Aberrant DNA methylation is associated with aggressive clinicopathological features and poor survival in cutaneous melanoma

Promoter methylation of tumour suppressor genes (TSGs) has recently been implicated in the pathogenesis of several types of cancer. Regarding melanoma, over 100 genes that contribute to its pathogenesis have been identified to be aberrantly hypermethylated.This is a retrospective observational study that aims to analyse the prevalence of CpG island methylation in a series of primary melanomas, to identify the associations with the main clinicopathological features, and to explore the prognostic significance of methylation in melanoma survival.DNA methylation was analysed using methylation-specific multiplex ligation-dependent probe amplification in a series of 170 melanoma formalin-fixed paraffin-embedded tumour samples. The relationship between the methylation status, known somatic mutations and clinicopathological features was evaluated. Disease-free survival (DFS) and overall survival (OS) were displayed by the Kaplan-Meier method.In the entire cohort, one or more genes were detected to be methylated in 55% of the patients. The most prevalent methylated genes were RARB 31%, PTEN 24%, APC 16%, CDH13 16%, ESR1 14%, CDKN2A 6% and RASSF1 5%. An association between aberrant methylation and aggressive clinicopathological features was observed (older age, increased Breslow thickness, presence of mitosis and ulceration, fast-growing melanomas, advancing stage and TERT mutations). Furthermore, Kaplan-Meier survival analysis showed a correlation of methylation and poorer DFS and OS.Aberrant methylation of TSGs is a frequent event in melanoma. It is associated with aggressive clinicopathological features and poorer survival. Epigenetic alterations may represent a significant prognostic marker with utility in routine practice.