Somatic Alterations in Critical Genes in Malignant Melanoma: Effect on Global Gene Expression

Melanoma is the most aggressive skin tumour and the number of cases and deaths has increased faster than many other cancers. Activating mutations in the B-RAF and N-RAS proto-oncogenes and deletion of the tumour suppressor gene CDKN2A occur at high frequencies in melanomas. This study characterises the widely unknown consequences of the most prominent somatic alterations in the B-RAF, N-RAS, and CDKN2A genes on gene expression in melanoma. Additionally, the effect of the V600E B-RAF mutation on gene expression in benign melanocytic nevi, known precursors of melanoma, was examined. In summary, the studied alterations significantly influence expression of various genes in the RAS-RAF-MEK-ERK, Rb, and PI3K/AKT pathways. MAPK pathway activation occurs in the early stages of melanocyte transformation, antagonised by several tumour suppressing mechanisms. Among others, CDKN1C was identified as novel gene, whose loss most likely constitutes a second genetic ´hit´ required for melanoma progression. Besides new therapeutic targets to treat melanoma patients, the data may encode new markers for early recognition of individuals with increased risk for development of malignant melanoma.