title: Evaluation of copy number variation and gene expression in neurofibromatosis type-1-associated malignant peripheral nerve sheath tumours.
abstract: BACKGROUND
  Neurofibromatosis type-1 (NF1) is a complex neurogenetic disorder characterised by the development of benign and malignant tumours of the peripheral nerve sheath (MPNSTs). Whilst biallelic NF1 gene inactivation contributes to benign tumour formation, additional cellular changes in gene structure and/or expression are required to induce malignant transformation. Although few molecular profiling studies have been performed on the process of progression of pre-existing plexiform neurofibromas to MPNSTs, the integrated analysis of copy number alterations (CNAs) and gene expression is likely to be key to understanding the molecular mechanisms underlying NF1-MPNST tumorigenesis. In a pilot study, we employed this approach to identify genes differentially expressed between benign and malignant NF1 tumours.
  
  
  RESULTS
  SPP1 (osteopontin) was the most differentially expressed gene (85-fold increase in expression), compared to benign plexiform neurofibromas. Short hairpin RNA (shRNA) knockdown of SPP1 in NF1-MPNST cells reduced tumour spheroid size, wound healing and invasion in four different MPNST cell lines. Seventy-six genes were found to exhibit concordance between CNA and gene expression level.
  
  
  CONCLUSIONS
  Pathway analysis of these genes suggested that glutathione metabolism and Wnt signalling may be specifically involved in NF1-MPNST development. SPP1 is associated with malignant transformation in NF1-associated MPNSTs and could prove to be an important target for therapeutic intervention.
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK. thomasl41@cardiff.ac.uk.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Thomas
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK. jincywinston@gmail.com.
authors.forename: Jincy
authors.initials: J
authors.lastname: Winston
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK. ellieradm@yahoo.co.uk.
authors.forename: Ellie
authors.initials: E
authors.lastname: Rad
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK. mortm@cardiff.ac.uk.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mort
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK. doddkm@cardiff.ac.uk.
authors.forename: Kayleigh M
authors.initials: KM
authors.lastname: Dodd
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK. teea@cardiff.ac.uk.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Tee
authors.affiliation: Almac Diagnostics, 19 Seagoe Industrial Estate, Craigavon, Northern Ireland, BT63 5QD, UK. fionnuala.mcdyer@almacgroup.com.
authors.forename: Fionnuala
authors.initials: F
authors.lastname: McDyer
authors.affiliation: Almac Diagnostics, 19 Seagoe Industrial Estate, Craigavon, Northern Ireland, BT63 5QD, UK. stephen.moore@almacgroup.com.
authors.forename: Stephen
authors.initials: S
authors.lastname: Moore
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK. CooperDN@cardiff.ac.uk.
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK. upadhyaya@cardiff.ac.uk.
authors.forename: Meena
authors.initials: M
authors.lastname: Upadhyaya
mesh_terms: D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018317:Nerve Sheath Neoplasms / Q000150:complications / Q000235:genetics*; D009456:Neurofibromatosis 1 / Q000150:complications / Q000235:genetics*; D053495:Osteopontin / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C506895:SPP1 protein, human; D053495:Osteopontin