Abstract
In melanoma, the presence of promoter related hypermethylation has previously been reported, however, no methylation-based distinction has been drawn among the diverse melanoma subtypes. Here, we investigated DNA methylation changes associated with melanoma progression and links between methylation patterns and other types of somatic alterations, including the most frequent mutations and DNA copy number changes. Our results revealed that the methylome, presenting in early stage samples and associated with the BRAFV600E mutation, gradually decreased in the medium and late stages of the disease. An inverse relationship among the other predefined groups and promoter methylation was also revealed except for histologic subtype, whereas the more aggressive, nodular subtype melanomas exhibited hypermethylation as well. The Breslow thickness, which is a continuous variable, allowed for the most precise insight into how promoter methylation decreases from stage to stage. Integrating our methylation results with a high-throughput copy number alteration dataset, local correlations were detected in the MYB and EYA4 genes. With regard to the effects of DNA hypermethylation on melanoma patients' survival, correcting for clinical cofounders, only the KIT gene was associated with a lower overall survival rate. In this study, we demonstrate the strong influence of promoter localized DNA methylation changes on melanoma initiation and show how hypermethylation decreases in melanomas associated with less favourable clinical outcomes. Furthermore, we establish the methylation pattern as part of an integrated apparatus of somatic DNA alterations.
Highlights
DNA methylation, along with covalent histone posttranslational modifications, chromatin remodelling and non-coding RNAmediated gene interference, represents an important mechanism in the integrated apparatus of epigenetic regulation [1,2]
It has become widely accepted that Knudson’s two-hit hypothesis is often confirmed through a combination of differing types of genomic alterations [17,18], which prompted us to investigate whether methylation patterns are associated with other types of somatic alterations, such as the most frequent mutations (BRAF and NRAS) and DNA copy number (CN) alterations
As the multivariate permutation test provides a tight probabilistic control on the proportion of false discoveries, this test was used for class comparison on each predefined subgroup according to the following criteria: CpG sites were considered differentially methylated when their p values were less than 0.01 and FDR rates were below 0.2
Summary
DNA methylation, along with covalent histone posttranslational modifications, chromatin remodelling and non-coding RNAmediated gene interference, represents an important mechanism in the integrated apparatus of epigenetic regulation [1,2]. In addition to playing a role in several physiological processes [3,4,5], epigenetic mechanisms have been described as key factors in modifying the accessibility of DNA to transcription factors and, in altering the gene expression patterns of several cancer types [6,7,8]. In the field of malignant melanoma epigenetics, there are substantial amounts of data available regarding gene silencing associated with the localised CpG hypermethylation of specific gene promoters. We and others have demonstrated the association of BRAF and NRAS mutations with CN alterations using BAC arrays, suggesting a central role of BRAF mutations in gene copy number changes [21,24,25]. We aimed to obtain better insight into how the DNA methylation changes are associated with distinct somatic alterations and contribute to melanoma progression
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