Publication

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

Holand, M., Kolberg, M., Danielsen, S. A., Bjerkehagen, B., Eilertsen, I. A., Hektoen, M., Mandahl, N., van den Berg, E., Smeland, S., Mertens, F., Hall, K. S., Picci, P., Sveen, A. & Lothe, R. A., Nov-2018, In : Modern Pathology. 31, 11, p. 1694-1707 14 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Holand, M., Kolberg, M., Danielsen, S. A., Bjerkehagen, B., Eilertsen, I. A., Hektoen, M., Mandahl, N., van den Berg, E., Smeland, S., Mertens, F., Hall, K. S., Picci, P., Sveen, A., & Lothe, R. A. (2018). Inferior survival for patients with malignant peripheral nerve sheath tumors defined by aberrant TP53. Modern Pathology, 31(11), 1694-1707. https://doi.org/10.1038/s41379-018-0074-y

Author

Holand, Maren ; Kolberg, Matthias ; Danielsen, Stine Aske ; Bjerkehagen, Bodil ; Eilertsen, Ina A. ; Hektoen, Merete ; Mandahl, Nils ; van den Berg, Eva ; Smeland, Sigbjorn ; Mertens, Fredrik ; Hall, Kirsten Sundby ; 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.

Harvard

Holand, M, Kolberg, M, Danielsen, SA, Bjerkehagen, B, Eilertsen, IA, Hektoen, M, Mandahl, N, van den Berg, E, Smeland, S, Mertens, F, Hall, KS, 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

Standard

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

In: Modern Pathology, Vol. 31, No. 11, 11.2018, p. 1694-1707.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Holand M, Kolberg M, Danielsen SA, Bjerkehagen B, Eilertsen IA, Hektoen M et al. Inferior survival for patients with malignant peripheral nerve sheath tumors defined by aberrant TP53. Modern Pathology. 2018 Nov;31(11):1694-1707. https://doi.org/10.1038/s41379-018-0074-y


BibTeX

@article{f119609d59e949e7850115e115315784,
title = "Inferior survival for patients with malignant peripheral nerve sheath tumors defined by aberrant TP53",
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, suggestin g a common {"}P53-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.",
keywords = "COPY NUMBER VARIATION, NEUROFIBROMATOSIS TYPE-1, GENE OCCUR, P53, CANCER, METHYLATION, EXPRESSION, MUTATIONS, TRANSFORMATION, INACTIVATION",
author = "Maren Holand and Matthias Kolberg and Danielsen, {Stine Aske} and Bodil Bjerkehagen and Eilertsen, {Ina A.} and Merete Hektoen and Nils Mandahl and {van den Berg}, Eva and Sigbjorn Smeland and Fredrik Mertens and Hall, {Kirsten Sundby} and Piero Picci and Anita Sveen and Lothe, {Ragnhild A.}",
year = "2018",
month = nov,
doi = "10.1038/s41379-018-0074-y",
language = "English",
volume = "31",
pages = "1694--1707",
journal = "Modern Pathology",
issn = "0893-3952",
publisher = "Nature Publishing Group",
number = "11",

}

RIS

TY - JOUR

T1 - Inferior survival for patients with malignant peripheral nerve sheath tumors defined by aberrant TP53

AU - Holand, Maren

AU - Kolberg, Matthias

AU - Danielsen, Stine Aske

AU - Bjerkehagen, Bodil

AU - Eilertsen, Ina A.

AU - Hektoen, Merete

AU - Mandahl, Nils

AU - van den Berg, Eva

AU - Smeland, Sigbjorn

AU - Mertens, Fredrik

AU - Hall, Kirsten Sundby

AU - Picci, Piero

AU - Sveen, Anita

AU - Lothe, Ragnhild A.

PY - 2018/11

Y1 - 2018/11

N2 - 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, suggestin g a common "P53-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.

AB - 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, suggestin g a common "P53-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.

KW - COPY NUMBER VARIATION

KW - NEUROFIBROMATOSIS TYPE-1

KW - GENE OCCUR

KW - P53

KW - CANCER

KW - METHYLATION

KW - EXPRESSION

KW - MUTATIONS

KW - TRANSFORMATION

KW - INACTIVATION

U2 - 10.1038/s41379-018-0074-y

DO - 10.1038/s41379-018-0074-y

M3 - Article

VL - 31

SP - 1694

EP - 1707

JO - Modern Pathology

JF - Modern Pathology

SN - 0893-3952

IS - 11

ER -

ID: 67392609