Topoisomerase-II alpha is upregulated in malignant peripheral nerve sheath tumors and associated with clinical outcome.
OBJECTIVE
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.


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 alpha (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.


CONCLUSIONS
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.
Skotheim
Rolf I
RI
Department of Genetics, Institute for Cancer Research, the Norwegian Radium Hospital and University of Oslo, Norway.
Kallioniemi
Anne
A
Bjerkhagen
Bodil
B
Mertens
Fredrik
F
Brekke
Helge R
HR
Monni
Outi
O
Mousses
Spyro
S
Mandahl
Nils
N
Soeter
Gunnar
G
Nesland
Jahn M
JM
Smeland
Sigbjørn
S
Kallioniemi
Olli-P
OP
Lothe
Ragnhild A
RA
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D004250:DNA Topoisomerases, Type II / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D018317:Nerve Sheath Neoplasms / Q000235:genetics*; D016019:Survival Analysis; D015854:Up-Regulation
D004250:DNA Topoisomerases, Type II