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[Biological role and prognostic significance of genetic alterations in human malignant melanomas].

Metastatic process accounts for the vast majority of melanoma associated mortality, and also results in difficulties in the effective treatment. Therefore, identification of novel biomarkers could contribute to melanoma prognosis, and may also provide new opportunities for efficient cancer treatment. Several signaling pathways have been identified as key regulators in melanoma progression, including the frequent activation of Ras/MAPK signaling pathway through the mutant BRAF or NRAS genes. Besides, alterations of CCND1 may also be of great importance. The oncogene plays a significant role in the G1/S phase transition of the cell cycle, and its transcriptional activation is primarily carried out by the Ras/MAPK cascade. One of our aims was to determine the genetic and gene expression alterations of CCND1 during melanoma progression, considering the mutation status of BRAF and NRAS genes. Analysis of CCND1 copy number alterations revealed significant association with poor clinical outcome in primary melanomas, which was influenced by the mutation status of BRAF or NRAS in the term of sun exposure. Regarding gene expression, CCND1 mRNA level decreased in lesions with multiple metastases and were correlated with both the mRNA levels and mutation status of BRAF and NRAS. CCND1 protein expression was associated with Breslow thickness, metastasis formation and shorter survival time. However, the proportion of cells expressing the protein showed a heterogeneous distribution, influencing the association with clinical-pathological parameters. Therefore melanoma cell lines with different biological behavior were also analyzed for protein expression. These experiments revealed an increasing CCND1 protein level throughout primary cancer progression, which then decreased in the metastasis. The other purpose of our study was to determine the role of 7q31 region in melanoma progression, which was found frequently altered using array comparative genomic hybridization (aCGH). 7q31 is a gene dense locus, including the FRA7G fragile site, which serves as a mutation hot spot. In its close vicinity TES (focal adhesions) and CAV1 (lipid rafts) genes are located. Using interphase FISH, significant associations were found between 7q31 copy number alterations and poor clinical outcome. Both mRNA and protein levels of CAV1 decreased in thick lesions whereas primary melanomas forming multiple metastases were featured by decreased TES mRNA level.