title: High-resolution DNA copy number profiling of malignant peripheral nerve sheath tumors using targeted microarray-based comparative genomic hybridization.
abstract: OBJECTIVE
  Neurofibromatosis type 1 (NF1) is an autosomal dominant condition that predisposes to benign and malignant tumors. The lifetime risk of a malignant peripheral nerve sheath tumor (MPNST) in NF1 is approximately 10%. These tumors have a poor survival rate and their molecular basis remains unclear. We report the first comprehensive investigation of DNA copy number across multitude of genes in NF1 tumors using high-resolution array comparative genomic hybridization (CGH), with the aim to identify molecular signatures that delineate malignant from benign NF1 tumors.
  
  
  METHODS
  We constructed an exon-level resolution microarray encompassing 57 selected genes and profiled DNA from 35 MPNSTs, 16 plexiform, and 8 dermal neurofibromas. Bioinformatic analysis was done on array CGH data to identify concurrent aberrations in malignant tumors.
  
  
  RESULTS
  The array CGH profiles of MPNSTs and neurofibromas were markedly different. A number of MPNST-specific alterations were identified, including amplifications of ITGB4, PDGFRA, MET, TP73, and HGF plus deletions in NF1, HMMR/RHAMM, MMP13, L1CAM2, p16INK4A/CDKN2A, and TP53. Copy number changes of HMMR/RHAMM, MMP13, p16INK4A/CDKN2A, and ITGB4 were observed in 46%, 43%, 39%, and 32%, respectively of the malignant tumors, implicating these genes in MPNST pathogenesis. Concomitant amplifications of HGF, MET, and PDGFRA genes were also revealed in MPNSTs, suggesting the putative role of p70S6K pathway in NF1 tumor progression.
  
  
  CONCLUSIONS
  This study highlights the potential of array CGH in identifying novel diagnostic markers for MPNSTs.
authors.affiliation: Institute of Medical Genetics, Cardiff University, School of Medicine, Heath Park, Cardiff, United Kingdom. kiran.mantripragada@gmail.com
authors.forename: Kiran K
authors.initials: KK
authors.lastname: Mantripragada
authors.forename: Gillian
authors.initials: G
authors.lastname: Spurlock
authors.forename: Lan
authors.initials: L
authors.lastname: Kluwe
authors.forename: Nadia
authors.initials: N
authors.lastname: Chuzhanova
authors.forename: Rosalie E
authors.initials: RE
authors.lastname: Ferner
authors.forename: Ian M
authors.initials: IM
authors.lastname: Frayling
authors.forename: Jan P
authors.initials: JP
authors.lastname: Dumanski
authors.forename: Abhijit
authors.initials: A
authors.lastname: Guha
authors.forename: Victor
authors.initials: V
authors.lastname: Mautner
authors.forename: Meena
authors.initials: M
authors.lastname: Upadhyaya
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006801:Humans; D007091:Image Processing, Computer-Assisted; D018317:Nerve Sheath Neoplasms / Q000235:genetics*; D009455:Neurofibroma / Q000235:genetics; D009456:Neurofibromatosis 1 / Q000150:complications / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D014408:Biomarkers, Tumor