{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T06:46:26Z","timestamp":1775976386684,"version":"3.50.1"},"reference-count":121,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T00:00:00Z","timestamp":1622592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health though Bando per la Valorizzazione della Ricerca in ambito Oncologico 2020-Fondi 5 per Mille","award":["-"],"award-info":[{"award-number":["-"]}]},{"name":"Italian Ministry of Health though Bando per la Valorizzazione della Ricerca in ambito Oncologico 2019-Fondi 5 per Mille","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Malignant pleural mesothelioma (MPM) is a clinical emergency of our time. Being strongly associated with asbestos exposure, incidence of this cancer is ramping up these days in many industrialized countries and it will soon start to increase in many developing areas where the use of this silicate derivate is still largely in use. Deficiency of reliable markers for the early identification of these tumors and the limited efficacy of the currently available therapeutic options are the basis of the impressive mortality rate of MPM. These shortcomings reflect the very poor information available about the molecular basis of this disease. Results of the recently released deep profiling studies point to the epigenome as a central element in MPM development and progression. First, MPM is characterized by a low mutational burden and a highly peculiar set of mutations that hits almost exclusively epigenetic keepers or proteins controlling chromatin organization and function. Furthermore, asbestos does not seem to be associated with a distinctive mutational signature, while the precise mapping of epigenetic changes caused by this carcinogen has been defined, suggesting that alterations in epigenetic features are the driving force in the development of this disease. Last but not least, consistent evidence also indicates that, in the setting of MPM, chromatin rewiring and epigenetic alterations of cancer cells heavily condition the microenvironment, including the immune response. In this review we aim to point to the relevance of the epigenome in MPM and to highlight the dependency of this tumor on chromatin organization and function. We also intend to discuss the opportunity of targeting these mechanisms as potential therapeutic options for MPM.<\/jats:p>","DOI":"10.3390\/jcm10112470","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T10:38:39Z","timestamp":1622630319000},"page":"2470","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Molecular Fingerprints of Malignant Pleural Mesothelioma: Not Just a Matter of Genetic Alterations"],"prefix":"10.3390","volume":"10","author":[{"given":"Eugenia","family":"Lorenzini","sequence":"first","affiliation":[{"name":"Laboratory of Translational Research, Azienda USL\u2014IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"},{"name":"Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5541-2075","authenticated-orcid":false,"given":"Alessia","family":"Ciarrocchi","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Research, Azienda USL\u2014IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Torricelli","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Research, Azienda USL\u2014IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,2]]},"reference":[{"key":"ref_1","first-page":"491","article-title":"Malignant pleural mesothelioma: An epidemiological perspective","volume":"1","author":"Robinson","year":"2012","journal-title":"Ann. Cardiothorac. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1183\/09031936.96.09091932","article-title":"The epidemiology of mesothelioma in historical context","volume":"9","author":"McDonald","year":"1996","journal-title":"Eur. Respir. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1002\/jcp.22724","article-title":"Malignant mesothelioma: Facts, myths, and hypotheses","volume":"227","author":"Carbone","year":"2012","journal-title":"J. Cell. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"647","DOI":"10.5858\/arpa.2012-0214-OA","article-title":"Guidelines for pathologic diagnosis of malignant mesothelioma: 2012 update of the consensus statement from the International Mesothelioma Interest Group","volume":"137","author":"Husain","year":"2013","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.jtho.2015.11.005","article-title":"The 2015 World Health Organization Classification of Tumors of the Pleura: Advances since the 2004 Classification","volume":"11","author":"Churg","year":"2016","journal-title":"J. Thorac. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/S0140-6736(10)60251-6","article-title":"Health experts concerned over India\u2019s asbestos industry","volume":"375","author":"Burki","year":"2010","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Galateau-Sall\u00e9, F. (2006). Pathology of Malignant Mesothelioma, Springer.","DOI":"10.1007\/978-1-84628-012-2"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/ng.3520","article-title":"Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations","volume":"48","author":"Bueno","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/nrc.2017.42","article-title":"Novel insights into mesothelioma biology and implications for therapy","volume":"17","author":"Yap","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1016\/j.jtho.2016.05.020","article-title":"The Genetic Landscape of Malignant Pleural Mesothelioma: Results from Massively Parallel Sequencing","volume":"11","author":"Hylebos","year":"2016","journal-title":"J. Thorac. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1158\/2159-8290.CD-18-0804","article-title":"Integrative Molecular Characterization of Malignant Pleural Mesothelioma","volume":"8","author":"Hmeljak","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1093\/carcin\/bgn059","article-title":"Asbestos exposure predicts cell cycle control gene promoter methylation in pleural mesothelioma","volume":"29","author":"Christensen","year":"2008","journal-title":"Carcinogenesis"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9073","DOI":"10.1158\/0008-5472.CAN-09-1595","article-title":"Epigenetic profiles distinguish malignant pleural mesothelioma from lung adenocarcinoma","volume":"69","author":"Goto","year":"2009","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.freeradbiomed.2015.05.002","article-title":"Malignant mesothelioma as an oxidative stress-induced cancer: An update","volume":"86","author":"Chew","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1016\/S0891-5849(03)00060-1","article-title":"Multiple roles of oxidants in the pathogenesis of asbestos-induced diseases","volume":"34","author":"Shukla","year":"2003","journal-title":"Free Radic. Biol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1007\/s00204-018-2179-y","article-title":"DNA methylation profiling of asbestos-treated MeT5A cell line reveals novel pathways implicated in asbestos response","volume":"92","author":"Casalone","year":"2018","journal-title":"Arch. Toxicol."},{"key":"ref_17","first-page":"1257","article-title":"Pleural macrophage recruitment and activation in asbestos-induced pleural injury","volume":"105","author":"Choe","year":"1997","journal-title":"Environ. Heal. Perspect."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1006\/abbi.1996.0059","article-title":"Participation of nitric oxide and iron in the oxidation of DNA in asbestos-treated human lung epithelial cells","volume":"326","author":"Chao","year":"1996","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1002\/(SICI)1097-4652(199908)180:2<158::AID-JCP3>3.0.CO;2-R","article-title":"Cellular and molecular mechanisms of asbestos-induced fibrosis","volume":"180","author":"Robledo","year":"1999","journal-title":"J. Cell. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1136\/thx.54.7.638","article-title":"The molecular basis of asbestos induced lung injury","volume":"54","author":"Kamp","year":"1999","journal-title":"Thorax"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/S0021-9258(18)48474-8","article-title":"8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G-T and A-C substitutions","volume":"267","author":"Cheng","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"12611","DOI":"10.1073\/pnas.1006542107","article-title":"Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation","volume":"107","author":"Yang","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"10397","DOI":"10.1073\/pnas.0604008103","article-title":"TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappaB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis","volume":"103","author":"Yang","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Sage, A.P., Martinez, V.D., Minatel, B.C., Pewarchuk, M.E., Marshall, E.A., MacAulay, G.M., Hubaux, R., Pearson, D.D., Goodarzi, A.A., and Dellaire, G. (2018). Genomics and Epigenetics of Malignant Mesothelioma. High Throughput, 7.","DOI":"10.3390\/ht7030020"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"85","DOI":"10.2174\/156652407779940413","article-title":"DNA methylation in health, disease, and cancer","volume":"7","author":"Shames","year":"2007","journal-title":"Curr. Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1158\/0008-5472.CAN-08-2586","article-title":"Epigenetic profiles distinguish pleural mesothelioma from normal pleura and predict lung asbestos burden and clinical outcome","volume":"69","author":"Christensen","year":"2009","journal-title":"Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.molonc.2014.11.007","article-title":"MiR-score: A novel 6-microRNA signature that predicts survival outcomes in patients with malignant pleural mesothelioma","volume":"9","author":"Kirschner","year":"2015","journal-title":"Mol. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1016\/j.jtho.2017.05.024","article-title":"Tumor Suppressor microRNAs Contribute to the Regulation of PD-L1 Expression in Malignant Pleural Mesothelioma","volume":"12","author":"Kao","year":"2017","journal-title":"J. Thorac. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.jtho.2017.10.016","article-title":"Dysregulated Expression of the MicroRNA miR-137 and Its Target YBX1 Contribute to the Invasive Characteristics of Malignant Pleural Mesothelioma","volume":"13","author":"Johnson","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1002\/gcc.20880","article-title":"Integrative analysis of microRNA, mRNA and aCGH data reveals asbestos- and histology-related changes in lung cancer","volume":"50","author":"Nymark","year":"2011","journal-title":"Genes Chromosom. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6953","DOI":"10.1158\/0008-5472.CAN-08-0365","article-title":"BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization","volume":"68","author":"Ventii","year":"2008","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1038\/nm.3947","article-title":"Loss of BAP1 function leads to EZH2-dependent transformation","volume":"21","author":"LaFave","year":"2015","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5071","DOI":"10.1128\/MCB.00396-10","article-title":"The ubiquitin carboxyl hydrolase BAP1 forms a ternary complex with YY1 and HCF-1 and is a critical regulator of gene expression","volume":"30","author":"Yu","year":"2010","journal-title":"Mol. Cell. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1038\/sj.emboj.7601967","article-title":"Dynamic histone H3 methylation during gene induction: HYPB\/Setd2 mediates all H3K36 trimethylation","volume":"27","author":"Edmunds","year":"2008","journal-title":"EMBO J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1016\/j.celrep.2014.05.026","article-title":"SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability","volume":"7","author":"Pfister","year":"2014","journal-title":"Cell Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/ng.2699","article-title":"Integrated molecular analysis of clear-cell renal cell carcinoma","volume":"45","author":"Sato","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/ng.2894","article-title":"Identification of functional cooperative mutations of SETD2 in human acute leukemia","volume":"46","author":"Zhu","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1158\/0008-5472.CAN-20-2906","article-title":"Histone Methyltransferase SETDB1: A Common Denominator of Tumorigenesis with Therapeutic Potential","volume":"81","author":"Strepkos","year":"2021","journal-title":"Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"8321","DOI":"10.18632\/oncotarget.7032","article-title":"Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas","volume":"7","author":"Kang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1158\/0008-5472.CAN-14-1008","article-title":"Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma","volume":"75","author":"Guo","year":"2015","journal-title":"Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.lungcan.2008.08.014","article-title":"Functional inactivation of NF2\/merlin in human mesothelioma","volume":"64","author":"Thurneysen","year":"2009","journal-title":"Lung Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"10854","DOI":"10.1073\/pnas.92.24.10854","article-title":"High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas","volume":"92","author":"Bianchi","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","first-page":"1227","article-title":"Neurofibromatosis type 2 (NF2) gene is somatically mutated in mesothelioma but not in lung cancer","volume":"55","author":"Sekido","year":"1995","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4485","DOI":"10.1158\/1078-0432.CCR-11-2375","article-title":"New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment","volume":"18","author":"Ladanyi","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.cell.2010.01.029","article-title":"Merlin\/NF2 suppresses tumorigenesis by inhibiting the E3 ubiquitin ligase CRL4(DCAF1) in the nucleus","volume":"140","author":"Li","year":"2010","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4235","DOI":"10.1128\/MCB.01578-08","article-title":"Loss of the tumor suppressor gene NF2, encoding merlin, constitutively activates integrin-dependent mTORC1 signaling","volume":"29","author":"Okada","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1111\/j.1440-1827.2011.02666.x","article-title":"Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation","volume":"61","author":"Sekido","year":"2011","journal-title":"Pathol. Int."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3191","DOI":"10.1158\/1078-0432.CCR-16-1971","article-title":"Co-occurring Mutations of Tumor Suppressor Genes, LATS2 and NF2, in Malignant Pleural Mesothelioma","volume":"23","author":"Tranchant","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1158\/0008-5472.CAN-10-2164","article-title":"LATS2 is a tumor suppressor gene of malignant mesothelioma","volume":"71","author":"Murakami","year":"2011","journal-title":"Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Sekido, Y. (2018). Targeting the Hippo Pathway Is a New Potential Therapeutic Modality for Malignant Mesothelioma. Cancers, 10.","DOI":"10.3390\/cancers10040090"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1097\/JTO.0000000000000493","article-title":"Hippo pathway gene mutations in malignant mesothelioma: Revealed by RNA and targeted exon sequencing","volume":"10","author":"Miyanaga","year":"2015","journal-title":"J. Thorac. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Torricelli, F., Lococo, F., Di Stefano, T.S., Lorenzini, E., Piana, S., Valli, R., Rena, O., Veronesi, G., Bille, A., and Ciarrocchi, A. (2020). Deep Sequencing Analysis Identified a Specific Subset of Mutations Distinctive of Biphasic Malignant Pleural Mesothelioma. Cancers, 12.","DOI":"10.3390\/cancers12092454"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.ejca.2020.03.002","article-title":"Genomic analysis in short- and long-term patients with malignant pleura mesothelioma treated with palliative chemotherapy","volume":"132","author":"Torricelli","year":"2020","journal-title":"Eur. J. Cancer"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1038\/s41467-019-09307-6","article-title":"Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications","volume":"10","author":"Blum","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1610322","DOI":"10.1080\/23723556.2019.1610322","article-title":"Unraveling the cellular heterogeneity of malignant pleural mesothelioma through a deconvolution approach","volume":"6","author":"Blum","year":"2019","journal-title":"Mol. Cell. Oncol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nrg816","article-title":"The fundamental role of epigenetic events in cancer","volume":"3","author":"Jones","year":"2002","journal-title":"Nat. Rev. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/S0092-8674(02)00655-4","article-title":"A unified theory of gene expression","volume":"108","author":"Orphanides","year":"2002","journal-title":"Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/978-1-4939-1804-1_12","article-title":"Methylation profile landscape in mesothelioma: Possible implications in early detection, disease progression, and therapeutic options","volume":"1238","author":"Zhang","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"5686","DOI":"10.1158\/0008-5472.CAN-10-0190","article-title":"Integrated profiling reveals a global correlation between epigenetic and genetic alterations in mesothelioma","volume":"70","author":"Christensen","year":"2010","journal-title":"Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1158\/0008-5472.743.65.3","article-title":"Secreted frizzled-related protein 4 is silenced by hypermethylation and induces apoptosis in beta-catenin-deficient human mesothelioma cells","volume":"65","author":"He","year":"2005","journal-title":"Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"6672","DOI":"10.1038\/sj.onc.1207881","article-title":"Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma","volume":"23","author":"Lee","year":"2004","journal-title":"Oncogene"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0169-5002(02)00178-2","article-title":"Inactivation of p16INK4a expression in malignant mesothelioma by methylation","volume":"38","author":"Wong","year":"2002","journal-title":"Lung Cancer"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1093\/carcin\/23.7.1127","article-title":"Alterations of the p16(INK4) locus in human malignant mesothelial tumors","volume":"23","author":"Hirao","year":"2002","journal-title":"Carcinogenesis"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.lungcan.2007.06.015","article-title":"DNA methylation profile of 28 potential marker loci in malignant mesothelioma","volume":"58","author":"Tsou","year":"2007","journal-title":"Lung Cancer"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1111\/j.1745-7254.2007.00692.x","article-title":"Roles of secreted frizzled-related proteins in cancer","volume":"28","author":"Shi","year":"2007","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2536187","DOI":"10.1155\/2017\/2536187","article-title":"SFRP Tumour Suppressor Genes Are Potential Plasma-Based Epigenetic Biomarkers for Malignant Pleural Mesothelioma","volume":"2017","author":"Cheng","year":"2017","journal-title":"Dis. Markers"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1097\/JTO.0b013e3182a0840a","article-title":"ZIC1 is silenced and has tumor suppressor function in malignant pleural mesothelioma","volume":"8","author":"Cheng","year":"2013","journal-title":"J. Thorac. Oncol."},{"key":"ref_68","first-page":"4855","article-title":"Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis","volume":"54","author":"Greenblatt","year":"1994","journal-title":"Cancer Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"350","DOI":"10.21037\/tlcr.2017.06.06","article-title":"Targeting the epigenome in malignant pleural mesothelioma","volume":"6","author":"McLoughlin","year":"2017","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/ng1531","article-title":"Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer","volume":"37","author":"Fraga","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nrc2876","article-title":"Covalent histone modifications--miswritten, misinterpreted and mis-erased in human cancers","volume":"10","author":"Chi","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/38664","article-title":"Histone acetylation in chromatin structure and transcription","volume":"389","author":"Grunstein","year":"1997","journal-title":"Nature"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"55789","DOI":"10.18632\/oncotarget.10048","article-title":"The multifaceted role of lysine acetylation in cancer: Prognostic biomarker and therapeutic target","volume":"7","author":"Trisciuoglio","year":"2016","journal-title":"Oncotarget"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Eckschlager, T., Plch, J., Stiborova, M., and Hrabeta, J. (2017). Histone Deacetylase Inhibitors as Anticancer Drugs. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071414"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"13757","DOI":"10.18632\/oncotarget.3765","article-title":"Loss of the deubiquitylase BAP1 alters class I histone deacetylase expression and sensitivity of mesothelioma cells to HDAC inhibitors","volume":"6","author":"Sacco","year":"2015","journal-title":"Oncotarget"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1158\/1541-7786.MCR-19-0564","article-title":"RAIN Is a Novel Enhancer-Associated lncRNA That Controls RUNX2 Expression and Promotes Breast and Thyroid Cancer","volume":"18","author":"Rossi","year":"2020","journal-title":"Mol Cancer Res."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Catalanotto, C., Cogoni, C., and Zardo, G. (2016). MicroRNA in Control of Gene Expression: An Overview of Nuclear Functions. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17101712"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1101\/gr.082701.108","article-title":"Most mammalian mRNAs are conserved targets of microRNAs","volume":"19","author":"Friedman","year":"2009","journal-title":"Genome Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.cell.2009.01.002","article-title":"MicroRNAs: Target recognition and regulatory functions","volume":"136","author":"Bartel","year":"2009","journal-title":"Cell"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1373\/clinchem.2008.112805","article-title":"MicroRNAs: Novel biomarkers for human cancer","volume":"55","author":"Bartels","year":"2009","journal-title":"Clin. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"4997","DOI":"10.2147\/CMAR.S205723","article-title":"Analyzing biological and molecular characteristics and genomic damage induced by exposure to asbestos","volume":"11","author":"Ospina","year":"2019","journal-title":"Cancer Manag. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1158\/1055-9965.EPI-18-0453","article-title":"Four-miRNA Signature to Identify Asbestos-Related Lung Malignancies","volume":"28","author":"Santarelli","year":"2019","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3128","DOI":"10.1093\/annonc\/mdt412","article-title":"Restoring expression of miR-16: A novel approach to therapy for malignant pleural mesothelioma","volume":"24","author":"Reid","year":"2013","journal-title":"Ann. Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"5553","DOI":"10.1158\/0008-5472.CAN-08-4277","article-title":"miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer","volume":"69","author":"Bandi","year":"2009","journal-title":"Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"9645940","DOI":"10.1155\/2017\/9645940","article-title":"MicroRNA Expression in Malignant Pleural Mesothelioma and Asbestosis: A Pilot Study","volume":"2017","author":"Mozzoni","year":"2017","journal-title":"Dis. Markers"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Santarelli, L., Strafella, E., Staffolani, S., Amati, M., Emanuelli, M., Sartini, D., Pozzi, V., Carbonari, D., Bracci, M., and Pignotti, E. (2011). Association of MiR-126 with soluble mesothelin-related peptides, a marker for malignant mesothelioma. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0018232"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.clinbiochem.2012.02.009","article-title":"Clinical significance of circulating miR-126 quantification in malignant mesothelioma patients","volume":"45","author":"Tomasetti","year":"2012","journal-title":"Clin. Biochem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"445","DOI":"10.3389\/fonc.2020.00445","article-title":"Circulating Epigenetic Biomarkers in Malignant Pleural Mesothelioma: State of the Art and critical Evaluation","volume":"10","author":"Ferrari","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.jtho.2018.10.163","article-title":"Peripheral Blood DNA Methylation as Potential Biomarker of Malignant Pleural Mesothelioma in Asbestos-Exposed Subjects","volume":"14","author":"Guarrera","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.lungcan.2006.06.017","article-title":"Promoter methylation of RASSF1A, RARbeta and DAPK predict poor prognosis of patients with malignant mesothelioma","volume":"54","author":"Fischer","year":"2006","journal-title":"Lung Cancer"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"740","DOI":"10.3389\/fonc.2019.00740","article-title":"Liquid Biopsy in Malignant Pleural Mesothelioma: State of the Art, Pitfalls, and Perspectives","volume":"9","author":"Cavallari","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Weber, D.G., Johnen, G., Bryk, O., Jockel, K.H., and Bruning, T. (2012). Identification of miRNA-103 in the cellular fraction of human peripheral blood as a potential biomarker for malignant mesothelioma--a pilot study. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030221"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.lungcan.2015.09.021","article-title":"Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma","volume":"90","author":"Santarelli","year":"2015","journal-title":"Lung Cancer"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Cavalleri, T., Angelici, L., Favero, C., Dioni, L., Mensi, C., Bareggi, C., Palleschi, A., Rimessi, A., Consonni, D., and Bordini, L. (2017). Plasmatic extracellular vesicle microRNAs in malignant pleural mesothelioma and asbestos-exposed subjects suggest a 2-miRNA signature as potential biomarker of disease. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176680"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1097\/JTO.0b013e3182572e83","article-title":"Increased circulating miR-625-3p: A potential biomarker for patients with malignant pleural mesothelioma","volume":"7","author":"Kirschner","year":"2012","journal-title":"J. Thorac. Oncol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"129","DOI":"10.2217\/bmm-2017-0224","article-title":"Clinical evaluation of circulating miR-548a-3p and -20a expression in malignant pleural mesothelioma patients","volume":"12","author":"Matboli","year":"2018","journal-title":"Biomark. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3203","DOI":"10.1002\/jcb.27586","article-title":"Clinical significance of serum DRAM1 mRNA, ARSA mRNA, hsa-miR-2053 and lncRNA-RP1-86D1.3 axis expression in malignant pleural mesothelioma","volume":"120","author":"Matboli","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Lamberti, M., Capasso, R., Lombardi, A., Di Domenico, M., Fiorelli, A., Feola, A., Perna, A.F., Santini, M., Caraglia, M., and Ingrosso, D. (2015). Two Different Serum MiRNA Signatures Correlate with the Clinical Outcome and Histological Subtype in Pleural Malignant Mesothelioma Patients. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0135331"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Weber, D.G., Brik, A., Casjens, S., Burek, K., Lehnert, M., Pesch, B., Taeger, D., Bruning, T., and Johnen, G. (2019). Are circulating microRNAs suitable for the early detection of malignant mesothelioma? Results from a nested case-control study. BMC Res. Notes, 12.","DOI":"10.1186\/s13104-019-4113-7"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1097\/PAP.0000000000000161","article-title":"Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors","volume":"24","author":"Hendry","year":"2017","journal-title":"Adv. Anat. Pathol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"16456","DOI":"10.1038\/s41598-017-16551-7","article-title":"Circulating complement component 4d (C4d) correlates with tumor volume, chemotherapeutic response and survival in patients with malignant pleural mesothelioma","volume":"7","author":"Klikovits","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1038\/bjc.2013.815","article-title":"Circulating fibrinogen is a prognostic and predictive biomarker in malignant pleural mesothelioma","volume":"110","author":"Ghanim","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Vogl, M., Rosenmayr, A., Bohanes, T., Scheed, A., Brndiar, M., Stubenberger, E., and Ghanim, B. (2021). Biomarkers for Malignant Pleural Mesothelioma-A Novel View on Inflammation. Cancers, 13.","DOI":"10.3390\/cancers13040658"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"777","DOI":"10.2174\/1568026615666150825141152","article-title":"Improvement of malignant pleural mesothelioma immunotherapy by epigenetic modulators","volume":"16","author":"Hamaidia","year":"2016","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1038\/sj.bjc.6600174","article-title":"Cancer testis antigens expression in mesothelioma: Role of DNA methylation and bioimmunotherapeutic implications","volume":"86","author":"Sigalotti","year":"2002","journal-title":"Br. J. Cancer"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S0140-6736(20)32714-8","article-title":"First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): A multicentre, randomised, open-label, phase 3 trial","volume":"397","author":"Baas","year":"2021","journal-title":"Lancet"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ctrv.2014.10.007","article-title":"Malignant pleural mesothelioma: New hope in the horizon with novel therapeutic strategies","volume":"41","author":"Remon","year":"2015","journal-title":"Cancer Treat. Rev."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2818","DOI":"10.1158\/1078-0432.CCR-08-1579","article-title":"Valproate, in combination with pemetrexed and cisplatin, provides additional efficacy to the treatment of malignant mesothelioma","volume":"15","author":"Vandermeers","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1097\/JTO.0b013e3181c5e366","article-title":"Histone deacetylase inhibitors in malignant pleural mesothelioma: Preclinical rationale and clinical trials","volume":"5","author":"Paik","year":"2010","journal-title":"J. Thorac. Oncol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1183\/09031936.00037310","article-title":"Valproate-doxorubicin: Promising therapy for progressing mesothelioma. A phase II study","volume":"37","author":"Scherpereel","year":"2011","journal-title":"Eur. Res. J."},{"key":"ref_111","first-page":"1096","article-title":"Vorinostat\/SAHA-induced apoptosis in malignant mesothelioma is FLIP\/caspase 8-dependent and HR23B-independent","volume":"48","author":"Hurwitz","year":"2012","journal-title":"Eur. Res. J."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/S1470-2045(15)70056-2","article-title":"Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): A phase 3, double-blind, randomised, placebo-controlled trial","volume":"16","author":"Krug","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.lungcan.2010.10.016","article-title":"Premature senescence induced by DNA demethylating agent (Decitabine) as therapeutic option for malignant pleural mesothelioma","volume":"71","author":"Amatori","year":"2011","journal-title":"Lung Cancer"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1183\/09031936.00081310","article-title":"A 5-aza-2\u2019-deoxycytidine\/valproate combination induces cytotoxic T-cell response against mesothelioma","volume":"38","author":"Leclercq","year":"2011","journal-title":"Eur. Res. J."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s13148-018-0517-9","article-title":"Assessment of new HDAC inhibitors for immunotherapy of malignant pleural mesothelioma","volume":"10","author":"Bensaid","year":"2018","journal-title":"Clin. Epigenet."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1186\/s12943-018-0915-9","article-title":"BRD4 and Cancer: Going beyond transcriptional regulation","volume":"17","author":"Donati","year":"2018","journal-title":"Mol. Cancer"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"e1398874","DOI":"10.1080\/2162402X.2017.1398874","article-title":"Bromodomain inhibition exerts its therapeutic potential in malignant pleural mesothelioma by promoting immunogenic cell death and changing the tumor immune-environment","volume":"7","author":"Riganti","year":"2018","journal-title":"Oncoimmunology"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"e196","DOI":"10.1016\/S2352-3026(16)00021-1","article-title":"Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: A dose-escalation, open-label, pharmacokinetic, phase 1 study","volume":"3","author":"Amorim","year":"2016","journal-title":"Lancet Haematol."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Manzotti, G., Ciarrocchi, A., and Sancisi, V. (2019). Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy. Cancers, 11.","DOI":"10.3390\/cancers11030304"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1158\/0008-5472.CAN-14-2087","article-title":"Histone Deacetylase Inhibitors Repress Tumoral Expression of the Proinvasive Factor RUNX2","volume":"75","author":"Sancisi","year":"2015","journal-title":"Cancer Res."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"7199","DOI":"10.1158\/1078-0432.CCR-17-1178","article-title":"Immunomodulation by Entinostat in Renal Cell Carcinoma Patients Receiving High-Dose Interleukin 2: A Multicenter, Single-Arm, Phase I\/II Trial (NCI-CTEP#7870)","volume":"23","author":"Pili","year":"2017","journal-title":"Clin. Cancer Res."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/11\/2470\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:10:13Z","timestamp":1760163013000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/11\/2470"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,2]]},"references-count":121,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["jcm10112470"],"URL":"https:\/\/doi.org\/10.3390\/jcm10112470","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,2]]}}}