The DNA methylation landscape of human melanoma

•We discovered 179 tumor-specific methylation peaks present in all (27/27) melanomas.•We describe 3 gene categories for the interplay between H3K27me3 and DNA methylation.•We found no relationship between BRAF mutations and the number of methylation peaks.•Gene expression analysis showed upregulated immune response genes in melanomas.•Melanocyte differentiation factors KIT, PAX3 and SOX10 were methylated and silenced in tumors.

Using MIRA-seq, we have characterized the DNA methylome of metastatic melanoma and normal melanocytes. Individual tumors contained several thousand hypermethylated regions. We discovered 179 tumor-specific methylation peaks present in all (27/27) melanomas that may be effective disease biomarkers, and 3113 methylation peaks were seen in > 40% of the tumors. We found that 150 of the approximately 1200 tumor-associated methylation peaks near transcription start sites (TSSs) were marked by H3K27me3 in melanocytes. DNA methylation in melanoma was specific for distinct H3K27me3 peaks rather than for broadly covered regions. However, numerous H3K27me3 peak-associated TSS regions remained devoid of DNA methylation in tumors. There was no relationship between BRAF mutations and the number of methylation peaks. Gene expression analysis showed upregulated immune response genes in melanomas presumably as a result of lymphocyte infiltration. Down-regulated genes were enriched for melanocyte differentiation factors; e.g., KIT, PAX3 and SOX10 became methylated and downregulated in melanoma.