000148322 001__ 148322 000148322 005__ 20240229112700.0 000148322 0247_ $$2doi$$a10.1038/s41586-019-1815-x 000148322 0247_ $$2pmid$$apmid:31802000 000148322 0247_ $$2ISSN$$a0028-0836 000148322 0247_ $$2ISSN$$a1476-4687 000148322 0247_ $$2altmetric$$aaltmetric:72054371 000148322 037__ $$aDKFZ-2019-02880 000148322 041__ $$aeng 000148322 082__ $$a500 000148322 1001_ $$0P:(DE-He78)b84967c4f073b71405404f3719c788cd$$aLambo, Sander$$b0$$eFirst author 000148322 245__ $$aThe molecular landscape of ETMR at diagnosis and relapse. 000148322 260__ $$aLondon [u.a.]$$bNature Publ. Group52462$$c2019 000148322 3367_ $$2DRIVER$$aarticle 000148322 3367_ $$2DataCite$$aOutput Types/Journal article 000148322 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1607597412_23614 000148322 3367_ $$2BibTeX$$aARTICLE 000148322 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000148322 3367_ $$00$$2EndNote$$aJournal Article 000148322 500__ $$a#EA:B062#LA:B062#2019 Dec;576(7786):274-280 000148322 520__ $$aEmbryonal 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. 000148322 536__ $$0G:(DE-HGF)POF3-312$$a312 - Functional and structural genomics (POF3-312)$$cPOF3-312$$fPOF III$$x0 000148322 588__ $$aDataset connected to CrossRef, PubMed, 000148322 7001_ $$0P:(DE-He78)932918ed0e8d8790a81235528019a8e0$$aGröbner, Susanne$$b1 000148322 7001_ $$aRausch, Tobias$$b2 000148322 7001_ $$aWaszak, Sebastian M$$b3 000148322 7001_ $$aSchmidt, Christin$$b4 000148322 7001_ $$aGorthi, Aparna$$b5 000148322 7001_ $$aRomero, July Carolina$$b6 000148322 7001_ $$0P:(DE-He78)c865b84c0142dfa1def7dfeb70302918$$aMauermann, Monika$$b7 000148322 7001_ $$0P:(DE-He78)b0b3740107f746e09dc23fdf25eb0629$$aBrabetz, Sebastian$$b8 000148322 7001_ $$0P:(DE-He78)6e11760c6fdd0c35cd056cf36243ecd5$$aKrausert, Sonja$$b9 000148322 7001_ $$0P:(DE-He78)e84b3187ddd3529f884082e30f228c66$$aBuchhalter, Ivo$$b10 000148322 7001_ $$aKoster, Jan$$b11 000148322 7001_ $$aZwijnenburg, Danny A$$b12 000148322 7001_ $$0P:(DE-He78)45440b44791309bd4b7dbb4f73333f9b$$aSill, Martin$$b13 000148322 7001_ $$0P:(DE-He78)a8c698e0904394407c5261932915daa5$$aHübner, Jens-Martin$$b14 000148322 7001_ $$0P:(DE-He78)e73a0a4fab40344d89d693cbe1df3109$$aMack, Norman$$b15 000148322 7001_ $$0P:(DE-He78)9ce969bf1ac7913b3f2b1cf4dd7f823e$$aSchwalm, Benjamin$$b16 000148322 7001_ $$aRyzhova, Marina$$b17 000148322 7001_ $$0P:(DE-He78)744146d3b5a3df1e0ac555e5bf1ee5cc$$aHovestadt, Volker$$b18 000148322 7001_ $$aPapillon-Cavanagh, Simon$$b19 000148322 7001_ $$aChan, Jennifer A$$b20 000148322 7001_ $$aLandgraf, Pablo$$b21 000148322 7001_ $$aHo, Ben$$b22 000148322 7001_ $$0P:(DE-He78)0be2f86573954f87e97f8a4dbb05cb0f$$aMilde, Till$$b23 000148322 7001_ $$0P:(DE-He78)143af26de9d57bf624771616318aaf7c$$aWitt, Olaf$$b24 000148322 7001_ $$0P:(DE-He78)3de637452ba900e2bdd359b8f41953bf$$aEcker, Jonas$$b25 000148322 7001_ $$0P:(DE-He78)a1f4b408b9155beb2a8f7cba4d04fe88$$aSahm, Felix$$b26 000148322 7001_ $$aSumerauer, David$$b27 000148322 7001_ $$aEllison, David W$$b28 000148322 7001_ $$aOrr, Brent A$$b29 000148322 7001_ $$aDarabi, Anna$$b30 000148322 7001_ $$aHaberler, Christine$$b31 000148322 7001_ $$aFigarella-Branger, Dominique$$b32 000148322 7001_ $$aWesseling, Pieter$$b33 000148322 7001_ $$aSchittenhelm, Jens$$b34 000148322 7001_ $$0P:(DE-He78)a244aa021112b9002419791434bbc71c$$aRemke, Marc$$b35$$udkfz 000148322 7001_ $$aTaylor, Michael D$$b36 000148322 7001_ $$aGil-da-Costa, Maria J$$b37 000148322 7001_ $$aŁastowska, Maria$$b38 000148322 7001_ $$aGrajkowska, Wiesława$$b39 000148322 7001_ $$aHasselblatt, Martin$$b40 000148322 7001_ $$aHauser, Peter$$b41 000148322 7001_ $$aPietsch, Torsten$$b42 000148322 7001_ $$aUro-Coste, Emmanuelle$$b43 000148322 7001_ $$aBourdeaut, Franck$$b44 000148322 7001_ $$aMasliah-Planchon, Julien$$b45 000148322 7001_ $$aRigau, Valérie$$b46 000148322 7001_ $$aAlexandrescu, Sanda$$b47 000148322 7001_ 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