Purpose:To better understand the molecular mechanisms of malignant melanoma progression and metastasis, gene expression profiling was done of primary melanomas and melanoma metastases. Experimental Design: Tumor cell^specific gene expression in 19 primary melanomas and 22 melanoma metastases was analyzed using oligonucleotide microarrays after laser-capture microdissection of melanoma cells. Statistical analysis was done by random permutation analysis and support vector machines. Microarray data were further validated by immunohistochemistry and immunoblotting. Results: Overall, 308 genes were identified that showed significant differential expression between primary melanomas and melanoma metastases (false discovery rate V 0.05). Significantly overrepresented gene ontology categories in the list of 308 genes were cell cycle regulation, mitosis, cell communication, and cell adhesion. Overall, 47 genes showed up-regulation in metastases. These included Cdc6, Cdk1, septin 6, mitosin, kinesin family member 2C, osteopontin, and fibronectin. Down-regulated genes included E-cadherin, fibroblast growth factor binding protein, and desmocollin 1 and desmocollin 3, stratifin/14-3-3r, and the chemokine CCL27. Using support vector machine analysis of gene expression data, a performance of >85% correct classifications for primary melanomas and metastases was reached. Further analysis showed that subtypes of primary melanomas displayed characteristic gene expression patterns, as do thin tumors (V1.0 mm Breslow thickness) compared with intermediate and thick tumors (>2.0 mm Breslow thickness). Conclusions: Taken together, this large-scale gene expression study of malignant melanoma identified molecular signatures related to metastasis, melanoma subtypes, and tumor thickness. These findings not only provide deeper insights into the pathogenesis of melanoma progression but may also guide future research on innovative treatments.The incidence of malignant melanoma is steadily increasing with a present lifetime risk of 1 in 75 among the Caucasian population (1). The underlying factors for this phenomenon are largely unknown. After diagnosis of malignant melanoma, the single most important factor for the prognosis of melanoma patients is vertical tumor thickness as described earlier by Breslow (2). It could be shown that tumors of a few-millimeter thickness already show a high potential for metastasis with a fatal outcome for the patient. In the metastatic stage, melanoma patients have only few treatment options, consisting of monochemotherapies with dacarbazine (DTIC) or temozolomide, or polychemotherapy regimens combining DTIC with other chemotherapeutic agents such as cisplatin and 1,3-bis(2-chloroethyl)-1-nitrosourea (3 -5). Although significant clinical response rates were achieved by these treatment modalities, there was no substantial effect on the overall survival of these patients. Unfortunately, little is known about factors that contribute to the process of melanoma progression and metastasis.In recent years, DN...

In this paper we derive a method for evaluating and improving techniques for selecting informative genes from microarray data. Genes of interest are typically selected by ranking genes according to a test-statistic and then choosing the top k genes. A problem with this approach is that many of these genes are highly correlated. For classification purposes it would be ideal to have distinct but still highly informative genes. We propose three different pre-filter methods-two based on clustering and one based on correlation-to retrieve groups of similar genes. For these groups we apply a test-statistic to finally select genes of interest. We show that this filtered set of genes can be used to significantly improve existing classifiers.

Objective-The present study addresses the question, "Are plaque smooth muscles cells (SMCs) genetically distinct from medial SMCs as reflected by the ability to maintain a distinctive expression phenotype in vitro?" Methods and Results-Multiple cell strains were developed from carotid endarcterectomy specimens, and quadruplicate array hybridizations were completed for each sample. A new normalization protocol was developed and used to analyze the data. Permutation analysis suggests that most of the significant differences in expression could not have occurred by chance. A broad pattern of significant expression differences, consisting of almost 5% of the genes probed, was detected. Quantitative polymerase chain reaction (QPCR) confirmation was found in 70% of a subset of genes selected for validation. Conclusions-The SMC cultures were nearly indistinguishable by morphological features, population doubling time, and sensitivity to cell death induced by Fas cross-linking. Surprisingly, array expression analysis identified differences so extensive that we conclude that plaque and medial SMCs are distinctly different SMC cell types. (Arterioscler Thromb

Background: Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the fibrillin-1 gene. This syndrome constitutes a significant identifiable subtype of aortic aneurysmal disease, accounting for over 5% of ascending and thoracic aortic aneurysms.