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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
Author(s) -
Upadhyaya Meena,
Spurlock Gill,
Thomas Laura,
Thomas Nick S. T.,
Richards Mark,
Mautner ViktorFelix,
Cooper David N.,
Guha Abhijit,
Yan Jim
Publication year - 2012
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22044
Subject(s) - biology , cancer research , loss of heterozygosity , neurofibroma , carcinogenesis , neurofibromatosis , neurofibromatosis type 2 , genetics , cancer , gene , allele
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.