Topoisomerase-IIα is upregulated in malignant peripheral nerve sheath tumors and associated with clinical outcome

Rolf I. Skotheim, Anne Kallioniemi, Bodil Bjerkhagen, Fredrik Mertens, Helge R. Brekke, Outi Monni, Spyro Mousses, Nils Mandahl, Gunnar Soeter, Jahn M. Nesland, Sigbjorn Smeland, Olli Kallioniemi, Ragnhild, A. Lothe

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Abstract

Purpose: To identify target genes of clinical significance for patients with malignant peripheral-nerve sheath tumor (MPNST), an aggressive cancer for which no consensus therapy exists.

Materials and Methods: Biopsies and clinical data from 51 patients with MPNST were included in this study. Based on our previous research implicating chromosome arm 17q amplification in MPNST, we performed gene expression analyses of 14 MPNSTs using chromosome 17–specific cDNA microarrays. Copy numbers of selected gene probes and centromere probes were then determined by interphase fluorescence in situ hybridization in 16 MPNSTs. Finally, we generated a tissue microarray containing 79 samples from 44 MPNSTs, on which in situ protein expressions of candidate genes were examined and related to clinical end points.

Results: Among several deregulated genes found by cDNA microarray analyses, topoisomerase IIα (TOP2A) was the most overexpressed gene in MPNSTs compared with benign neurofibromas. Excess copies of the TOP2A were also seen at the DNA level in 10 of 16 cases, and high expression of the TOP2A protein was seen in 83% of the tumors on the tissue microarray. The TOP2A-expressing tumors were associated with poor cancer-specific survival and presence of metastases.

Conclusion: We have identified TOP2A as a target gene in MPNST, using a focused gene expression profiling followed by a DNA copy number evaluation and clinical validation of the encoded protein using a tissue microarray. This study is the first to suggest that TOP2A expression may be a predictive factor for adverse outcome in MPNST.
Original languageEnglish
Pages (from-to)4586-4591
JournalJournal of Clinical Oncology
Volume21
Issue number24
DOIs
Publication statusPublished - 2003
MoE publication typeA1 Journal article-refereed

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Type II DNA Topoisomerase
Neurilemmoma
Oligonucleotide Array Sequence Analysis
Genes
Neoplasms
Chromosomes
Gene Expression
Neurofibroma
Gene Dosage
Centromere
DNA
Interphase
Gene Expression Profiling
Microarray Analysis
Fluorescence In Situ Hybridization
Proteins
Neoplasm Metastasis
Biopsy
Survival

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Skotheim, R. I., Kallioniemi, A., Bjerkhagen, B., Mertens, F., Brekke, H. R., Monni, O., ... Lothe, R. A. (2003). Topoisomerase-IIα is upregulated in malignant peripheral nerve sheath tumors and associated with clinical outcome. Journal of Clinical Oncology, 21(24), 4586-4591. https://doi.org/10.1200/JCO.2003.07.067
Skotheim, Rolf I. ; Kallioniemi, Anne ; Bjerkhagen, Bodil ; Mertens, Fredrik ; Brekke, Helge R. ; Monni, Outi ; Mousses, Spyro ; Mandahl, Nils ; Soeter, Gunnar ; Nesland, Jahn M. ; Smeland, Sigbjorn ; Kallioniemi, Olli ; Lothe, Ragnhild, A. / Topoisomerase-IIα is upregulated in malignant peripheral nerve sheath tumors and associated with clinical outcome. In: Journal of Clinical Oncology. 2003 ; Vol. 21, No. 24. pp. 4586-4591.
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title = "Topoisomerase-IIα is upregulated in malignant peripheral nerve sheath tumors and associated with clinical outcome",
abstract = "Purpose: To identify target genes of clinical significance for patients with malignant peripheral-nerve sheath tumor (MPNST), an aggressive cancer for which no consensus therapy exists.Materials and Methods: Biopsies and clinical data from 51 patients with MPNST were included in this study. Based on our previous research implicating chromosome arm 17q amplification in MPNST, we performed gene expression analyses of 14 MPNSTs using chromosome 17–specific cDNA microarrays. Copy numbers of selected gene probes and centromere probes were then determined by interphase fluorescence in situ hybridization in 16 MPNSTs. Finally, we generated a tissue microarray containing 79 samples from 44 MPNSTs, on which in situ protein expressions of candidate genes were examined and related to clinical end points.Results: Among several deregulated genes found by cDNA microarray analyses, topoisomerase IIα (TOP2A) was the most overexpressed gene in MPNSTs compared with benign neurofibromas. Excess copies of the TOP2A were also seen at the DNA level in 10 of 16 cases, and high expression of the TOP2A protein was seen in 83{\%} of the tumors on the tissue microarray. The TOP2A-expressing tumors were associated with poor cancer-specific survival and presence of metastases.Conclusion: We have identified TOP2A as a target gene in MPNST, using a focused gene expression profiling followed by a DNA copy number evaluation and clinical validation of the encoded protein using a tissue microarray. This study is the first to suggest that TOP2A expression may be a predictive factor for adverse outcome in MPNST.",
author = "Skotheim, {Rolf I.} and Anne Kallioniemi and Bodil Bjerkhagen and Fredrik Mertens and Brekke, {Helge R.} and Outi Monni and Spyro Mousses and Nils Mandahl and Gunnar Soeter and Nesland, {Jahn M.} and Sigbjorn Smeland and Olli Kallioniemi and Lothe, {Ragnhild, A.}",
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Skotheim, RI, Kallioniemi, A, Bjerkhagen, B, Mertens, F, Brekke, HR, Monni, O, Mousses, S, Mandahl, N, Soeter, G, Nesland, JM, Smeland, S, Kallioniemi, O & Lothe, RA 2003, 'Topoisomerase-IIα is upregulated in malignant peripheral nerve sheath tumors and associated with clinical outcome', Journal of Clinical Oncology, vol. 21, no. 24, pp. 4586-4591. https://doi.org/10.1200/JCO.2003.07.067

Topoisomerase-IIα is upregulated in malignant peripheral nerve sheath tumors and associated with clinical outcome. / Skotheim, Rolf I.; Kallioniemi, Anne; Bjerkhagen, Bodil; Mertens, Fredrik; Brekke, Helge R.; Monni, Outi; Mousses, Spyro; Mandahl, Nils; Soeter, Gunnar; Nesland, Jahn M.; Smeland, Sigbjorn; Kallioniemi, Olli; Lothe, Ragnhild, A.

In: Journal of Clinical Oncology, Vol. 21, No. 24, 2003, p. 4586-4591.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Topoisomerase-IIα is upregulated in malignant peripheral nerve sheath tumors and associated with clinical outcome

AU - Skotheim, Rolf I.

AU - Kallioniemi, Anne

AU - Bjerkhagen, Bodil

AU - Mertens, Fredrik

AU - Brekke, Helge R.

AU - Monni, Outi

AU - Mousses, Spyro

AU - Mandahl, Nils

AU - Soeter, Gunnar

AU - Nesland, Jahn M.

AU - Smeland, Sigbjorn

AU - Kallioniemi, Olli

AU - Lothe, Ragnhild, A.

PY - 2003

Y1 - 2003

N2 - Purpose: To identify target genes of clinical significance for patients with malignant peripheral-nerve sheath tumor (MPNST), an aggressive cancer for which no consensus therapy exists.Materials and Methods: Biopsies and clinical data from 51 patients with MPNST were included in this study. Based on our previous research implicating chromosome arm 17q amplification in MPNST, we performed gene expression analyses of 14 MPNSTs using chromosome 17–specific cDNA microarrays. Copy numbers of selected gene probes and centromere probes were then determined by interphase fluorescence in situ hybridization in 16 MPNSTs. Finally, we generated a tissue microarray containing 79 samples from 44 MPNSTs, on which in situ protein expressions of candidate genes were examined and related to clinical end points.Results: Among several deregulated genes found by cDNA microarray analyses, topoisomerase IIα (TOP2A) was the most overexpressed gene in MPNSTs compared with benign neurofibromas. Excess copies of the TOP2A were also seen at the DNA level in 10 of 16 cases, and high expression of the TOP2A protein was seen in 83% of the tumors on the tissue microarray. The TOP2A-expressing tumors were associated with poor cancer-specific survival and presence of metastases.Conclusion: We have identified TOP2A as a target gene in MPNST, using a focused gene expression profiling followed by a DNA copy number evaluation and clinical validation of the encoded protein using a tissue microarray. This study is the first to suggest that TOP2A expression may be a predictive factor for adverse outcome in MPNST.

AB - Purpose: To identify target genes of clinical significance for patients with malignant peripheral-nerve sheath tumor (MPNST), an aggressive cancer for which no consensus therapy exists.Materials and Methods: Biopsies and clinical data from 51 patients with MPNST were included in this study. Based on our previous research implicating chromosome arm 17q amplification in MPNST, we performed gene expression analyses of 14 MPNSTs using chromosome 17–specific cDNA microarrays. Copy numbers of selected gene probes and centromere probes were then determined by interphase fluorescence in situ hybridization in 16 MPNSTs. Finally, we generated a tissue microarray containing 79 samples from 44 MPNSTs, on which in situ protein expressions of candidate genes were examined and related to clinical end points.Results: Among several deregulated genes found by cDNA microarray analyses, topoisomerase IIα (TOP2A) was the most overexpressed gene in MPNSTs compared with benign neurofibromas. Excess copies of the TOP2A were also seen at the DNA level in 10 of 16 cases, and high expression of the TOP2A protein was seen in 83% of the tumors on the tissue microarray. The TOP2A-expressing tumors were associated with poor cancer-specific survival and presence of metastases.Conclusion: We have identified TOP2A as a target gene in MPNST, using a focused gene expression profiling followed by a DNA copy number evaluation and clinical validation of the encoded protein using a tissue microarray. This study is the first to suggest that TOP2A expression may be a predictive factor for adverse outcome in MPNST.

U2 - 10.1200/JCO.2003.07.067

DO - 10.1200/JCO.2003.07.067

M3 - Article

VL - 21

SP - 4586

EP - 4591

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 24

ER -