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

Abstract

Background

Promoter methylation of tumor suppressor genes (TSGs) has recently been implicated in the pathogenesis of several types of cancer. Regarding melanoma, over a hundred genes that contribute to its pathogenesis have been identified to be aberrantly hypermethylated. This is a retrospective observational study that aims to analyze the prevalence of CpG island methylation in a series of primary melanoma, to identify the associations with the main clinicopathological features, and to explore the prognostic significance of methylation in melanoma survival.

Materials and Methods

DNA methylation was analyzed using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in a series of 170 melanoma formalin-fixed paraffin embedded (FFPE) tumor 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.

Results

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, 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 overall survival OS.

Conclusions

Aberrant methylation of TSGs is a frequent event in melanoma. It is associated to aggressive clinicopathological features and poorer survival. Epigenetic alterations may represent a significant prognostic marker with utility in routine practice.

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