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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 LU ; van Den Berg, Eva; Smeland, Sigbjørn and Mertens, Fredrik LU , et al. (2018) In Modern Pathology p.1-14
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... (More)

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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Modern Pathology
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14 pages
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Nature Publishing Group
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  • scopus:85049092760
ISSN
0893-3952
DOI
10.1038/s41379-018-0074-y
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English
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yes
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5b805635-0d68-49a3-8886-50dd5330cbeb
date added to LUP
2018-07-09 13:14:52
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2018-07-10 03:00:05
@article{5b805635-0d68-49a3-8886-50dd5330cbeb,
  abstract     = {<p>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.</p>},
  author       = {Høland, Maren and Kolberg, Matthias and Danielsen, Stine Aske and Bjerkehagen, Bodil and Eilertsen, Ina A. and Hektoen, Merete and Mandahl, Nils and van Den Berg, Eva and Smeland, Sigbjørn and Mertens, Fredrik and Sundby Hall, Kirsten and Picci, Piero and Sveen, Anita and Lothe, Ragnhild A.},
  issn         = {0893-3952},
  language     = {eng},
  month        = {06},
  pages        = {1--14},
  publisher    = {Nature Publishing Group},
  series       = {Modern Pathology},
  title        = {Inferior survival for patients with malignant peripheral nerve sheath tumors defined by aberrant TP53},
  url          = {http://dx.doi.org/10.1038/s41379-018-0074-y},
  year         = {2018},
}