title: Altered global methylation and hydroxymethylation status in vulvar lichen sclerosus: further support for epigenetic mechanisms.
abstract: BACKGROUND
  Epigenetics refers to functionally relevant changes in the genome other than those of DNA sequence that can lead to changes in gene expression or cellular phenotype. There is evidence that epigenetics is relevant in the pathogenesis of autoimmune diseases such as vulvar lichen sclerosus (VLS), as well as in cancer, including cutaneous squamous cell carcinoma, which is frequently associated with VLS.
  
  
  OBJECTIVE
  To study the global methylation and hydroxymethylation status in healthy controls and VLS lesions before and after long-term ultraviolet (UV)A1 treatment.
  
  
  METHODS
  We studied 12 controls and 10 patients with VLS who were treated with medium-dose UVA1 four times weekly for 3 months. Immunohistochemistry and mutation analyses (polymerase chain reaction) were performed for 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), isocitrate dehydrogenases (IDHs) and the ten-eleven translocation (TET)2 enzyme.
  
  
  RESULTS
  After 3 months of treatment, 5mC was significantly increased in VLS compared with baseline and controls. However, compared with controls 5hmC levels were significantly reduced in baseline VLS, but normalized after UVA1 treatment. Compared with controls, IDH1 expression was significantly higher in both treated and baseline VLS. By contrast, IDH2 levels were significantly reduced in baseline VLS compared with controls and UVA1-treated VLS. However, gene sequencing of the IDH1, IDH2 and TET2 genes did not reveal evidence of mutations.
  
  
  CONCLUSIONS
  VLS is associated with altered expression of IDH enzymes and aberrant hydroxymethylation, indicating an epigenetic background for the pathogenesis of VLS. UVA1 phototherapy may cause normalization of 5hmC patterns, but also global DNA hypermethylation in VLS lesions, raising concerns with respect to an increased risk of photocarcinogenesis.
authors.affiliation: Department of Dermatology, Ruhr-University Bochum, Gudrunstraße 56, 44791, Bochum, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Gambichler
authors.forename: S
authors.initials: S
authors.lastname: Terras
authors.forename: A
authors.initials: A
authors.lastname: Kreuter
authors.forename: M
authors.initials: M
authors.lastname: Skrygan
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D049308:Dioxygenases; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014467:Ultraviolet Therapy; D007724:Vulvar Lichen Sclerosus / Q000235:genetics* / Q000532:radiotherapy
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D044503:5-Methylcytosine; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; D049308:Dioxygenases; C541081:TET2 protein, human