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Transcriptomic subtyping of malignant peripheral nerve sheath tumours highlights immune signatures, genomic profiles, patient survival and therapeutic targets

Høland, Maren ; Berg, Kaja C.G. ; Eilertsen, Ina A. ; Bjerkehagen, Bodil ; Kolberg, Matthias ; Boye, Kjetil ; Lingjærde, Ole Christian ; Guren, Tormod K. ; Mandahl, Nils LU and van den Berg, Eva , et al. (2023) In EBioMedicine 97.
Abstract

Background: Malignant peripheral nerve sheath tumour (MPNST) is an aggressive orphan disease commonly affecting adolescents or young adults. Current knowledge of molecular tumour biology has been insufficient for development of rational treatment strategies. We aimed to discover molecular subtypes of potential clinical relevance. Methods: Fresh frozen samples of MPNSTs (n = 94) and benign neurofibromas (n = 28) from 115 patients in a European multicentre study were analysed by DNA copy number and/or transcriptomic profiling. Unsupervised transcriptomic subtyping was performed and the subtypes characterized for genomic aberrations, clinicopathological associations and patient survival. Findings: MPNSTs were classified into two... (More)

Background: Malignant peripheral nerve sheath tumour (MPNST) is an aggressive orphan disease commonly affecting adolescents or young adults. Current knowledge of molecular tumour biology has been insufficient for development of rational treatment strategies. We aimed to discover molecular subtypes of potential clinical relevance. Methods: Fresh frozen samples of MPNSTs (n = 94) and benign neurofibromas (n = 28) from 115 patients in a European multicentre study were analysed by DNA copy number and/or transcriptomic profiling. Unsupervised transcriptomic subtyping was performed and the subtypes characterized for genomic aberrations, clinicopathological associations and patient survival. Findings: MPNSTs were classified into two transcriptomic subtypes defined primarily by immune signatures and proliferative processes. “Immune active” MPNSTs (44%) had sustained immune signals relative to neurofibromas, were more frequently low-grade (P = 0.01) and had favourable prognostic associations in a multivariable model of disease-specific survival with clinicopathological factors (hazard ratio 0.25, P = 0.003). “Immune deficient” MPNSTs were more aggressive and characterized by proliferative signatures, high genomic complexity, aberrant TP53 and PRC2 loss, as well as high relative expression of several potential actionable targets (EGFR, ERBB2, EZH2, KIF11, PLK1, RRM2). Integrated gene-wise analyses suggested a DNA copy number-basis for proliferative transcriptomic signatures in particular, and the tumour copy number burden further stratified the transcriptomic subtypes according to patient prognosis (P < 0.01). Interpretation: Approximately half of MPNSTs belong to an “immune deficient” transcriptomic subtype associated with an aggressive disease course, PRC2 loss and expression of several potential therapeutic targets, providing a rationale for molecularly-guided intervention trials. Funding: Research grants from non-profit organizations, as stated in the Acknowledgements.

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type
Contribution to journal
publication status
published
subject
keywords
Data integration, DNA copy number aberrations, MPNST, Prognosis, Transcriptomic subtypes
in
EBioMedicine
volume
97
article number
104829
publisher
Elsevier
external identifiers
  • pmid:37837931
  • scopus:85173544949
ISSN
2352-3964
DOI
10.1016/j.ebiom.2023.104829
language
English
LU publication?
yes
id
5056eb72-33dd-4481-909f-fcc2d5517817
date added to LUP
2023-12-05 14:42:47
date last changed
2024-04-18 10:24:10
@article{5056eb72-33dd-4481-909f-fcc2d5517817,
  abstract     = {{<p>Background: Malignant peripheral nerve sheath tumour (MPNST) is an aggressive orphan disease commonly affecting adolescents or young adults. Current knowledge of molecular tumour biology has been insufficient for development of rational treatment strategies. We aimed to discover molecular subtypes of potential clinical relevance. Methods: Fresh frozen samples of MPNSTs (n = 94) and benign neurofibromas (n = 28) from 115 patients in a European multicentre study were analysed by DNA copy number and/or transcriptomic profiling. Unsupervised transcriptomic subtyping was performed and the subtypes characterized for genomic aberrations, clinicopathological associations and patient survival. Findings: MPNSTs were classified into two transcriptomic subtypes defined primarily by immune signatures and proliferative processes. “Immune active” MPNSTs (44%) had sustained immune signals relative to neurofibromas, were more frequently low-grade (P = 0.01) and had favourable prognostic associations in a multivariable model of disease-specific survival with clinicopathological factors (hazard ratio 0.25, P = 0.003). “Immune deficient” MPNSTs were more aggressive and characterized by proliferative signatures, high genomic complexity, aberrant TP53 and PRC2 loss, as well as high relative expression of several potential actionable targets (EGFR, ERBB2, EZH2, KIF11, PLK1, RRM2). Integrated gene-wise analyses suggested a DNA copy number-basis for proliferative transcriptomic signatures in particular, and the tumour copy number burden further stratified the transcriptomic subtypes according to patient prognosis (P &lt; 0.01). Interpretation: Approximately half of MPNSTs belong to an “immune deficient” transcriptomic subtype associated with an aggressive disease course, PRC2 loss and expression of several potential therapeutic targets, providing a rationale for molecularly-guided intervention trials. Funding: Research grants from non-profit organizations, as stated in the Acknowledgements.</p>}},
  author       = {{Høland, Maren and Berg, Kaja C.G. and Eilertsen, Ina A. and Bjerkehagen, Bodil and Kolberg, Matthias and Boye, Kjetil and Lingjærde, Ole Christian and Guren, Tormod K. and Mandahl, Nils and van den Berg, Eva and Palmerini, Emanuela and Smeland, Sigbjørn and Picci, Piero and Mertens, Fredrik and Sveen, Anita and Lothe, Ragnhild A.}},
  issn         = {{2352-3964}},
  keywords     = {{Data integration; DNA copy number aberrations; MPNST; Prognosis; Transcriptomic subtypes}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{EBioMedicine}},
  title        = {{Transcriptomic subtyping of malignant peripheral nerve sheath tumours highlights immune signatures, genomic profiles, patient survival and therapeutic targets}},
  url          = {{http://dx.doi.org/10.1016/j.ebiom.2023.104829}},
  doi          = {{10.1016/j.ebiom.2023.104829}},
  volume       = {{97}},
  year         = {{2023}},
}