Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

The molecular landscape of ETMR at diagnosis and relapse

Lambo, Sander ; Darabi, Anna LU and Kool, Marcel (2019) In Nature 576. p.274-280
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
; and
author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature
volume
576
pages
7 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85076033900
  • pmid:31802000
ISSN
0028-0836
DOI
10.1038/s41586-019-1815-x
language
English
LU publication?
yes
id
9216e425-2680-45c0-9d51-3a51782769ee
date added to LUP
2020-01-02 11:21:18
date last changed
2022-04-18 19:33:32
@article{9216e425-2680-45c0-9d51-3a51782769ee,
  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       = {{Lambo, Sander and Darabi, Anna and Kool, Marcel}},
  issn         = {{0028-0836}},
  language     = {{eng}},
  month        = {{12}},
  pages        = {{274--280}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature}},
  title        = {{The molecular landscape of ETMR at diagnosis and relapse}},
  url          = {{http://dx.doi.org/10.1038/s41586-019-1815-x}},
  doi          = {{10.1038/s41586-019-1815-x}},
  volume       = {{576}},
  year         = {{2019}},
}