Altered molecular pathways in melanocytic lesions

Abstract

To identify gene expression changes in melanocytic lesions, biopsies from 18 common nevi (CMN), 11 dysplastic nevi (DN), 8 radial and 15 vertical growth phase melanomas (RGPM, VGPM), and 5 melanoma metastases (MTS) were analyzed using whole genome microarrays. The comparison between CMN and RGPM showed an enrichment of Gene Ontology terms related to inter and intracellular junctions, whereas the transition from RGPM to VGPM underlined the alteration of apoptosis. Upregulation of genes involved in dsDNA break repair and downregulation of cellular adhesion genes were observed in MTS with respect to VGPM. DN exhibited rather heterogeneous molecular profiles, with some proliferation genes expressed at higher levels than in CMN, altered regulation of transcription compared to RGPM and a subset of processes, such as mismatch repair, equally expressed as in VGPM. Furthermore, the expression profile of genes involved into cellular detoxification and antigen presentation split them into two classes, with different proliferation potential. Finally, molecular profiling of individual lesions identified altered biological processes, such as regulation of apoptosis, regulation of transcription and T-cell activation, not associated with specific histological classes but rather with subgroups of samples without apparent relationship. This holds true for dysplastic nevi in particular. Our data indicate that generally the intersection between stage specific and sample specific molecular alterations may lead to a more precise determination of the individual progression risk of melanocytic lesions.Malignant cutaneous melanoma originates in melanocytes, the pigment-producing cells of the skin and eye. This entity is relatively rare compared with other skin cancers (<5%), but is still responsible for 80% of all skin cancer-related deaths. Early-stage melanoma is a curable disease if properly excised, whereas the life span of patients with advanced disease is relatively short, and little progress has been made in the treatment of metastatic melanoma. 1 Moreover, there are no available markers to predict which early stage tumors have a high progression risk. 2 The initiation and progression of melanoma is characterized by a sequence of cytoarchitectural modifications and by stromal (dermis and subcutis) invasion, on which the Clark's method of microstaging is based. 3 The driving force behind those processes is the acquisition of somatic mutations in key regulatory genes. The vertical growth phase, which involves the escape from keratinocyte-mediated growth control, is the most critical event along this progression. 4 Gene expression profiling utilizing microarrays is an efficient method to discover altered molecular mechanisms and allows detection of the expression levels of thousands of genes in one experiment. 5 The most relevant studies conducted to define the transcriptional changes occurring during melanoma progression have recently been described in a comprehensive review. 6 However, the majority of these studies have been carri...

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