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Background  Cutaneous melanoma is the deadliest skin cancer, with an increasing incidence and mortality rate. Currently, staging of patients with primary melanoma is performed using histological biomarkers such as tumor thickness and ulceration. As disruption of the epigenomic landscape is recognized as a widespread feature inherent in tumor development and progression, we aimed to identify novel biomarkers providing additional clinical information over current factors using unbiased genome-wide DNA methylation analyses.    Methods  We performed a comprehensive DNA methylation analysis during all progression stages of melanoma using Infinium HumanMethylation450 BeadChips on a discovery cohort of benign nevi (n = 14) and malignant melanoma from both primary (n = 33) and metastatic (n = 28) sites, integrating the DNA methylome with gene expression data. We validated the discovered biomarkers in three independent validation cohorts by pyrosequencing and immunohistochemistry.    Results  We identified and validated biomarkers for, and pathways involved in, melanoma development (e.g.,  HOXA9  DNA methylation) and tumor progression (e.g.,  TBC1D16  DNA methylation). In addition, we determined a prognostic signature with potential clinical applicability and validated  PON3  DNA methylation and OVOL1 protein expression as biomarkers with prognostic information independent of tumor thickness and ulceration.    Conclusions  Our data underscores the importance of epigenomic regulation in triggering metastatic dissemination through the inactivation of central cancer-related pathways. Inactivation of cell-adhesion and differentiation unleashes dissemination, and subsequent activation of inflammatory and immune system programs impairs anti-tumoral defense pathways. Moreover, we identify several markers of tumor development and progression previously unrelated to melanoma, and determined a prognostic signature with potential clinical utility.    Electronic supplementary material  The online version of this article (doi:10.1186/s12916-017-0851-3) contains supplementary material, which is available to authorized users.

Comprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma