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Topoisomerase-II 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 Ster, Jahn M. Nesland, Sigbjørn Smeland, Olli-P. Kallioniemi, Ragnhild A. Lothe

From the Departments of Genetics and Pathology, Institute for Cancer Research, and the Department of Oncology, the Norwegian Radium Hospital and University of Oslo, Oslo, Norway; the Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere; Biomedicum Biochip Center, Biomedicum Helsinki, Helsinki; and VTT Technical Research Centre of Finland and University of Turku, Turku, Finland; Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD; and the Department of Clinical Genetics, University Hospital, Lund, Sweden.

Address reprint requests to Ragnhild A. Lothe, PhD, Department of Genetics, Institute for Cancer Research, the Norwegian Radium Hospital, N-0310 Oslo, Norway; e-mail: rlothe{at}radium.uio.no.

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 II (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.

Supported by the Research Council of Norway (R.I.S.) and the Norwegian Cancer Society (R.I.S. and R.A.L.).

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