This manuscript is dedicated to the memory of Professor Abhijit Guha, who sadly passed away on 8 November 2011, shortly before this article was accepted for publication.
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†
Article first published online: 5 MAR 2012
© 2012 Wiley Periodicals, Inc.
Special Issue: Focus on the NIH Undiagnosed Diseases Program
Volume 33, Issue 4, pages 763–776, April 2012
How to Cite
Upadhyaya, M., Spurlock, G., Thomas, L., Thomas, N. S. T., Richards, M., Mautner, V.-F., Cooper, D. N., Guha, A. and Yan, J. (2012), 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. Hum. Mutat., 33: 763–776. doi: 10.1002/humu.22044
Communicated by Paolo M. Fortina
- Issue published online: 12 MAR 2012
- Article first published online: 5 MAR 2012
- Accepted manuscript online: 13 FEB 2012 12:00AM EST
- Manuscript Accepted: 18 JAN 2012
- Manuscript Received: 5 OCT 2011
- neurofibromatosis type-1;
- benign and malignant tumors;
- copy number alterations;
- Rho–GTPase pathway genes;
- cell adhesion;
- wound healing;
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. Hum Mutat 33:763–776, 2012. © 2012 Wiley Periodicals, Inc.