title: KIT is a frequent target for epigenetic silencing in cutaneous melanoma.
abstract: The receptor tyrosine kinase KIT and its ligand, stem cell factor (SCF), are essential for the proliferation and survival of normal melanocytes. In melanomas arising on mucosal, acral, and chronically sun-damaged skin, activating KIT mutations have been identified as oncogenic drivers and potent therapeutic targets. Through an initial whole-genome screen for aberrant promoter methylation in melanoma, we identified the KIT promoter as a target for hypermethylation in 43/110 melanoma cell lines, and in 3/12 primary and 11/29 metastatic cutaneous melanomas. Methylation density at the KIT promoter correlated inversely with promoter activity in vitro and in vivo, and the expression of KIT was restored after treatment with the demethylating agent 5-aza-2'-deoxycytidine. Hypermethylation of KIT showed no direct or inverse correlations with well-documented melanoma drivers. Growth of melanoma cells in the presence of SCF led to reduced KIT expression and increased methylation density at the KIT promoter, suggesting that SCF may exert a selection pressure for the loss of KIT. The frequent loss of KIT in cutaneous melanoma by promoter hypermethylation suggests that distinct KIT signaling pathways have opposing roles in the pathogenesis of melanoma subtypes.
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Christina
authors.initials: C
authors.lastname: Dahl
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Cecilie
authors.initials: C
authors.lastname: Abildgaard
authors.affiliation: Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Rikke
authors.initials: R
authors.lastname: Riber-Hansen
authors.affiliation: Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Steiniche
authors.affiliation: Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Johanne
authors.initials: J
authors.lastname: Lade-Keller
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark. Electronic address: perg@cancer.dk.
authors.forename: Per
authors.initials: P
authors.lastname: Guldberg
mesh_terms: D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D011401:Promoter Regions, Genetic; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics*; D019089:Stem Cell Factor / Q000502:physiology
chemical_list: D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit