Genetic and epigenetic factors in the etiology of the cutaneous melanoma

Abstract

The cutaneous melanoma is a rare skin cancer highly aggressive that accounts for up to 75% of the deaths by cutaneous tumors. The majority is sporadic but about 10% of the cases occurs in individuals carrying a germinative mutation. There are two main known melanoma predisposition genes exhibiting highly penetrant mutations: CDKN2A and CDK4, both of them also somatically inactivated in sporadic melanomas. However, CDKN2A mutations (mainly affecting p16) are detected in only 20-40% of the hereditary cutaneous melanoma - characterized by familial aggregation and/or multiple primary melanomas - indicating that a great proportion of the melanoma susceptibility has no known genetic etiology. This scenario indicates either the existence of susceptibility genes yet not revealed or alternative mechanisms to point mutations.Rare genomic deletions and duplications, and genetic variants conferring intermediate cancer risk can also increase the cancer susceptibility; recently, studies have suggested that germinative epimutations (such as aberrant DNA methylation pattern) can provoke cancer predisposition. The identification of the etiology of the melanoma susceptibility is crucial not only to the ascertaining of individuals with a high cancer risk but also to the widening of the tumor biology understanding; susceptibility cancer genes often are also mutated in sporadic tumors. Therefore, the research on the genome and epigenome of patients and their tumors can aid in the identification of molecular pathways involved in the genesis and progression of the cutaneous melanoma that could be future targets for intervention.The main objective of this project is the identification of novel genetic and epigenetic factors associated to the susceptibility and development of cutaneous melanomas. The experimental design to achieving this goal is: (a) investigation of the genome (mainly CNV analysis, and TERT mutation screening) and epigenome (CDKN2A promotor methylation and global DNA methylation for a subset)of a group of patients with high melanoma predisposition who are negative for CDKN2A/CDK4 mutations; (b) study of the methylome of 30 cutaneous melanoma aiming to establish correlation with the mutational profile of the genes NRAS, BRAF, KIT, and TERT. Following the analysis of these data, genes will be selected for validation of their relevance in the cutanelus melanoma. (AU)