title: Promoter CpG island hypermethylation in dysplastic nevus and melanoma: CLDN11 as an epigenetic biomarker for malignancy.
abstract: Dysplastic nevi are melanocytic lesions that represent an intermediate stage between common nevus and melanoma. Histopathological distinction of dysplastic nevus from melanoma can be challenging and there is a requirement for molecular diagnostic markers. In this study, we examined promoter CpG island methylation of a selected panel of genes, identified in a genome-wide methylation screen, across a spectrum of 405 melanocytic neoplasms. Promoter methylation analysis in common nevi, dysplastic nevi, primary melanomas, and metastatic melanomas demonstrated progressive epigenetic deregulation. Dysplastic nevi were affected by promoter methylation of genes that are frequently methylated in melanoma but not in common nevi. We assessed the diagnostic value of the methylation status of five genes in distinguishing primary melanoma from dysplastic nevus. In particular, CLDN11 promoter methylation was specific for melanoma, as it occurred in 50% of primary melanomas but in only 3% of dysplastic nevi. A diagnostic algorithm that incorporates methylation of the CLDN11, CDH11, PPP1R3C, MAPK13, and GNMT genes was validated in an independent sample set and helped distinguish melanoma from dysplastic nevus (area under the curve 0.81). Melanoma-specific methylation of these genes supports the utility as epigenetic biomarkers and could point to their significance in melanoma development.
authors.affiliation: Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands; The first two and last three authors contributed equally to this work.
authors.forename: Linda
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands; The first two and last three authors contributed equally to this work.
authors.forename: Karin
authors.initials: K
authors.lastname: van den Hurk
authors.affiliation: Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Peter T M
authors.initials: PTM
authors.lastname: Moerkerk
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands; Current address: Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jelle J
authors.initials: JJ
authors.lastname: Goeman
authors.affiliation: Leiden Cytology and Pathology Laboratory, Leiden, The Netherlands.
authors.forename: Samuel
authors.initials: S
authors.lastname: Beck
authors.affiliation: Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Nelleke A
authors.initials: NA
authors.lastname: Gruis
authors.affiliation: Laboratory of Translational Cell and Tissue Research, Department of Pathology, University Hospital, University of Leuven, Leuven, Belgium.
authors.forename: Joost J
authors.initials: JJ
authors.lastname: van den Oord
authors.affiliation: Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands; The first two and last three authors contributed equally to this work.
authors.forename: Véronique J
authors.initials: VJ
authors.lastname: Winnepenninckx
authors.affiliation: Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands; The first two and last three authors contributed equally to this work.
authors.forename: Manon
authors.initials: M
authors.lastname: van Engeland
authors.affiliation: Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands; The first two and last three authors contributed equally to this work. Electronic address: rvandoorn@lumc.nl.
authors.forename: Remco
authors.initials: R
authors.lastname: van Doorn
mesh_terms: D000465:Algorithms; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000502:physiology; D015820:Cadherins / Q000235:genetics / Q000502:physiology; D063646:Carcinogenesis / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D057167:Claudins / Q000235:genetics* / Q000502:physiology; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics* / Q000502:physiology; D004273:DNA, Neoplasm / Q000235:genetics*; D004416:Dysplastic Nevus Syndrome / Q000235:genetics* / Q000503:physiopathology; D057890:Epigenomics; D050938:Glycine N-Methyltransferase / Q000235:genetics / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008545:Melanoma / Q000235:genetics* / Q000503:physiopathology; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012680:Sensitivity and Specificity; D012878:Skin Neoplasms / Q000235:genetics* / Q000503:physiopathology
chemical_list: D014408:Biomarkers, Tumor; C120453:CLDN11 protein, human; D015820:Cadherins; D002352:Carrier Proteins; D057167:Claudins; D004273:DNA, Neoplasm; D047908:Intracellular Signaling Peptides and Proteins; C491294:PPP1R3C protein, human; C086960:osteoblast cadherin; C494510:GNMT protein, human; D050938:Glycine N-Methyltransferase; D010749:Phosphoprotein Phosphatases