Abstract
BackgroundCutaneous melanoma (CM) is the most aggressive subtype of skin cancer, with increasing incidence over the past several decades. DNA methylation is a key element of several biological processes such as genomic imprinting, cell differentiation and senescence, and deregulation of this mechanism has been implicated in several diseases, including cancer. In order to understand the relationship of DNA methylation in CMs, we searched for an epigenetic signature of cutaneous melanomas by comparing the DNA methylation profiles between tumours and benign melanocytes, the precursor cells of CM.MethodsWe used 20 primary CMs and three primary cell cultures of melanocytes as a discovery cohort. The tumours mutational background was collected as previously reported. Methylomes were obtained using the HM450K DNA methylation assay, and differential methylation analysis was performed. DNA methylation data of CMs from TCGA were recovered to validate our findings.ResultsA signature of 514 differentially methylated genes (DMGs) was evident in CMs compared to melanocytes, which was independent of the presence of driver mutations. Pathway analysis of this CM signature revealed an enrichment of proteins involved in the binding of DNA regulatory regions (hypermethylated sites), and related to transmembrane signal transducer activities (hypomethylated sites). The methylation signature was validated in an independent dataset of primary CMs, as well as in lymph node and distant metastases (correlation of DNA methylation level: r > 0,95; Pearson’s test: p < 2.2e-16).ConclusionsCMs exhibited a DMGs signature, which was independent of the mutational background and possibly established prior to genetic alterations. This signature provides important insights into how epigenetic deregulation contributes to melanomagenesis in general.
Highlights
Cutaneous melanoma (CM) is the most aggressive subtype of skin cancer, with increasing incidence over the past several decades
A set of 514 differentially methylated genes constitute an epigenetic signature for primary cutaneous melanomas As previously reported [7], this group of CMs is composed of 12 tumours harbouring CDKN2A inactivation; twelve tumours carried TERT promoter mutations, one sample had a KIT mutation, four samples had NRAS mutations, and seven had BRAF mutations
A total of 1396 differentially methylated genes (DMGs) promoters were detected in CMs compared to control melanocytes, the majority of which (1039) were hypermethylated
Summary
Cutaneous melanoma (CM) is the most aggressive subtype of skin cancer, with increasing incidence over the past several decades. DNA methylation is a key element of several biological processes such as genomic imprinting, cell differentiation and senescence, and deregulation of this mechanism has been implicated in several diseases, including cancer. In order to understand the relationship of DNA methylation in CMs, we searched for an epigenetic signature of cutaneous melanomas by comparing the DNA methylation profiles between tumours and benign melanocytes, the precursor cells of CM. DNA methylation is a key element of several biological processes such as genomic imprinting, cell differentiation and senescence, and deregulation of this. Efforts to understand the molecular biology of CM has led to improvements in the clinic, such as the discovery of recurrent mutations in the MAP kinase pathway, which are responsible for the transduction of proliferative extracellular signals. A hotspot mutation in the BRAF oncogene (BRAFV600E) is a target for selective inhibitors, which has been shown to improve the overall and progression-free survival of a group of patients [3].
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