TY  - JOUR
AU  - Lambo, Sander
AU  - Gröbner, Susanne
AU  - Rausch, Tobias
AU  - Waszak, Sebastian M
AU  - Schmidt, Christin
AU  - Gorthi, Aparna
AU  - Romero, July Carolina
AU  - Mauermann, Monika
AU  - Brabetz, Sebastian
AU  - Krausert, Sonja
AU  - Buchhalter, Ivo
AU  - Koster, Jan
AU  - Zwijnenburg, Danny A
AU  - Sill, Martin
AU  - Hübner, Jens-Martin
AU  - Mack, Norman
AU  - Schwalm, Benjamin
AU  - Ryzhova, Marina
AU  - Hovestadt, Volker
AU  - Papillon-Cavanagh, Simon
AU  - Chan, Jennifer A
AU  - Landgraf, Pablo
AU  - Ho, Ben
AU  - Milde, Till
AU  - Witt, Olaf
AU  - Ecker, Jonas
AU  - Sahm, Felix
AU  - Sumerauer, David
AU  - Ellison, David W
AU  - Orr, Brent A
AU  - Darabi, Anna
AU  - Haberler, Christine
AU  - Figarella-Branger, Dominique
AU  - Wesseling, Pieter
AU  - Schittenhelm, Jens
AU  - Remke, Marc
AU  - Taylor, Michael D
AU  - Gil-da-Costa, Maria J
AU  - Łastowska, Maria
AU  - Grajkowska, Wiesława
AU  - Hasselblatt, Martin
AU  - Hauser, Peter
AU  - Pietsch, Torsten
AU  - Uro-Coste, Emmanuelle
AU  - Bourdeaut, Franck
AU  - Masliah-Planchon, Julien
AU  - Rigau, Valérie
AU  - Alexandrescu, Sanda
AU  - Wolf, Stephan
AU  - Li, Xiao-Nan
AU  - Schüller, Ulrich
AU  - Snuderl, Matija
AU  - Karajannis, Matthias A
AU  - Giangaspero, Felice
AU  - Jabado, Nada
AU  - von Deimling, Andreas
AU  - Jones, David T W
AU  - Korbel, Jan O
AU  - von Hoff, Katja
AU  - Lichter, Peter
AU  - Huang, Annie
AU  - Bishop, Alexander J R
AU  - Pfister, Stefan M
AU  - Korshunov, Andrey
AU  - Kool, Marcel
TI  - The molecular landscape of ETMR at diagnosis and relapse.
JO  - Nature 
VL  - 576
IS  - 7786
SN  - 1476-4687
CY  - London [u.a.]
PB  - Nature Publ. Group52462
M1  - DKFZ-2019-02880
SP  - 274-280
PY  - 2019
N1  - #EA:B062#LA:B062#2019 Dec;576(7786):274-280
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:31802000
DO  - DOI:10.1038/s41586-019-1815-x
UR  - https://inrepo02.dkfz.de/record/148322
ER  -