title: Microarray-based copy number analysis of neurofibromatosis type-1 (NF1)-associated malignant peripheral nerve sheath tumors reveals a role for Rho-GTPase pathway genes in NF1 tumorigenesis.
abstract: Neurofibromatosis type-1 (NF1) is associated with the growth of benign and malignant tumors. Approximately 15% of NF1 patients develop malignant peripheral nerve sheath tumors (MPNSTs), underlining the need to identify specific diagnostic/prognostic biomarkers associated with MPNST development. The Affymetrix Genome-Wide Human single-nucleotide polymorphism (SNP) Array 6.0 was used to perform SNP genotyping and copy number alteration (CNA), loss-of-heterozygosity (LOH), and copy number neutral-LOH (CNN-LOH) analyses of DNA isolated from 15 MPNSTs, five benign plexiform neurofibromas (PNFs), and patient-matched lymphocyte DNAs. MPNSTs exhibited high-level CNN-LOH, with recurrent changes occurring in MPNSTs but not PNFs. CNN-LOH was evident in MPNSTs but occurred less frequently than genomic deletions. CNAs involving the ITGB8, PDGFA, Ras-related C3 botulinum toxin substrate 1 (RAC1) (7p21-p22), PDGFRL (8p22-p21.3), and matrix metallopeptidase 12 (MMP12) (11q22.3) genes were specific to MPNSTs. Pathway analysis revealed the MPNST-specific amplification of seven Rho-GTPase pathway genes and several cytoskeletal remodeling/cell adhesion genes. In knockdown experiments employing short-hairpin RAC1, ROCK2, PTK2, and LIMK1 RNAs to transfect both control and MPNST-derived cell lines, cell adhesion was significantly increased in the MPNST cell lines, whereas wound healing, cell migration, and invasiveness were reduced, consistent with a role for these Rho-GTPase pathway genes in MPNST development and metastasis. These results suggest new targets for therapeutic intervention in relation to MPNSTs.
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK. upadhyaya@cardiff.ac.uk
authors.forename: Meena
authors.initials: M
authors.lastname: Upadhyaya
authors.forename: Gill
authors.initials: G
authors.lastname: Spurlock
authors.forename: Laura
authors.initials: L
authors.lastname: Thomas
authors.forename: Nick S T
authors.initials: NS
authors.lastname: Thomas
authors.forename: Mark
authors.initials: M
authors.lastname: Richards
authors.forename: Viktor-Felix
authors.initials: VF
authors.lastname: Mautner
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.forename: Abhijit
authors.initials: A
authors.lastname: Guha
authors.forename: Jim
authors.initials: J
authors.lastname: Yan
mesh_terms: D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D051417:Focal Adhesion Kinase 1 / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D054461:Lim Kinases / Q000235:genetics; D019656:Loss of Heterozygosity; D053508:Matrix Metalloproteinase 12 / Q000235:genetics; D018317:Nerve Sheath Neoplasms / Q000235:genetics* / Q000473:pathology; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000235:genetics; D054460:rho-Associated Kinases / Q000235:genetics
chemical_list: C550706:PDGFRL protein, human; D010982:Platelet-Derived Growth Factor; C107953:RAC1 protein, human; D025521:Tumor Suppressor Proteins; C075278:platelet-derived growth factor A; D017479:Receptors, Platelet-Derived Growth Factor; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C515892:LIMK1 protein, human; D054461:Lim Kinases; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; D053508:Matrix Metalloproteinase 12; D020558:GTP Phosphohydrolases; D020830:rac1 GTP-Binding Protein