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

Maren Høland; Kaja C G Berg; Ina A Eilertsen; Bodil Bjerkehagen; Matthias Kolberg; Kjetil Boye; Ole Christian Lingjærde; Tormod K Guren; Nils Mandahl; Eva van den Berg; Emanuela Palmerini; Sigbjørn Smeland; Piero Picci; Fredrik Mertens; Anita Sveen; Ragnhild A Lothe

doi:10.1016/j.ebiom.2023.104829

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

EBioMedicine. 2023 Nov:97:104829. doi: 10.1016/j.ebiom.2023.104829. Epub 2023 Oct 12.

Authors

Maren Høland¹, Kaja C G Berg², Ina A Eilertsen², Bodil Bjerkehagen³, Matthias Kolberg², Kjetil Boye⁴, Ole Christian Lingjærde⁵, Tormod K Guren⁴, Nils Mandahl⁶, Eva van den Berg⁷, Emanuela Palmerini⁸, Sigbjørn Smeland⁹, Piero Picci¹⁰, Fredrik Mertens⁶, Anita Sveen¹, Ragnhild A Lothe¹¹

Affiliations

¹ Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
² Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
³ Institute for Clinical Medicine, University of Oslo, Oslo, Norway; Division of Laboratory Medicine, Department of Pathology, Oslo University Hospital, Oslo, Norway.
⁴ Division of Cancer Medicine, Department of Oncology, Oslo University Hospital, Oslo, Norway.
⁵ Department of Informatics, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
⁶ Department of Clinical Genetics, University and Regional Laboratories, Lund University, Lund, Sweden.
⁷ Department of Genetics, The University Medical Center Groningen, the Netherlands.
⁸ Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
⁹ Institute for Clinical Medicine, University of Oslo, Oslo, Norway; Division of Cancer Medicine, Department of Oncology, Oslo University Hospital, Oslo, Norway.
¹⁰ Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
¹¹ Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Institute for Clinical Medicine, University of Oslo, Oslo, Norway. Electronic address: rlothe@rr-research.no.

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 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.

Keywords: DNA copy number aberrations; Data integration; MPNST; Prognosis; Transcriptomic subtypes.

Publication types

Multicenter Study

MeSH terms

Adolescent
DNA
Genomics
Humans
Nerve Sheath Neoplasms* / diagnosis
Nerve Sheath Neoplasms* / genetics
Nerve Sheath Neoplasms* / metabolism
Neurofibroma* / genetics
Neurofibroma* / pathology
Neurofibrosarcoma*
Transcriptome
Young Adult

Substances

DNA