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

Abstract

BackgroundCutaneous 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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 materialThe online version of this article (doi:10.1186/s12916-017-0851-3) contains supplementary material, which is available to authorized users.

Survival between synchronous and non-synchronous multiple primary cutaneous melanomas—a SEER database analysis

“…Thus, the potential pathology of synchronous MPM needs to be illustrated in the future. Furthermore, many molecular events such as mutation (Demunter et al, 2001;Griewank et al, 2014), copy number variation (Rákosy et al, 2010;Gerami et al, 2011), epigenetic variation (Roh et al, 2016;Wouters et al, 2017), expression of genes (Brown et al, 2012;Schramm et al, 2012) and non-coding RNAs (Xiong, Bing & Guo, 2019;Yang, Xu & Zeng, 2018) were reported to be involved in the prognosis of CM. Further laboratory studies aimed to investigate the potential molecular mechanisms of synchronous MPM occurrence and its prognostic roles are also in need.…”

Epigenetics in Melanoma Development and Drug Resistance

“…DNA methylation changes, however, are not limited to melanoma development (nevi versus primary melanoma) but are also apparent in melanoma progression (primary melanoma versus metastatic melanoma). DNA methylation profiling using Illumina Infinium Human Methylation 450 K Beadchips of 14 normal nevi, 33 primary melanomas and 28 melanoma metastases identified gene promoters that were hypermethylated during melanoma development or melanoma progression [56]. Promoter methylation of several identified genes including HOXA9, MEOX2, RBP1, TFAP2B, TWIST1…”

“…AKT3 and TFAP2B protein expression was also confirmed as biomarkers suitable for staining by immunohistochemistry. Furthermore, Wouters, et al were able to correlate hypomethylation of MEOX2, OLIG3 and PON3 promoter hypomethylation with increased overall free survival [56]. Another major player in melanoma development that has been shown to be regulated by DNA methylation is Phosphatase and Tensin Homolog (PTEN).…”

Epigenetics of skin cancer: Interventions by selected bioactive phytochemicals

“…However, in the process of neoplastic transformation, DNA methylation in cancer cells is different as compared to regular cells with focal hypermethylation of CpG islands in many genes . Thus, an altered DNA methylation profile is hallmark of almost all types of human cancers, including skin cancer …”