title: DDEF1 is located in an amplified region of chromosome 8q and is overexpressed in uveal melanoma.
abstract: OBJECTIVE
  The molecular pathogenesis of uveal melanoma is poorly understood but is usually accompanied by amplification of chromosome 8q, suggesting the activation of one or more oncogenes. We recently identified a gene expression profile that distinguishes low-grade from high-grade melanomas. In this profile, a cluster of genes at chromosome 8q was overexpressed in high-grade tumors, providing an opportunity to search for potential oncogenes in this region.
  
  
  METHODS
  Gene expression microarray analysis was done on 25 primary uveal melanomas. Microarray comparative genomic hybridization (CGH), quantitative PCR, and immunohistochemistry were done on a subset of these tumors. Cell motility was measured using a wound-healing assay.
  
  
  RESULTS
  In melanomas analyzed for microarray gene expression and CGH, gain of chromosome 8q correlated most strongly with expression of DDEF1, a gene located at 8q24. In contrast, the nearby MYC oncogene exhibited no significant change in expression. Confirming the microarray findings, DDEF1 mRNA levels and protein expression were significantly higher in high-grade melanomas. Furthermore, ectopic expression of DDEF1 in low-grade melanoma cells resulted in a significant increase in cell motility, a feature of high-grade metastasizing cells.
  
  
  CONCLUSIONS
  These findings suggest that DDEF1 overexpression may be a pathogenetically relevant consequence of chromosome 8q amplification, which commonly occurs in high-grade uveal melanomas. We conclude that DDEF1 may act as an oncogene in this cancer, and it may be a useful diagnostic marker and therapeutic target.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Justis P
authors.initials: JP
authors.lastname: Ehlers
authors.forename: Lori
authors.initials: L
authors.lastname: Worley
authors.forename: Michael D
authors.initials: MD
authors.lastname: Onken
authors.forename: J William
authors.initials: JW
authors.lastname: Harbour
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics*; D002465:Cell Movement; D002898:Chromosomes, Human, Pair 8; D005784:Gene Amplification; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014604:Uveal Neoplasms / Q000235:genetics* / Q000473:pathology; D018909:src Homology Domains
chemical_list: C117891:ASAP1 protein, human; D048868:Adaptor Proteins, Signal Transducing