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A High-Throughput Study in Melanoma Identifies Epithelial-Mesenchymal Transition as a Major Determinant of Metastasis

¹ Molecular Pathology Programme and ² Histology and Immunohistochemistry Unit, Centro Nacional de Investigaciones Oncológicas; Departments of ³ Pathology and ⁴ Dermatology, Hospital Universitario 12 de Octubre; ⁵ Centro Nacional de Epidemiología, Instituto de Salud Carlos III, Madrid, Spain; and Departments of ⁶ Pathology and ⁷ Dermatology, Hospital Universitario San Cecilio, Granada, Spain

Requests for reprints: Miguel A. Piris, Programa de Patología Molecular, Centro Nacional de Investigaciones Oncológicas, C/Melchor Fernández Almagro 3, Madrid 28029, Spain. Phone: 34-91-224-69-00; Fax: 34-91-224-69-23; E-mail: mapiris{at}cnio.es.

Metastatic disease is the primary cause of death in cutaneous malignant melanoma (CMM) patients. To understand the mechanisms of CMM metastasis and identify potential predictive markers, we analyzed gene-expression profiles of 34 vertical growth phase melanoma cases using cDNA microarrays. All patients had a minimum follow-up of 36 months. Twenty-one cases developed nodal metastatic disease and 13 did not. Comparison of gene expression profiling of metastatic and nonmetastatic melanoma cases identified 243 genes with a >2-fold differential expression ratio and a false discovery rate of <0.2 (206 up-regulated and 37 down-regulated). This set of genes included molecules involved in cell cycle and apoptosis regulation, epithelial-mesenchymal transition (EMT), signal transduction, nucleic acid binding and transcription, protein synthesis and degradation, metabolism, and a specific group of melanoma- and neural-related proteins. Validation of these expression data in an independent series of melanomas using tissue microarrays confirmed that the expression of a set of proteins included in the EMT group (N-cadherin, osteopontin, and SPARC/osteonectin) were significantly associated with metastasis development. Our results suggest that EMT-related genes contribute to the promotion of the metastatic phenotype in primary CMM by supporting specific adhesive, invasive, and migratory properties. These data give a better understanding of the biology of this aggressive tumor and may provide new prognostic and patient stratification markers in addition to potential therapeutic targets. [Cancer Res 2007;67(7):3450–60]

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