Investigation of mutational profile in cutaneous melanoma and impact on the global DNA methylation pattern

Abstract

Melanoma is a malignant tumor that originates in melanocytes. Although rare, cutaneous melanoma is responsible for 75% of all deaths from tumors in this anatomical site, and is considered an aggressive and difficult to treat disease.Mutations in BRAF and NRAS genes are present in 25% -80% and 20% of melanoma cases, respectively. Mutations that occur more frequently in these genes result in an increase in catalytic activity of their products, leading to constitutive activation of pathways related to the control of cell growth and proliferation.DNA methylation is a major mechanism of epigenetic control; in tumor cells, both events of global DNA hypomethylation, as events of hypermethylation in promoter regions of tumor suppressor genes, which contribute to the emergence of the malignant phenotype, were observed. The DNA methylation status of the entire genome of many samples can be investigated in a comprehensive, reduced cost manner, using microarray-based technologies such as the Illumina bead array, that simultaneously analyze> 450,000 CpGs dinucleotides, representing 99% of the RefSeq gene.We propose in this project perform an integrated analysis of the overall profile of DNA methylation in a group of cutaneous melanomas and correlate this profile with the mutational pattern of BRAF, NRAS and KIT genes. We expect this strategy to assist in the design of a specific epigenetic panel for tumors with these mutations, with the identification of expressed genes controlled by DNA methylation, which play a relevant role in the tumorigenesis of cutaneous melanoma.