The molecular landscape of ETMR at diagnosis and relapse

  • Nature. 2019 Dec;576(7786):274-280. doi: 10.1038/s41586-019-1815-x.
Sander Lambo  1  2  3 ,  Susanne N Gröbner  1  2  3 ,  Tobias Rausch  4 ,  Sebastian M Waszak  4 ,  Christin Schmidt  1  2  3 ,  Aparna Gorthi  5  6 ,  July Carolina Romero  5  6 ,  Monika Mauermann  1  2  3 ,  Sebastian Brabetz  1  2  3 ,  Sonja Krausert  1  2  3 ,  Ivo Buchhalter  7 ,  Jan Koster  8 ,  Danny A Zwijnenburg  8 ,  Martin Sill  1  2  3 ,  Jens-Martin Hübner  1  2  3 ,  Norman Mack  1  2  3 ,  Benjamin Schwalm  1  2  3 ,  Marina Ryzhova  9 ,  Volker Hovestadt  10 ,  Simon Papillon-Cavanagh  11 ,  Jennifer A Chan  12 ,  Pablo Landgraf  13 ,  Ben Ho  14 ,  Till Milde  1  3  15  16 ,  Olaf Witt  1  3  15  16 ,  Jonas Ecker  1  15  16 ,  Felix Sahm  1  3  17  18 ,  David Sumerauer  19 ,  David W Ellison  20 ,  Brent A Orr  20 ,  Anna Darabi  21 ,  Christine Haberler  22 ,  Dominique Figarella-Branger  23  24 ,  Pieter Wesseling  25  26 ,  Jens Schittenhelm  27  28 ,  Marc Remke  3  29  30 ,  Michael D Taylor  30 ,  Maria J Gil-da-Costa  31 ,  Maria Łastowska  32 ,  Wiesława Grajkowska  32 ,  Martin Hasselblatt  33 ,  Peter Hauser  34 ,  Torsten Pietsch  35 ,  Emmanuelle Uro-Coste  36  37 ,  Franck Bourdeaut  38 ,  Julien Masliah-Planchon  39  40 ,  Valérie Rigau  41  42 ,  Sanda Alexandrescu  43 ,  Stephan Wolf  44 ,  Xiao-Nan Li  45  46  47 ,  Ulrich Schüller  48  49  50 ,  Matija Snuderl  51 ,  Matthias A Karajannis  52 ,  Felice Giangaspero  53  54 ,  Nada Jabado  11 ,  Andreas von Deimling  1  17  18 ,  David T W Jones  1  3  55 ,  Jan O Korbel  4 ,  Katja von Hoff  56  57 ,  Peter Lichter  3  10 ,  Annie Huang  14  58 ,  Alexander J R Bishop  5  6  59 ,  Stefan M Pfister  1  2  3  16 ,  Andrey Korshunov  17  18 ,  Marcel Kool  60  61  62
Affiliations
  • 1. Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  • 2. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 3. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 4. European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
  • 5. Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, USA.
  • 6. Greehey Children's Cancer Research Institute, University of Texas Health at San Antonio, San Antonio, TX, USA.
  • 7. Omics IT and Data Management Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 8. Department of Oncogenomics, Academic Medical Center, Amsterdam, The Netherlands.
  • 9. Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow, Russia.
  • 10. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 11. Department of Pediatrics, McGill University Health Center, McGill University, Montreal, Quebec, Canada.
  • 12. Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
  • 13. Department of Pediatrics, Pediatric Oncology and Hematology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • 14. Division of Hematology/Oncology Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 15. Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 16. Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
  • 17. Department of Neuropathology, Heidelberg University Hospital, Heidelberg, Germany.
  • 18. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 19. Department of Pediatric Hematology and Oncology, University Hospital Motol, Prague, Czech Republic.
  • 20. Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 21. Department of Clinical Sciences Lund, Section of Neurosurgery, Faculty of Medicine, Lund University, Lund, Sweden.
  • 22. Institute of Neurology, Medical University of Vienna, Vienna, Austria.
  • 23. Aix-Marseille University, Neurophysiopathology Institute (INP), CNRS, Marseille, France.
  • 24. Department of Pathology, APHM, Marseille, France.
  • 25. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
  • 26. Department of Pathology, Amsterdam University Medical Centers/location VUmc, Amsterdam, The Netherlands.
  • 27. Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tübingen, Tübingen, Germany.
  • 28. Center for CNS Tumors, Comprehensive Cancer Center Tübingen-Stuttgart, University Hospital of Tübingen, Tübingen, Germany.
  • 29. Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.
  • 30. Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • 31. Pediatric Hematology and Oncology Division, University Hospital São João Alameda Hernani Monteiro, Porto, Portugal.
  • 32. Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland.
  • 33. Institute of Neuropathology, University Hospital Münster, Münster, Germany.
  • 34. 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
  • 35. Institute of Neuropathology, Brain Tumor Reference Center of the German Society of Neuropathology and Neuroanatomy, University of Bonn Medical Center, Bonn, Germany.
  • 36. Department of Pathology, Toulouse University Hospital, Toulouse, France.
  • 37. INSERM U1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France.
  • 38. INSERM U830, Laboratory of Translational Research in Pediatric Oncology, SIREDO Pediatric Oncology Center, Paris Sciences Lettres Research University, Curie Institute, Paris, France.
  • 39. Pediatric Oncology Department, SIREDO Pediatric Oncology Centre, Curie Institute, Paris, France.
  • 40. Paris Sciences et Lettres Research University, Institut Curie Hospital, Laboratory of Somatic Genetics, Paris, France.
  • 41. Department of Pathology, Montpellier University Medical Center, Montpellier, France.
  • 42. Institute for Neuroscience of Montpellier (INM), INSERM U1051, Montpellier University Hospital, Montpellier, France.
  • 43. Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 44. Genomics and Proteomics Core Facility, High Throughput Sequencing Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 45. Brain Tumor Program, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
  • 46. Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
  • 47. Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 48. Institute of Neuropathology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
  • 49. Research Institute Children's Cancer Center, Hamburg, Germany.
  • 50. Department of Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
  • 51. Department of Pathology, NYU Langone Health, New York, NY, USA.
  • 52. 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.
  • 53. Department of Radiological, Oncological and Anatomopathological Sciences, Sapienza University of Rome, Rome, Italy.
  • 54. IRCCS Neuromed-Mediterranean Neurological Institute, Pozzilli, Italy.
  • 55. Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 56. Department of Pediatric Oncology/Hematology, Charité University Medicine, Berlin, Germany.
  • 57. Department for Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
  • 58. Department of Pediatrics, Medical Biophysics, Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
  • 59. Mays Cancer Center, University of Texas Health at San Antonio, San Antonio, TX, USA.
  • 60. Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany. [email protected].
  • 61. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].
  • 62. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].
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 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.

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