Clonal chromosome aberrations were detected in 8 short-term cultured malignant peripheral nerve sheath tumors (MPNST). Seven had a near-triploid chromosome number and I was in the hyperhaploid-hypodiploid range. No recurrent structural rearrangements were found; the bands most frequently involved (3 tumors) were 7p11, 12p13 and 14q11. The most common numerical changes were loss of a sex chromosome (all tumors) and loss of at least 1 copy of chromosomes 8, 16 and 22 (4 tumors). Pooling our data with those on the 20 previously published MPNST with abnormal karyotypes, we found that the chromosome number has often been in the triploid range (12 tumors), with stem line variation between 34 and 270. All chromosome arms, except 22p and the Y chromosome, were involved in recombinations. The most frequently rearranged bands were 7p22 (6 tumors) and 1p21, 7p11 and 14q11 (5 tumors each). Most numerical and unbalanced structural aberrations have led to loss of genetic material, in particular from Xq26-qter (13 tumors); 11q22-qter and 13p (12 tumors); 9p22-pter, 11p13-pter, 17p and 17q11-21 (11 tumors); 1p22-32 and 1p34-pter (10 tumors) and 6q25-qter and chromosome 16 (9 tumors).
"Like most sarcomas, MPNSTs have a complex and variable karyotype with multiple chromosomal gains and losses (Glover et al., 1991). Recurrent copy number gains are found on chromosomes 7, 8q, 15q, and 17q and losses on 1p, 9p, 11, 12p, 14q, 17q, 18, 22q, X, and Y (Mertens et al., 1995, 2000; Lothe et al., 1996; Schmidt et al., 2000, 2001; Storlazzi et al., 2006; Mantripragada et al., 2009). The spectrum of PNSTs ranges from benign to high-grade malignant. "
[Show abstract][Hide abstract] ABSTRACT: Benign peripheral nerve sheath tumors (PNSTs) are a characteristic feature of neurofibromatosis type I (NF1) patients. NF1 individuals have an 8-13% lifetime risk of developing a malignant PNST (MPNST). Atypical neurofibromas are symptomatic, hypercellular PNSTs, composed of cells with hyperchromatic nuclei in the absence of mitoses. Little is known about the origin and nature of atypical neurofibromas in NF1 patients. In this study, we classified the atypical neurofibromas in the spectrum of NF1-associated PNSTs by analyzing 65 tumor samples from 48 NF1 patients. We compared tumor-specific chromosomal copy number alterations between benign neurofibromas, atypical neurofibromas, and MPNSTs (low-, intermediate-, and high-grade) by karyotyping and microarray-based comparative genome hybridization (aCGH). In 15 benign neurofibromas (4 subcutaneous and 11 plexiform), no copy number alterations were found, except a single event in a plexiform neurofibroma. One highly significant recurrent aberration (15/16) was identified in the atypical neurofibromas, namely a deletion with a minimal overlapping region (MOR) in chromosome band 9p21.3, including CDKN2A and CDKN2B. Copy number loss of the CDKN2A/B gene locus was one of the most common events in the group of MPNSTs, with deletions in low-, intermediate-, and high-grade MPNSTs. In one tumor, we observed a clear transition from a benign-atypical neurofibroma toward an intermediate-grade MPNST, confirmed by both histopathology and aCGH analysis. These data support the hypothesis that atypical neurofibromas are premalignant tumors, with the CDKN2A/B deletion as the first step in the progression toward MPNST.
Genes Chromosomes and Cancer 12/2011; 50(12):1021-32. DOI:10.1002/gcc.20921 · 4.04 Impact Factor
"Cytogenetically, MPNSTs have complex karyotypes with multiple losses frequently observed in chromosome regions 1p, 9p, 17q and 22 [4,5]. Several comparative genomic hybridization (CGH) studies have revealed a higher frequency of gains compared to losses, involving chromosome regions 5p, 7p, 7q, 8q and 17q [6-10]. "
[Show abstract][Hide abstract] ABSTRACT: 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).
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.
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.
Molecular Cancer 06/2008; 7(1):48. DOI:10.1186/1476-4598-7-48 · 4.26 Impact Factor
"Karyotypes were mainly in the triploid range, with complex changes (for review see  ). Certain chromosomal regions appeared to be more frequently involved , such as 1p, 9p, 11, 12p, 14q, 17q, 18, 22q, X, and Y, which are often lost, whereas gains are frequently observed for chromosome 7  . Comparative genomic hybridization (CGH) analysis confirmed the high number of gains and losses in MPNST: gains for 5p, 7p, 8q, and 17q, including high-level DNA copy number gains and losses for 1p and 13q      . "
[Show abstract][Hide abstract] ABSTRACT: Malignant peripheral nerve sheath tumors (MPNST) are rare soft-tissue malignancies. The genetic basis of these tumors is still poorly understood. Cytogenetic analyses predominantly revealed complex karyotypes, precluding the identification of recurrent chromosomal changes. We report loss of 1p material in a near-diploid karyotype with few or no additional structural chromosome changes in two sporadic cases of MPNST, indicating an important role of 1p loss in MPNST development. In one of these two tumors, a distal 1p deletion (1p31.2 approximately pter) was detected suggesting involvement of a tumor suppressor gene located within this distal region of 1p. Further evidence for recurrent 1p loss in MPNST was obtained by interphase fluorescence in situ hybridization, which showed loss of 1p material in 3 out of 13 tumors. These findings together with data from the literature suggest that loss of a tumor suppressor gene located within distal 1p is implicated in the pathogenesis of MPNST.
Cancer Genetics and Cytogenetics 07/2003; 143(2):120-4. DOI:10.1016/S0165-4608(02)00853-1 · 1.93 Impact Factor
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