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-CavanaghJennifer 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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

93 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)274-280
Aantal pagina's7
TijdschriftNature
Volume576
Nummer van het tijdschrift7786
DOI's
StatusGepubliceerd - 12 dec. 2019

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