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Blood DNA methylation, nevi number, and the risk of melanoma

Pergoli, Lauraa; Favero, Chiaraa; Pfeiffer, Ruth M.d; Tarantini, Letiziaa; Calista, Donatoc; Cavalleri, Tommasoa; Angelici, Lauraa; Consonni, Dariob; Bertazzi, Pier A.a,b; Pesatori, Angela C.a,b; Landi, Maria T.d; Bollati, Valentinaa,b

doi: 10.1097/CMR.0000000000000112

Germline mutations determining increased cutaneous malignant melanoma (CMM) risk have been identified in familial and sporadic CMM cases, but they account only for a small proportion of CMM cases. Recent evidence suggests that germline epimutations (e.g. DNA methylation alterations), which can be inherited similarly to genomic mutations and can be detected in normal body cells (including blood), might increase susceptibility to cancer. The aim of the study was to identify germline epimutations of genes that were found to be mutated in familial CMM (p16INK4a, p14ARF, CDK4, MC1R, hTERT), immune and inflammatory genes (ICAM-1, TNFα), DNA mismatch repair gene (MLH1), and repetitive elements (ALU, LINE-1, HERV-w). We measured DNA methylation using bisulfite pyrosequencing in peripheral blood mononuclear cells from 167 CMM cases and 164 sex-matched and age-matched controls. We used multivariable logistic regression models to evaluate the association between methylation levels and CMM status or presence of dysplastic nevi. We found an association between the risk of CMM and peripheral blood mononuclear cell methylation levels of TNFα [odds ratio (OR)=1.11, 95% confidence interval (CI)=1.03–1.18], CDK4 (OR=0.76, 95% CI=0.64–0.91), and MLH1 (OR=1.12, 95% CI=1.02–1.22). In control participants, the risk of developing dysplastic nevi was associated with methylation levels of TNFα (OR=0.81, 95% CI=0.69–0.95), hTERT (OR=0.90, 95% CI=0.82–0.99), and ALU (OR=1.56, 95% CI=1.02–2.39). Epimutations in CMM susceptibility genes and in genes involved in response to oxidative damage are associated with the risk of developing CMM or dysplastic nevi. Further studies measuring methylation levels of these genes in prospectively collected samples are warranted to further elucidate their role in the development and progression of CMM.

aCenter of Molecular and Genetic Epidemiology, Department of Clinical Sciences and Community Health, Università degli Studi di Milano

bEpidemiology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan

cDermatology Unit, Bufalini Hospital, Cesena, Italy

dDivision of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA

All supplementary digital content is available directly from the corresponding author.

Correspondence to Valentina Bollati, PhD, Center of Molecular and Genetic Epidemiology, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via San Barnaba 8, 20122 Milan, Italy Tel: +39 02 503 20127; fax: +39 02 503 20126; e-mail:

Received November 26, 2013

Accepted June 17, 2014

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins