title: Skewed expression of the genes encoding epigenetic modifiers in high-risk uveal melanoma.
abstract: OBJECTIVE
  Monosomy 3 (M3) or the presence of a specific RNA expression profile, known as class 2, is strongly associated with death from uveal melanoma (UM). Given the important role of epigenetic processes in cancer development and progression, we compared the transcriptional profiles of a selection of epigenetic regulators between primary UM with a good and a bad prognosis.
  
  
  METHODS
  Transcriptional levels of 59 epigenetic regulator genes were measured by quantitative PCR (qPCR) in 20 UM, 12 with monosomy of chromosome 3 (M3) and 8 with disomy of chromosome 3 (D3). Validation was performed in an independent cohort. Expression levels were compared to clinicopathological characteristics, including class type. Bisulfite sequencing was used to evaluate the role of DNA methylation in gene silencing.
  
  
  RESULTS
  In the first set of tumors, general downregulation of transcription of the genes encoding epigenetic regulatory enzymes was seen in association with M3. The 10 genes with the highest differential expression between M3 and D3 were selected and were analyzed in a second set of tumors. In the validation set, significantly lower levels of KAT2B (P = 0.008), HDAC11 (P = 0.009), KMT1C (P = 0.05), KDM4B (P = 0.003), KDM6B (P = 0.04), and BMI-1 (P = 0.001) transcripts were found in tumors with M3/class 2. Methylation of C-phosphate-G (CpG) residues was not observed on the putative regulatory regions of KAT2B, KDM4B, or KDM6B.
  
  
  CONCLUSIONS
  Expression levels of a number of histone-modifying genes and polycomb family members are significantly lower in uveal melanoma with monosomy 3/class 2, supporting a general dysregulation of epigenetic modifiers in UM with a bad prognosis.
authors.affiliation: Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Naoimh
authors.initials: N
authors.lastname: Herlihy
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Dogrusöz
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: T Huibertus
authors.initials: TH
authors.lastname: van Essen
authors.affiliation: Bascom Palmer Eye Institute, Miami, Florida, United States.
authors.forename: J William
authors.initials: JW
authors.lastname: Harbour
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Pieter A
authors.initials: PA
authors.lastname: van der Velden
authors.affiliation: Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marja C J A
authors.initials: MC
authors.lastname: van Eggermond
authors.affiliation: Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Geert W
authors.initials: GW
authors.lastname: Haasnoot
authors.affiliation: Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van den Elsen
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Jager
mesh_terms: D000328:Adult; D000368:Aged; D019175:DNA Methylation / Q000235:genetics; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D020868:Gene Silencing; D005809:Genes, Regulator / Q000235:genetics; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D011379:Prognosis; D014158:Transcription, Genetic / Q000235:genetics; D014602:Uvea / Q000473:pathology; D014604:Uveal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000098943:Uveal Melanoma
keywords: epigenetics; gene expression; melanoma; oncology; uvea