DNA copy number changes in high-grade malignant peripheral nerve sheath tumors by array CGH.
BACKGROUND
Malignant peripheral nerve sheath tumors (MPNSTs) are rare and highly aggressive soft tissue tumors showing complex chromosomal aberrations. In order to identify recurrent chromosomal regions of gain and loss, and thereby novel gene targets of potential importance for MPNST development and/or progression, we have analyzed DNA copy number changes in seven high-grade MPNSTs using microarray-based comparative genomic hybridization (array CGH).


RESULTS
Considerable more gains than losses were observed, and the most frequent minimal recurrent regions of gain included 1q24.1-q24.2, 1q24.3-q25.1, 8p23.1-p12, 9q34.11-q34.13 and 17q23.2-q25.3, all gained in five of seven samples. The 17q23.2-q25.3 region was gained in all five patients with poor outcome and not in the two patients with disease-free survival. cDNA microarray analysis and quantitative real-time reverse transcription PCR were used to investigate expression of genes located within these regions. The gene lysyl oxidase-like 2 (LOXL2) was identified as a candidate target for the 8p23.1-p12 gain. Within 17q, the genes topoisomerase II-alpha (TOP2A), ets variant gene 4 (E1A enhancer binding protein, E1AF) (ETV4) and baculoviral IAP repeat-containing 5 (survivin) (BIRC5) showed increased expression in all samples compared to two benign tumors. Increased expression of these genes has previously been associated with poor survival in other malignancies, and for TOP2A, in MPNSTs as well. In addition, we have analyzed the expression of five micro RNAs located within the 17q23.2-q25.3 region, but none of them showed high expression levels compared to the benign tumors.


CONCLUSIONS
Our study shows the potential of using DNA copy number changes obtained by array CGH to predict the prognosis of MPNST patients. Although no clear correlations between the expression level and patient outcome were observed, the genes TOP2A, ETV4 and BIRC5 are interesting candidate targets for the 17q gain associated with poor survival.
Department of Tumor Biology, Radiumhospitalet, Rikshospitalet, Oslo, Norway. stinek@rr-research.no
Stine H
SH
Kresse
Magne
M
Skårn
Hege O
HO
Ohnstad
Heidi M
HM
Namløs
Bodil
B
Bjerkehagen
Ola
O
Myklebost
Leonardo A
LA
Meza-Zepeda
D017500:Adenovirus E1A Proteins / Q000235:genetics; D000328:Adult; D000368:Aged; D000594:Amino Acid Oxidoreductases / Q000235:genetics; D000951:Antigens, Neoplasm / Q000235:genetics; D002886:Chromosomes, Human, Pair 17; D002898:Chromosomes, Human, Pair 8; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004273:DNA, Neoplasm / Q000032:analysis*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D018317:Nerve Sheath Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D020411:Oligonucleotide Array Sequence Analysis; D000075223:Poly-ADP-Ribose Binding Proteins; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D050783:Proto-Oncogene Proteins c-ets; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012983:Soft Tissue Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D000077022:Survivin
D017500:Adenovirus E1A Proteins; D000951:Antigens, Neoplasm; C107489:BIRC5 protein, human; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C079853:ETV4 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D000077022:Survivin; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human