Malignant peripheral nerve sheath tumor is a rare and aggressive disease with poor treatment response, mainly affecting adolescents and young adults. Few molecular biomarkers are used in the management of this cancer type, and although TP53 is one of few recurrently mutated genes in malignant peripheral nerve sheath tumor, the mutation prevalence and the corresponding clinical value of the TP53 network remains unsettled. We present a multi-level molecular study focused on aberrations in the TP53 network in relation to patient outcome in a series of malignant peripheral nerve sheath tumors from 100 patients and 38 neurofibromas, including TP53 sequencing, high-resolution copy number analyses of TP53 and MDM2, and gene expression profiling. Point mutations in TP53 were accompanied by loss of heterozygosity, resulting in complete loss of protein function in 8.2% of the malignant peripheral nerve sheath tumors. Another 5.5% had MDM2 amplification. TP53 mutation and MDM2 amplification were mutually exclusive and patients with either type of aberration in their tumor had a worse prognosis, compared to those without (hazard ratio for 5-year disease-specific survival 3.5, 95% confidence interval 1.78–6.98). Both aberrations had similar consequences on the gene expression level, as analyzed by a TP53-associated gene signature, a property also shared with the copy number aberrations and/or loss of heterozygosity at the TP53 locus, suggesting a common “TP53-mutated phenotype” in as many as 60% of the tumors. This was a poor prognostic phenotype (hazard ratio = 4.1, confidence interval:1.7–9.8), thus revealing a TP53-non-aberrant patient subgroup with a favorable outcome. The frequency of the “TP53-mutated phenotype” warrants explorative studies of stratified treatment strategies in malignant peripheral nerve sheath tumor.

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We are grateful to Mette Eknæs at the Department of Molecular Oncology (Oslo University Hospital) for excellent technical assistance.


This study was supported by the Norwegian Cancer Society (project number 6824048-2016 to AS and project number 72190-PR-2006-0442 to RAL), the Southern and Eastern Norway Regional Health Authority (RAL), the foundation “Stiftelsen Kristian Gerhard Jebsen”, and the Research Council of Norway.

Author information


  1. Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway

    • Maren Høland
    • , Matthias Kolberg
    • , Stine Aske Danielsen
    • , Ina A. Eilertsen
    • , Merete Hektoen
    • , Anita Sveen
    •  & Ragnhild A. Lothe
  2. Institute for Clinical Medicine, University of Oslo, Oslo, Norway

    • Maren Høland
    • , Sigbjørn Smeland
    •  & Ragnhild A. Lothe
  3. Department of Oral Biology, University of Oslo, Oslo, Norway

    • Bodil Bjerkehagen
  4. Department of Pathology, Division of Laboratory Medicine, Oslo University Hospital, Oslo, Norway

    • Bodil Bjerkehagen
  5. Department of Clinical Genetics, University and Regional Laboratories, Lund University, Lund, Sweden

    • Nils Mandahl
    •  & Fredrik Mertens
  6. Department of Genetics, The University Medical Center Groningen, Groningen, The Netherlands

    • Eva van den Berg
  7. Department of Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway

    • Sigbjørn Smeland
    •  & Kirsten Sundby Hall
  8. Laboratory of Experimental Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy

    • Piero Picci


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Correspondence to Ragnhild A. Lothe.

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