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
HUMAN MUTATION
Authors: Upadhyaya, Meena; Spurlock, Gill; Thomas, Laura; Thomas, Nick S. T.; Richards, Mark; Mautner, Viktor-Felix; Cooper, David N.; Guha, Abhijit; Yan, Jim
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 neutralLOH (CNNLOH) 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. CNNLOH 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 RhoGTPase 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 RhoGTPase pathway genes in MPNST development and metastasis. These results suggest new targets for therapeutic intervention in relation to MPNSTs. Hum Mutat 33:763776, 2012. (c) 2012 Wiley Periodicals, Inc.
Identification and characterisation of alternative transcriptional variants of PDGFRL in two lines of commercial poultry
ANIMAL GENETICS
Authors: McDerment, N. A.; Hocking, P. M.; Dunn, I. C.
Abstract
The platelet-derived growth factor (PDGF) family of genes and their receptors are involved in angiogenesis and steroid hormone production. A putative member of the family, platelet-derived growth factor receptor-like (PDGFRL), has been implicated in steroid-based feedback mechanisms within the chicken reproductive system. Three potential variants of PDGFRL were identified in the chicken, supported by in silico prediction and EST sequencing. The three potential transcripts have been further verified and the 50 terminal regions sequenced in this research. The sum of expression of all three transcripts in broiler breeders (the parents of broiler chickens) has been shown to be consistent with total expression of the gene. However, cumulative expression of the three transcripts in a range of tissues in egg layers was significantly short of total expression, indicating the existence of potential additional variants. Two additional variants were subsequently identified in egg layer cerebellum tissue and the 50 terminal regions sequenced. Sequence analysis of the three initial variants suggests that only one variant, which was the most abundant in broiler breeders and the majority of egg layer tissues, had a functional signal peptide. Although 50 RACE identified two additional transcripts in egg layers, the most likely protein translations indicated that these variants possessed no functional signal peptide, suggesting that, if they have a function, it is not a traditional one.