title: Higher Nevus Count Exhibits a Distinct DNA Methylation Signature in Healthy Human Skin: Implications for Melanoma.
abstract: High nevus count is the strongest risk factor for melanoma, and although gene variants have been discovered for both traits, epigenetic variation is unexplored. We investigated 322 healthy human skin DNA methylomes associated with total body nevi count, incorporating genetic and transcriptomic variation. DNA methylation changes were identified at genes involved in melanocyte biology, such as RAF1 (P = 1.2 × 10-6) and CTC1 (region: P = 6.3 × 10-4), and other genes including ARRDC1 (P = 3.1 × 10-7). A subset exhibited coordinated methylation and transcription changes within the same biopsy. The total analysis was also enriched for melanoma-associated DNA methylation variation (P = 6.33 × 10-6). In addition, we show that skin DNA methylation is associated in cis with known genome-wide association study single nucleotide polymorphisms for nevus count, at PLA2G6 (P = 1.7 × 10-49) and NID1 (P = 6.4 × 10-14), as well as melanoma risk, including in or near MC1R, MX2, and TERT/CLPTM1L (P < 1 × 10-10). Our analysis using a uniquely large dataset comprising healthy skin DNA methylomes identified known and additional regulatory loci and pathways in nevi and melanoma biology. This integrative study improves our understanding of predisposition to nevi and their potential contribution to melanoma pathogenesis.
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK; MRC London Institute of Medical Sciences, London, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK. Electronic address: l.roos@imperial.ac.uk.
authors.forename: Leonie
authors.initials: L
authors.lastname: Roos
authors.affiliation: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Johanna K
authors.initials: JK
authors.lastname: Sandling
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK; MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK; Human Development and Health Academic Unit, Institute of Developmental Sciences, University of Southampton, Southampton, UK; Epigenomic Medicine, Centre for Biological Sciences, Faculty of Environmental and Natural Sciences, University of Southampton, Southampton, UK.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Bell
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Glass
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: William Harvey Research Institute, Queen Mary University of London, London, UK.
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Veronique
authors.initials: V
authors.lastname: Bataille
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Jordana T
authors.initials: JT
authors.lastname: Bell
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D019175:DNA Methylation / Q000235:genetics*; D057890:Epigenomics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D008545:Melanoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D009506:Nevus / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D012016:Reference Values; D012042:Registries; D012878:Skin Neoplasms / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D006113:United Kingdom