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-Cavanagh; Jennifer 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

doi:10.1038/s41586-019-1815-x

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

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

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 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.

Original language	English (US)
Pages (from-to)	274-280
Number of pages	7
Journal	Nature
Volume	576
Issue number	7786
DOIs	https://doi.org/10.1038/s41586-019-1815-x
State	Published - Dec 12 2019
Externally published	Yes

ASJC Scopus subject areas

General

Access to Document

10.1038/s41586-019-1815-x

Cite this

Lambo, S., Gröbner, S. N., Rausch, T., Waszak, S. M., Schmidt, C., Gorthi, A., Romero, J. C., Mauermann, M., Brabetz, S., Krausert, S., Buchhalter, I., Koster, J., Zwijnenburg, D. A., Sill, M., Hübner, J. M., Mack, N., Schwalm, B., Ryzhova, M., Hovestadt, V., ... Kool, M. (2019). The molecular landscape of ETMR at diagnosis and relapse. Nature, 576(7786), 274-280. https://doi.org/10.1038/s41586-019-1815-x

Lambo, S, Gröbner, SN, Rausch, T, Waszak, SM, Schmidt, C, Gorthi, A, Romero, JC, Mauermann, M, Brabetz, S, Krausert, S, Buchhalter, I, Koster, J, Zwijnenburg, DA, Sill, M, Hübner, JM, Mack, N, Schwalm, B, Ryzhova, M, Hovestadt, V, Papillon-Cavanagh, S, Chan, JA, Landgraf, P, Ho, B, Milde, T, Witt, O, Ecker, J, Sahm, F, Sumerauer, D, Ellison, DW, Orr, BA, Darabi, A, Haberler, C, Figarella-Branger, D, Wesseling, P, Schittenhelm, J, Remke, M, Taylor, MD, Gil-da-Costa, MJ, Łastowska, M, Grajkowska, W, Hasselblatt, M, Hauser, P, Pietsch, T, Uro-Coste, E, Bourdeaut, F, Masliah-Planchon, J, Rigau, V, Alexandrescu, S, Wolf, S, Li, XN, Schüller, U, Snuderl, M, Karajannis, MA, Giangaspero, F, Jabado, N, von Deimling, A, Jones, DTW, Korbel, JO, von Hoff, K, Lichter, P, Huang, A, Bishop, AJR, Pfister, SM, Korshunov, A & Kool, M 2019, 'The molecular landscape of ETMR at diagnosis and relapse', Nature, vol. 576, no. 7786, pp. 274-280. https://doi.org/10.1038/s41586-019-1815-x

@article{94d3fe85368649e283d5a270a30ac4ea,

title = "The molecular landscape of ETMR at diagnosis and relapse",

abstract = "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.",

author = "Sander Lambo and Gr{\"o}bner, {Susanne N.} and Tobias Rausch and Waszak, {Sebastian M.} and Christin Schmidt and Aparna Gorthi and Romero, {July Carolina} and Monika Mauermann and Sebastian Brabetz and Sonja Krausert and Ivo Buchhalter and Jan Koster and Zwijnenburg, {Danny A.} and Martin Sill and H{\"u}bner, {Jens Martin} and Norman Mack and Benjamin Schwalm and Marina Ryzhova and Volker Hovestadt and Simon Papillon-Cavanagh and Chan, {Jennifer A.} and Pablo Landgraf and Ben Ho and Till Milde and Olaf Witt and Jonas Ecker and Felix Sahm and David Sumerauer and Ellison, {David W.} and Orr, {Brent A.} and Anna Darabi and Christine Haberler and Dominique Figarella-Branger and Pieter Wesseling and Jens Schittenhelm and Marc Remke and Taylor, {Michael D.} and Gil-da-Costa, {Maria J.} and Maria {\L}astowska and Wies{\l}awa Grajkowska and Martin Hasselblatt and Peter Hauser and Torsten Pietsch and Emmanuelle Uro-Coste and Franck Bourdeaut and Julien Masliah-Planchon and Val{\'e}rie Rigau and Sanda Alexandrescu and Stephan Wolf and Li, {Xiao Nan} and Ulrich Sch{\"u}ller and Matija Snuderl and Karajannis, {Matthias A.} and Felice Giangaspero and Nada Jabado and {von Deimling}, Andreas and Jones, {David T.W.} and Korbel, {Jan O.} and {von Hoff}, Katja and Peter Lichter and Annie Huang and Bishop, {Alexander J.R.} and Pfister, {Stefan M.} and Andrey Korshunov and Marcel Kool",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2019",

month = dec,

day = "12",

doi = "10.1038/s41586-019-1815-x",

language = "English (US)",

volume = "576",

pages = "274--280",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7786",

}

TY - JOUR

T1 - The molecular landscape of ETMR at diagnosis and relapse

AU - Lambo, Sander

AU - Gröbner, Susanne N.

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

PY - 2019/12/12

Y1 - 2019/12/12

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85076033900&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85076033900&partnerID=8YFLogxK

U2 - 10.1038/s41586-019-1815-x

DO - 10.1038/s41586-019-1815-x

M3 - Article

C2 - 31802000

AN - SCOPUS:85076033900

SN - 0028-0836

VL - 576

SP - 274

EP - 280

JO - Nature

JF - Nature

IS - 7786

ER -

The molecular landscape of ETMR at diagnosis and relapse

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this