nucleotide
RNA, Long Noncoding
Recurrence
Ribonuclease III

Chemicals

MIR17HG, human
MicroRNAs
Poly(ADP-ribose) Polymerase Inhibitors
RNA, Long Noncoding
Poly(ADP-ribose) Polymerases
DICER1 protein, human
Ribonuclease III
DEAD-box RNA Helicases
DNA Topoisomerases, Type I
TOP1 protein, human
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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