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Higher Nevus Count Exhibits a Distinct DNA Methylation Signature in Healthy Human Skin: Implications for Melanoma
Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England.;MRC London Inst Med Sci, London, England.;Imperial Coll London, Inst Clin Sci, Fac Med, Du Cane Rd, London W12 0NN, England..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England.;Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England.;Univ Southampton, Human Dev & Hlth Acad Unit, Inst Dev Sci, Southampton, Hants, England.;Univ Southampton, Fac Environm & Nat Sci, Ctr Biol Sci, Epigen Med, Southampton, Hants, England..
Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
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2017 (English)In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 137, no 4, p. 910-920Article in journal (Refereed) Published
Abstract [en]

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 = 1.2x10(-6)) and CTC1 (region: P = 6.3 x 10(-4)), and other genes including ARRDC1 (P = 3.1 x 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 x 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 x 10(-49)) and NID1 (P = 6.4 x 10(-14)), as well as melanoma risk, including in or near MC1R, MX2, and TERT/CLPTM1L (P < 1 x 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.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC , 2017. Vol. 137, no 4, p. 910-920
National Category
Dermatology and Venereal Diseases
Identifiers
URN: urn:nbn:se:uu:diva-319526DOI: 10.1016/j.jid.2016.11.029ISI: 000396884400020PubMedID: 27993549OAI: oai:DiVA.org:uu-319526DiVA, id: diva2:1087267
Funder
EU, FP7, Seventh Framework Programme, 316758Wellcome trustSwedish Research Council, Dnr 350-2012-256Available from: 2017-04-06 Created: 2017-04-06 Last updated: 2017-11-29Bibliographically approved

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