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  • Høland, MarenOslo university hospital,University of Oslo (author)

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

  • Article/chapterEnglish2023

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  • 2023

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  • LIBRIS-ID:oai:lup.lub.lu.se:5056eb72-33dd-4481-909f-fcc2d5517817
  • https://lup.lub.lu.se/record/5056eb72-33dd-4481-909f-fcc2d5517817URI
  • https://doi.org/10.1016/j.ebiom.2023.104829DOI

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  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

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  • 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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  • Berg, Kaja C.G.Oslo university hospital (author)
  • Eilertsen, Ina A.Oslo university hospital (author)
  • Bjerkehagen, BodilOslo university hospital,University of Oslo (author)
  • Kolberg, MatthiasOslo university hospital (author)
  • Boye, KjetilOslo university hospital (author)
  • Lingjærde, Ole ChristianUniversity of Oslo (author)
  • Guren, Tormod K.Oslo university hospital (author)
  • Mandahl, NilsLund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,Genetiska avvikelser i mjukdelstumörer,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine,The genetics of soft tissue tumors,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments(Swepub:lu)kgen-nma (author)
  • van den Berg, EvaUniversity Medical Center Groningen (author)
  • Palmerini, EmanuelaRizzoli Orthopedic Institute (author)
  • Smeland, SigbjørnOslo university hospital,University of Oslo (author)
  • Picci, PieroRizzoli Orthopedic Institute (author)
  • Mertens, FredrikLund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,Genetiska avvikelser i mjukdelstumörer,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine,The genetics of soft tissue tumors,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments(Swepub:lu)kgen-fme (author)
  • Sveen, AnitaOslo university hospital,University of Oslo (author)
  • Lothe, Ragnhild A.Oslo university hospital,University of Oslo (author)
  • Oslo university hospitalUniversity of Oslo (creator_code:org_t)

Related titles

  • In:EBioMedicine972352-3964

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