DNA methylation is an important component of epigenetic modifications$backslash$nthat influences the transcriptional machinery and aberrant in many$backslash$nhuman diseases. In this study we present the first genome-wide integrative$backslash$nanalysis of promoter methylation and gene expression for the identification$backslash$nof methylation markers in melanoma. Genome-wide promoter methylation$backslash$nand gene expression of eight early-passage human melanoma cell strains$backslash$nwere compared to newborn and adult melanocytes. We used linear mixed$backslash$neffect models (LME) in combination with a series of filters based$backslash$non the localization of promoter methylation relative to the transcription$backslash$nstart site, overall promoter CpG content, and differential gene expression$backslash$nto discover DNA methylation markers. This approach identified 76$backslash$nmarkers, of which 68 were hyper- and 8 hypo-methylated (LME P textless 0.05).$backslash$nPromoter methylation and differential gene expression of five markers$backslash$n(COL1A2, NPM2, HSPB6, DDIT4L, MT1G) were validated by sequencing$backslash$nof bisulfite modified DNA and real-time reverse transcriptase PCR,$backslash$nrespectively. Importantly, the incidence of promoter methylation$backslash$nof the validated markers increased moderately in early- and significantly$backslash$nin advanced-stage melanomas, employing early-passage cell strains$backslash$nand snap frozen tissues (n = 18 and n = 24, respectively) compared$backslash$nto normal melanocytes and nevi (n = 11 and n = 9, respectively).$backslash$nOur approach allows robust identification of methylation markers$backslash$nthat can be applied to other studies involving genome-wide promoter$backslash$nmethylation. In conclusion, this study represents the first unbiased$backslash$nsystematic effort to determine methylation markers in melanoma, and$backslash$nrevealed several novel genes regulated by promoter methylation that$backslash$nwere not described in cancer cells before.