{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T04:05:26Z","timestamp":1780545926717,"version":"3.54.1"},"reference-count":53,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T00:00:00Z","timestamp":1622073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for noninvasive tests aimed at an MPM risk assessment tool that might improve life expectancy. Three hundred asbestos-exposed subjects (163 MPM cases and 137 cancer-free controls), from the same geographical region in Italy, were recruited. The evaluation of asbestos exposure was conducted considering the frequency, the duration and the intensity of occupational, environmental and domestic exposure. A genome-wide methylation array was performed to identify novel blood DNA methylation (DNAm) markers of MPM. Multiple regression analyses adjusting for potential confounding factors and interaction between asbestos exposure and DNAm on the MPM odds ratio were applied. Epigenome-wide analysis (EWAS) revealed 12 single-CpGs associated with the disease. Two of these showed high statistical power (99%) and effect size (&gt;0.05) after false discovery rate (FDR) multiple comparison corrections: (i) cg03546163 in FKBP5, significantly hypomethylated in cases (Mean Difference in beta values (MD) = \u22120.09, 95% CI = \u22120.12|\u22120.06, p = 1.2 \u00d7 10\u22127), and (ii) cg06633438 in MLLT1, statistically hypermethylated in cases (MD = 0.07, 95% CI = 0.04|0.10, p = 1.0 \u00d7 10\u22126). Based on the interaction analysis, asbestos exposure and epigenetic profile together may improve MPM risk assessment. Above-median asbestos exposure and hypomethylation of cg03546163 in FKBP5 (OR = 20.84, 95% CI = 8.71|53.96, p = 5.5 \u00d7 10\u221211) and hypermethylation of cg06633438 in MLLT1 (OR = 11.71, 95% CI = 4.97|29.64, p = 5.9 \u00d7 10\u22128) genes compared to below-median asbestos exposure and hyper\/hypomethylation of single-CpG DNAm, respectively. Receiver Operation Characteristics (ROC) for Case-Control Discrimination showed a significant increase in MPM discrimination when DNAm information was added in the model (baseline model, BM: asbestos exposure, age, gender and white blood cells); area under the curve, AUC = 0.75; BM + cg03546163 at FKBP5. AUC = 0.89, 2.1 \u00d7 10\u22127; BM + cg06633438 at MLLT1. AUC = 0.89, 6.3 \u00d7 10\u22128. Validation and replication procedures, considering independent sample size and a different DNAm analysis technique, confirmed the observed associations. Our results suggest the potential application of DNAm profiles in blood to develop noninvasive tests for MPM risk assessment in asbestos-exposed subjects.<\/jats:p>","DOI":"10.3390\/cancers13112636","type":"journal-article","created":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T11:07:02Z","timestamp":1622113622000},"page":"2636","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["New DNA Methylation Signals for Malignant Pleural Mesothelioma Risk Assessment"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6080-0718","authenticated-orcid":false,"given":"Giovanni","family":"Cugliari","sequence":"first","affiliation":[{"name":"Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Allione","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5494-2218","authenticated-orcid":false,"given":"Alessia","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Catalano","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Casalone","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4400-1817","authenticated-orcid":false,"given":"Simonetta","family":"Guarrera","sequence":"additional","affiliation":[{"name":"Italian Institute for Genomic Medicine, IIGM, 10060 Candiolo, Italy"},{"name":"Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Grosso","sequence":"additional","affiliation":[{"name":"Mesothelioma Unit, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Ferrante","sequence":"additional","affiliation":[{"name":"Medical Statistics, Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy"},{"name":"Cancer Epidemiology Unit, CPO-Piemonte, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marika","family":"Sculco","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Eastern Piedmont, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"La Vecchia","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Eastern Piedmont, 28100 Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Pirazzini","sequence":"additional","affiliation":[{"name":"IRCCS Istituto delle Scienze Neurologiche di Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Libener","sequence":"additional","affiliation":[{"name":"Department of Integrated Activities Research and Innovation\u2013Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, 15122 Alessandria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Mirabelli","sequence":"additional","affiliation":[{"name":"Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Interdepartmental Center for Studies on Asbestos and Other Toxic Particulates \u201cG. Scansetti\u201d, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6413-5471","authenticated-orcid":false,"given":"Corrado","family":"Magnani","sequence":"additional","affiliation":[{"name":"Medical Statistics, Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy"},{"name":"Cancer Epidemiology Unit, CPO-Piemonte, 28100 Novara, Italy"},{"name":"Interdepartmental Center for Studies on Asbestos and Other Toxic Particulates \u201cG. Scansetti\u201d, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irma","family":"Dianzani","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Eastern Piedmont, 28100 Novara, Italy"},{"name":"Interdepartmental Center for Studies on Asbestos and Other Toxic Particulates \u201cG. Scansetti\u201d, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0674-7757","authenticated-orcid":false,"given":"Giuseppe","family":"Matullo","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Interdepartmental Center for Studies on Asbestos and Other Toxic Particulates \u201cG. Scansetti\u201d, University of Turin, 10126 Turin, Italy"},{"name":"Medical Genetics Unit, AOU Citt\u00e0 della Salute e della Scienza, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1093\/carcin\/bgt166","article-title":"Molecular pathogenesis of malignant mesothelioma","volume":"34","author":"Sekido","year":"2013","journal-title":"Carcinogenesis"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3389\/fonc.2018.00091","article-title":"New Perspectives on Diagnosis and Therapy of Malignant Pleural Mesothelioma","volume":"8","author":"Rossini","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Furuya, S., Chimed-Ochir, O., Takahashi, K., David, A., and Takala, J. (2018). Global Asbestos Disaster. Int. J. Environ. Res. 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