Inferior survival for patients with malignant peripheral nerve sheath tumors defined by aberrant TP53

Maren Høland, Matthias Kolberg, Stine Aske Danielsen, Bodil Bjerkehagen, Ina A. Eilertsen, Merete Hektoen, Nils Mandahl, Eva van den Berg, Sigbjørn Smeland, Fredrik Mertens, Kirsten Sundby Hall, Piero Picci, Anita Sveen, Ragnhild A. Lothe

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1694-1707
Number of pages14
JournalModern Pathology
Volume31
Issue number11
DOIs
StatePublished - Nov 1 2018

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Neurilemmoma
Survival
Loss of Heterozygosity
p53 Genes
Phenotype
Confidence Intervals
Neurofibroma
Neoplasms
Mutation
Gene Expression Profiling
Rare Diseases
Point Mutation
Young Adult
Biomarkers
Gene Expression
Therapeutics
Genes
Proteins

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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Inferior survival for patients with malignant peripheral nerve sheath tumors defined by aberrant TP53. / Høland, Maren; Kolberg, Matthias; Danielsen, Stine Aske; Bjerkehagen, Bodil; Eilertsen, Ina A.; Hektoen, Merete; Mandahl, Nils; van den Berg, Eva; Smeland, Sigbjørn; Mertens, Fredrik; Sundby Hall, Kirsten; Picci, Piero; Sveen, Anita; Lothe, Ragnhild A.

In: Modern Pathology, Vol. 31, No. 11, 01.11.2018, p. 1694-1707.

Research output: Contribution to journalArticle

Høland, M, Kolberg, M, Danielsen, SA, Bjerkehagen, B, Eilertsen, IA, Hektoen, M, Mandahl, N, van den Berg, E, Smeland, S, Mertens, F, Sundby Hall, K, Picci, P, Sveen, A & Lothe, RA 2018, 'Inferior survival for patients with malignant peripheral nerve sheath tumors defined by aberrant TP53', Modern Pathology, vol. 31, no. 11, pp. 1694-1707. https://doi.org/10.1038/s41379-018-0074-y
Høland, Maren ; Kolberg, Matthias ; Danielsen, Stine Aske ; Bjerkehagen, Bodil ; Eilertsen, Ina A. ; Hektoen, Merete ; Mandahl, Nils ; van den Berg, Eva ; Smeland, Sigbjørn ; Mertens, Fredrik ; Sundby Hall, Kirsten ; Picci, Piero ; Sveen, Anita ; Lothe, Ragnhild A. / Inferior survival for patients with malignant peripheral nerve sheath tumors defined by aberrant TP53. In: Modern Pathology. 2018 ; Vol. 31, No. 11. pp. 1694-1707.
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abstract = "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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AU - Eilertsen, Ina A.

AU - Hektoen, Merete

AU - Mandahl, Nils

AU - van den Berg, Eva

AU - Smeland, Sigbjørn

AU - Mertens, Fredrik

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AU - Picci, Piero

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AU - Lothe, Ragnhild A.

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