Genome‐wide promoter methylation analysis identifies epigenetic silencing of MAPK13 in primary cutaneous melanoma

• Published in: Pigment cell and melanoma research 2013-07, Vol.26 (4), p.542-554
• Main Authors: Gao, Linda, Smit, Marjon A., den Oord, Joost J., Goeman, Jelle J., Verdegaal, Els M. E., Burg, Sjoerd H., Stas, Marguerite, Beck, Samuel, Gruis, Nelleke A., Tensen, Cornelis P., Willemze, Rein, Peeper, Daniel S., Doorn, Remco
• Format: Article
• Language: English
• Subjects: Cell Proliferation; CpG Islands; Disease Progression; DNA Methylation; Epigenesis, Genetic; epigenetics; Epigenomics; Fibroblasts - cytology; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Gene Silencing; Genome-Wide Association Study; Humans; MAPK13; Melanocytes - cytology; melanoma; Melanoma - metabolism; Melanoma, Cutaneous Malignant; Mitogen-Activated Protein Kinase 13 - metabolism; Nevus - metabolism; p38; p38 Mitogen-Activated Protein Kinases - metabolism; primary cutaneous melanoma; Promoter Regions, Genetic; Skin Neoplasms - metabolism; Sulfites - chemistry
• ISSN: 1755-1471; 1755-148X
• DOI: 10.1111/pcmr.12096

Summary The involvement of epigenetic alterations in the pathogenesis of melanoma is increasingly recognized. Here, we performed genome‐wide DNA methylation analysis of primary cutaneous melanoma and benign melanocytic nevus interrogating 14 495 genes using BeadChip technology. This genome‐wide view of promoter methylation in primary cutaneous melanoma revealed an array of recurrent DNA methylation alterations with potential diagnostic applications. Among 106 frequently hypermethylated genes, there were many novel methylation targets and tumor suppressor genes. Highly recurrent methylation of the HOXA9, MAPK13, CDH11, PLEKHG6, PPP1R3C, and CLDN11 genes was established. Promoter methylation of MAPK13, encoding p38δ, was present in 67% of primary and 85% of metastatic melanomas. Restoration of MAPK13 expression in melanoma cells exhibiting epigenetic silencing of this gene reduced proliferation, indicative of tumor suppressive functions. This study demonstrates that DNA methylation alterations are widespread in melanoma and suggests that epigenetic silencing of MAPK13 contributes to melanoma progression.