Prognostic Significance of Promoter Hypermethylation and Diminished Gene Expression of SYNPO2 in Melanoma.

This is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication. NPG are providing this early version of the manuscript as a service to our customers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply. 3 Once cutaneous melanoma metastasizes prognosis of patients is generally poor in spite of recent therapeutic advances. Prognostic biomarkers are needed to better identify those patients with primary melanoma who are at increased risk of metastatic disease. Gene expression signatures have been defined that are associated with metastatic capacity of primary melanoma and survival diverse recurrent genetic alterations including those that drive the tumorigenic process. However, the underlying molecular changes that confer the capacity to melanoma cells to migrate and colonize distant body sites remain to be defined. Promoter CpG island hypermethylation constitutes a mechanism responsible for deregulated expression of genes involved in metastasis. We and others have identified epigenetic alterations in melanoma affecting genes with a potential role in tumour cell dissemination including CDH11 and SERPINB5 (Carmona et al., 2012; Dahl et al., 2015; Gao et al., 2013). Additionally a 17-gene methylation signature was found to predict disease course of stage IIIC melanoma patients (Sigalotti et al., 2012). As epigenetic biomarker for metastasis, promoter hypermethylation has the advantage that it is stable and can be reliably detected in clinical samples. The purpose of this study was to identify methylation events that can predict development of lethal metastatic disease in patients with primary cutaneous melanoma. To this end, we collected clinical follow-up data of 24 patients with primary melanoma whose tumours had been previously subjected to genome-wide DNA methylation profiling using Illumina 27K arrays, analyzing methylation of 14,495 genes (Gao et al., 2013). Thirteen patients had developed distant metastases, all of whom died due to melanoma, and in 11 patients no metastatic dissemination or tumour recurrence had been detected during a follow-up period of at least six years after diagnosis. We compared methylation profiles from primary melanomas of patients who developed lethal distant organ metastasis (M+) to those from primary melanomas of patients who had not developed metastasis (M-). CpG probes with an average-value difference (a measure of differential DNA methylation reflecting fluorescence intensity ratios between methylated and unmethylated alleles) …