The molecular landscape of ETMR at diagnosis and relapse

Sander Lambo; Susanne Gröbner; Tobias Rausch; Sebastian Waszak; Christin Schmidt; Aparna Gorthi; July Carolina Romero; Monika Mauermann; Sebastian Brabetz; Sonja Krausert; Ivo Buchhalter; Jan Koster; Danny Zwijnenburg; Martin Sill; Jens-Martin Hübner; Norman Mack; Benjamin Schwalm; Marina Ryzhova; Volker Hovestadt; Simon Papillon-Cavanagh; Jennifer Chan; Pablo Landgraf; Ben Ho; Till Milde; Olaf Witt; Jonas Ecker; Felix Sahm; David Sumerauer; David Ellison; Brent Orr; Anna Darabi; Christine Haberler; Dominique Figarella-Branger; Pieter Wesseling; Jens Schittenhelm; Marc Remke; Michael Taylor; Maria Gil-Da-Costa; Maria Łastowska; Wiesława Grajkowska; Martin Hasselblatt; Peter Hauser; Torsten T Pietsch; Emmanuelle Uro-Coste; Franck Bourdeaut; Julien Masliah-Planchon; Valérie Rigau; Sanda Alexandrescu; Stephan Wolf; Xiao-Nan Li; Ulrich Schüller; Matija Snuderl; Matthias Karajannis; Felice Giangaspero; Nada Jabado; Andreas von Deimling; David Jones; Jan Korbel; Katja von Hoff; Peter Lichter; Annie Huang; Alexander Bishop; Stefan Pfister; Andrey Korshunov; Marcel Kool

doi:10.1038/s41586-019-1815-x

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The molecular landscape of ETMR at diagnosis and relapse

Journal article

Open access

Peer reviewed

The molecular landscape of ETMR at diagnosis and relapse

Sander Lambo, Susanne Gröbner, Tobias Rausch, Sebastian Waszak, Christin Schmidt, Aparna Gorthi, July Carolina Romero, Monika Mauermann, Sebastian Brabetz, Sonja Krausert, …

Nature, Vol.576(7786), pp.274-280

12/2019

DOI: https://doi.org/10.1038/s41586-019-1815-x

PMCID: PMC6908757

Abstract

Cancer genetics

Cancer genomics

CNS cancer

Genomic instability

miRNAs

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 C19MC2,3,4 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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Title: The molecular landscape of ETMR at diagnosis and relapse
Creators - without role: Sander Lambo - Heidelberg University
Susanne Gröbner - German Cancer Research Center
Tobias Rausch - European Molecular Biology Laboratory
Sebastian Waszak - European Molecular Biology Laboratory
Christin Schmidt - German Cancer Research Center
Aparna Gorthi - The University of Texas Health Science Center at San Antonio
July Carolina Romero - The University of Texas at San Antonio
Monika Mauermann - German Cancer Research Center
Sebastian Brabetz - Heidelberg University
Sonja Krausert - German Cancer Research Center
Ivo Buchhalter - German Cancer Research Center
Jan Koster - Academic Medical Center
Danny Zwijnenburg - Academic Medical Center
Martin Sill - German Cancer Research Center
Jens-Martin Hübner - Heidelberg University
Norman Mack - German Cancer Research Center
Benjamin Schwalm - German Cancer Research Center
Marina Ryzhova - Burdenko Neurosurgery Institute
Volker Hovestadt - German Cancer Research Center
Simon Papillon-Cavanagh - McGill University
Jennifer Chan - University of Calgary
Pablo Landgraf - University Hospital Cologne
Ben Ho - Hospital for Sick Children
Till Milde - German Cancer Research Center
Olaf Witt - German Cancer Research Center
Jonas Ecker - Hopp Children's Cancer Center Heidelberg
Felix Sahm - Heidelberg University
David Sumerauer - University Hospital in Motol
David Ellison - St. Jude Children's Research Hospital
Brent Orr - St. Jude Children's Research Hospital
Anna Darabi - Lund University
Christine Haberler - Medical University of Vienna
Dominique Figarella-Branger - Centre National de la Recherche Scientifique
Pieter Wesseling - Princess Máxima Center
Jens Schittenhelm
Marc Remke - German Cancer Research Center
Michael Taylor - University of Toronto
Maria Gil-Da-Costa - Hospital de São João
Maria Łastowska - Children's Memorial Health Institute
Wiesława Grajkowska - Children's Memorial Health Institute
Martin Hasselblatt - University Hospital Münster
Peter Hauser - Semmelweis University
Torsten T Pietsch - Life & Brain
Emmanuelle Uro-Coste - Université de Toulouse
Franck Bourdeaut - Inserm
Julien Masliah-Planchon - Institut Curie
Valérie Rigau - Université de Montpellier, Institut des Neurosciences de Montpellier - INM
Sanda Alexandrescu - Harvard University
Stephan Wolf - Heidelberg University
Xiao-Nan Li - Lurie Children's Hospital
Ulrich Schüller - Universität Hamburg
Matija Snuderl - NYU Langone Health
Matthias Karajannis - Center for Cancer and Blood Disorders
Felice Giangaspero - Istituto Neurologico Mediterraneo
Nada Jabado - McGill University
Andreas von Deimling - Hopp Children's Cancer Center Heidelberg
David Jones - Heidelberg University
Jan Korbel - European Molecular Biology Laboratory
Katja von Hoff - Charité - Universitätsmedizin Berlin
Peter Lichter - German Cancer Research Center
Annie Huang - Hospital for Sick Children
Alexander Bishop
Stefan Pfister - German Cancer Research Center
Andrey Korshunov - Heidelberg University
Marcel Kool - Hopp Children's Cancer Center Heidelberg
Publication Details: Nature, Vol.576(7786), pp.274-280
Identifiers: 9941440209311
Academic Unit: Institut des Neurosciences de Montpellier - INM
Language: English
Resource Type: Journal article
Local Fields: hal-02441051