Lambo, Sander, Groebner, Susanne N., Rausch, Tobias ORCID: 0000-0001-5773-5620, Waszak, Sebastian M., Schmidt, Christin, Gorthi, Aparna, Romero, July Carolina, Mauermann, Monika, Brabetz, Sebastian, Krausert, Sonja, Buchhalter, Ivo, Koster, Jan, Zwijnenburg, Danny A., Sill, Martin, Huebner, Jens-Martin, Mack, Norman, Schwalm, Benjamin, Ryzhova, Marina ORCID: 0000-0001-7206-6365, Hovestadt, Volker, Papillon-Cavanagh, Simon ORCID: 0000-0002-0372-2266, Chan, Jennifer A., Landgraf, Pablo, Ho, Ben, Milde, Till, Witt, Olaf, Ecker, Jonas, Sahm, Felix ORCID: 0000-0001-5441-1962, Sumerauer, David, Ellison, David W., Orr, Brent A., Darabi, Anna, Haberler, Christine, Figarella-Branger, Dominique, Wesseling, Pieter, Schittenhelm, Jens, Remke, Marc, Taylor, Michael D., Gil-da-Costa, Maria J., Lastowska, Maria, Grajkowska, Wieslawa, Hasselblatt, Martin, Hauser, Peter, Pietsch, Torsten, Uro-Coste, Emmanuelle, Bourdeaut, Franck, Masliah-Planchon, Julien, Rigau, Valerie, Alexandrescu, Sanda, Wolf, Stephan, Li, Xiao-Nan, Schuller, Ulrich, Snuderl, Matija ORCID: 0000-0003-0752-0917, Karajannis, Matthias A., Giangaspero, Felice, Jabado, Nada, von Deimling, Andreas ORCID: 0000-0002-5863-540X, Jones, David T. W., Korbel, Jan O., von Hoff, Katja, Lichter, Peter, Huang, Annie, Bishop, Alexander J. R., Pfister, Stefan M., Korshunov, Andrey ORCID: 0000-0002-5257-3623 and Kool, Marcel (2019). The molecular landscape of ETMR at diagnosis and relapse. Nature, 576 (7786). S. 274 - 300. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4687

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Abstract

Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis(1). 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(2-4) 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lambo, SanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Groebner, Susanne N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rausch, TobiasUNSPECIFIEDorcid.org/0000-0001-5773-5620UNSPECIFIED
Waszak, Sebastian M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, ChristinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gorthi, AparnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Romero, July CarolinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mauermann, MonikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brabetz, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krausert, SonjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buchhalter, IvoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koster, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zwijnenburg, Danny A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sill, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huebner, Jens-MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mack, NormanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwalm, BenjaminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ryzhova, MarinaUNSPECIFIEDorcid.org/0000-0001-7206-6365UNSPECIFIED
Hovestadt, VolkerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Papillon-Cavanagh, SimonUNSPECIFIEDorcid.org/0000-0002-0372-2266UNSPECIFIED
Chan, Jennifer A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Landgraf, PabloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ho, BenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Milde, TillUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witt, OlafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ecker, JonasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sahm, FelixUNSPECIFIEDorcid.org/0000-0001-5441-1962UNSPECIFIED
Sumerauer, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ellison, David W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Orr, Brent A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Darabi, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haberler, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Figarella-Branger, DominiqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wesseling, PieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schittenhelm, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Remke, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Taylor, Michael D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gil-da-Costa, Maria J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lastowska, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grajkowska, WieslawaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hasselblatt, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hauser, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pietsch, TorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uro-Coste, EmmanuelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bourdeaut, FranckUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Masliah-Planchon, JulienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rigau, ValerieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alexandrescu, SandaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, Xiao-NanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schuller, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Snuderl, MatijaUNSPECIFIEDorcid.org/0000-0003-0752-0917UNSPECIFIED
Karajannis, Matthias A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giangaspero, FeliceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jabado, NadaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Deimling, AndreasUNSPECIFIEDorcid.org/0000-0002-5863-540XUNSPECIFIED
Jones, David T. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Korbel, Jan O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Hoff, KatjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lichter, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huang, AnnieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bishop, Alexander J. R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfister, Stefan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Korshunov, AndreyUNSPECIFIEDorcid.org/0000-0002-5257-3623UNSPECIFIED
Kool, MarcelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-124498
DOI: 10.1038/s41586-019-1815-x
Journal or Publication Title: Nature
Volume: 576
Number: 7786
Page Range: S. 274 - 300
Date: 2019
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-4687
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DNA-DAMAGE; ABUNDANT NEUROPIL; EMBRYONAL TUMOR; R-LOOPS; RNA; MEDULLOBLASTOMA; EXPRESSION; DICER1; CLASSIFICATION; CHROMOTHRIPSISMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/12449

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