DNA copy number changes in high-grade malignant peripheral nerve sheath tumors by array CGH

Stine H Kresse,Magne Skårn,Leonardo A Meza-Zepeda,Ola Myklebost,Heidi M Namløs,Hege O Ohnstad,Bodil Bjerkehagen

doi:10.1186/1476-4598-7-48

Stine H Kresse, Magne Skårn + Show 5 more

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https://doi.org/10.1186/1476-4598-7-48

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Abstract

BackgroundMalignant 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).ResultsConsiderable 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-α (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.ConclusionOur 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.

Highlights

Malignant peripheral nerve sheath tumors (MPNSTs) are rare and highly aggressive soft tissue tumors showing complex chromosomal aberrations
Altered chromosomal regions in MPNSTs DNA copy number changes in seven high-grade MPNSTs (Table 1) were analyzed using a 1 Mb resolution bacterialand P1 artificial chromosome (BAC and PAC) genomic microarray supplemented with the tiling-path between 1q12 and the beginning of 1q25
The expression level was determined relative to the average expression of two benign tumors

Summary

Introduction

Malignant peripheral nerve sheath tumors (MPNSTs) are rare and highly aggressive soft tissue tumors showing complex chromosomal aberrations. Malignant peripheral nerve sheath tumors (MPNSTs) are rare tumors that arise sporadically or as part of the neurofibromatosis type 1 (NF1) or -2 (NF2) autosomal inherited disorder. The NF1/von Recklinghausen neurofibromatosis, caused by germ line mutations of the NF1 tumor suppressor gene, is one of the most common autosomal dominant inherited disorders, occurring at a frequency of one in every 4,000 individuals [1]. Patients with this disease have an increased risk of benign and malignant tumors [2]. Recurrent gain of 7p15-p21 and 17q22-qter has been associated with poor overall survival [10], and increased copy number and expression of topoisomerase II-α (TOP2A) in 17q21.2 have been associated with poor cancer-specific survival and presence of metastasis [11]

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