Transcriptomic subtyping of malignant peripheral nerve sheath tumours highlights immune signatures, genomic profiles, patient survival and therapeutic targetsResearch in context
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
Affiliations
Maren Høland
Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Institute for Clinical Medicine, University of Oslo, Oslo, Norway
Kaja C.G. Berg
Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
Ina A. Eilertsen
Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
Bodil Bjerkehagen
Institute for Clinical Medicine, University of Oslo, Oslo, Norway; Division of Laboratory Medicine, Department of Pathology, Oslo University Hospital, Oslo, Norway
Matthias Kolberg
Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
Kjetil Boye
Division of Cancer Medicine, Department of Oncology, Oslo University Hospital, Oslo, Norway
Ole Christian Lingjærde
Department of Informatics, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway
Tormod K. Guren
Division of Cancer Medicine, Department of Oncology, Oslo University Hospital, Oslo, Norway
Nils Mandahl
Department of Clinical Genetics, University and Regional Laboratories, Lund University, Lund, Sweden
Eva van den Berg
Department of Genetics, The University Medical Center Groningen, the Netherlands
Emanuela Palmerini
Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
Sigbjørn Smeland
Institute for Clinical Medicine, University of Oslo, Oslo, Norway; Division of Cancer Medicine, Department of Oncology, Oslo University Hospital, Oslo, Norway
Piero Picci
Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
Fredrik Mertens
Department of Clinical Genetics, University and Regional Laboratories, Lund University, Lund, Sweden
Anita Sveen
Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Institute for Clinical Medicine, University of Oslo, Oslo, Norway
Ragnhild A. Lothe
Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Institute for Clinical Medicine, University of Oslo, Oslo, Norway; Corresponding author. P.O. Box 4950 Nydalen, NO-0424, Oslo, Norway.
Summary: 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.
