title: Blood DNA methylation, nevi number, and the risk of melanoma.
abstract: 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 (p16, p14, 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.
authors.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Pergoli
authors.forename: Chiara
authors.initials: C
authors.lastname: Favero
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Pfeiffer
authors.forename: Letizia
authors.initials: L
authors.lastname: Tarantini
authors.forename: Donato
authors.initials: D
authors.lastname: Calista
authors.forename: Tommaso
authors.initials: T
authors.lastname: Cavalleri
authors.forename: Laura
authors.initials: L
authors.lastname: Angelici
authors.forename: Dario
authors.initials: D
authors.lastname: Consonni
authors.forename: Pier A
authors.initials: PA
authors.lastname: Bertazzi
authors.forename: Angela C
authors.initials: AC
authors.lastname: Pesatori
authors.forename: Maria T
authors.initials: MT
authors.lastname: Landi
authors.forename: Valentina
authors.initials: V
authors.lastname: Bollati
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D020087:Alu Elements; D016022:Case-Control Studies; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D015686:Gene Products, env / Q000235:genetics; D006801:Humans; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000166:cytology; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D008545:Melanoma / Q000097:blood* / Q000235:genetics*; D015999:Multivariate Analysis; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009506:Nevus / Q000235:genetics* / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics; D011257:Pregnancy Proteins / Q000235:genetics; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics; D012307:Risk Factors; D012878:Skin Neoplasms; D019098:Telomerase / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics; D000096142:Cutaneous Malignant Melanoma
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015686:Gene Products, env; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D011257:Pregnancy Proteins; D044102:Receptor, Melanocortin, Type 1; D014409:Tumor Necrosis Factor-alpha; D025803:Tumor Suppressor Protein p14ARF; C405335:syncytin; D018799:Intercellular Adhesion Molecule-1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; C509186:TERT protein, human; D019098:Telomerase; D000070957:MutL Protein Homolog 1