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.
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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. / Upadhyaya, Meena; Spurlock, Gill; Thomas, Laura; Thomas, Nick S T; Richards, Mark; Mautner, Viktor Felix; Cooper, David N; Guha, Abhijit; Yan, Jim.
In: HUM MUTAT, Vol. 33, No. 4, 4, 2012, p. 763-776.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - 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.
AU - Upadhyaya, Meena
AU - Spurlock, Gill
AU - Thomas, Laura
AU - Thomas, Nick S T
AU - Richards, Mark
AU - Mautner, Viktor Felix
AU - Cooper, David N
AU - Guha, Abhijit
AU - Yan, Jim
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Humans
KW - Polymorphism, Single Nucleotide
KW - Gene Knockdown Techniques
KW - Oligonucleotide Array Sequence Analysis
KW - Loss of Heterozygosity
KW - Cell Movement/genetics
KW - Cell Adhesion/genetics
KW - Focal Adhesion Kinase 1/genetics
KW - GTP Phosphohydrolases/genetics/metabolism
KW - Lim Kinases/genetics
KW - Matrix Metalloproteinase 12/genetics
KW - Nerve Sheath Neoplasms/genetics/pathology
KW - Neurofibromatosis 1/genetics/pathology
KW - Platelet-Derived Growth Factor/genetics
KW - Receptors, Platelet-Derived Growth Factor/genetics
KW - Tumor Suppressor Proteins/genetics
KW - rac1 GTP-Binding Protein/genetics
KW - rho-Associated Kinases/genetics
KW - Humans
KW - Polymorphism, Single Nucleotide
KW - Gene Knockdown Techniques
KW - Oligonucleotide Array Sequence Analysis
KW - Loss of Heterozygosity
KW - Cell Movement/genetics
KW - Cell Adhesion/genetics
KW - Focal Adhesion Kinase 1/genetics
KW - GTP Phosphohydrolases/genetics/metabolism
KW - Lim Kinases/genetics
KW - Matrix Metalloproteinase 12/genetics
KW - Nerve Sheath Neoplasms/genetics/pathology
KW - Neurofibromatosis 1/genetics/pathology
KW - Platelet-Derived Growth Factor/genetics
KW - Receptors, Platelet-Derived Growth Factor/genetics
KW - Tumor Suppressor Proteins/genetics
KW - rac1 GTP-Binding Protein/genetics
KW - rho-Associated Kinases/genetics
M3 - SCORING: Journal article
VL - 33
SP - 763
EP - 776
JO - HUM MUTAT
JF - HUM MUTAT
SN - 1059-7794
IS - 4
M1 - 4
ER -
