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Article

DNA Methylation of FKBP5 as Predictor of Overall Survival in Malignant Pleural Mesothelioma

1
Department of Medical Sciences, University of Turin, 10126 Turin, Italy
2
Italian Institute for Genomic Medicine, IIGM, 10060 Candiolo, Italy
3
Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy
4
Division of Medical Oncology, SS. Antonio e Biagio General Hospital, 15121 Alessandria, Italy
5
Unit of Medical Statistics, Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy
6
Cancer Epidemiology Unit, CPO-Piemonte, 28100 Novara, Italy
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Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy
8
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy
9
Pathology Unit, SS. Antonio e Biagio General Hospital, 15122 Alessandria, Italy
10
Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, 10126 Turin, Italy
11
Interdepartmental Center for Studies on Asbestos and Other Toxic Particulates “G. Scansetti”, University of Turin, 10126 Turin, Italy
12
Medical Genetics Unit, AOU Città della Salute e della Scienza, 10126 Turin, Italy
*
Authors to whom correspondence should be addressed.
Disclosure: These authors expert witness in court trials for asbestos related diseases.
Cancers 2020, 12(11), 3470; https://doi.org/10.3390/cancers12113470
Received: 9 October 2020 / Revised: 12 November 2020 / Accepted: 18 November 2020 / Published: 21 November 2020
(This article belongs to the Special Issue Malignant Mesothelioma)
Our study is the first one to investigate DNA methylation changes in white blood cells (WBCs) from easily accessible peripheral blood as malignant pleural mesothelioma (MPM) survival biomarker. The Cox proportional hazards regression model highlighted that the methylation status of the CpG dinucleotide cg03546163 is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Biological validation and replication showed that epigenetic changes at the FKBP5 gene were robustly associated with overall survival (OS) in MPM cases. The identification of simple and valuable prognostic markers for MPM will enable clinicians to select patients who are most likely to benefit from aggressive therapies and avoid subjecting non-responder patients to ineffective treatment.
Malignant pleural mesothelioma (MPM) is an aggressive tumor with median survival of 12 months and limited effective treatments. The scope of this study was to study the relationship between blood DNA methylation (DNAm) and overall survival (OS) aiming at a noninvasive prognostic test. We investigated a cohort of 159 incident asbestos exposed MPM cases enrolled in an Italian area with high incidence of mesothelioma. Considering 12 months as a cut-off for OS, epigenome-wide association study (EWAS) revealed statistically significant (p value = 7.7 × 10−9) OS-related differential methylation of a single-CpG (cg03546163), located in the 5′UTR region of the FKBP5 gene. This is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Cases with DNAm < 0.45 at the cg03546163 had significantly poor survival compared with those showing DNAm ≥ 0.45 (mean: 243 versus 534 days; p value< 0.001). Epigenetic changes at the FKBP5 gene were robustly associated with OS in MPM cases. Our results showed that blood DNA methylation levels could be promising and dynamic prognostic biomarkers in MPM. View Full-Text
Keywords: malignant pleural mesothelioma; asbestos exposure; DNA methylation; lymphocyte-to-monocyte ratio; epigenome-wide analysis; survival analysis malignant pleural mesothelioma; asbestos exposure; DNA methylation; lymphocyte-to-monocyte ratio; epigenome-wide analysis; survival analysis
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MDPI and ACS Style

Cugliari, G.; Catalano, C.; Guarrera, S.; Allione, A.; Casalone, E.; Russo, A.; Grosso, F.; Ferrante, D.; Viberti, C.; Aspesi, A.; Sculco, M.; Pirazzini, C.; Libener, R.; Mirabelli, D.; Magnani, C.; Dianzani, I.; Matullo, G. DNA Methylation of FKBP5 as Predictor of Overall Survival in Malignant Pleural Mesothelioma. Cancers 2020, 12, 3470. https://doi.org/10.3390/cancers12113470

AMA Style

Cugliari G, Catalano C, Guarrera S, Allione A, Casalone E, Russo A, Grosso F, Ferrante D, Viberti C, Aspesi A, Sculco M, Pirazzini C, Libener R, Mirabelli D, Magnani C, Dianzani I, Matullo G. DNA Methylation of FKBP5 as Predictor of Overall Survival in Malignant Pleural Mesothelioma. Cancers. 2020; 12(11):3470. https://doi.org/10.3390/cancers12113470

Chicago/Turabian Style

Cugliari, Giovanni, Chiara Catalano, Simonetta Guarrera, Alessandra Allione, Elisabetta Casalone, Alessia Russo, Federica Grosso, Daniela Ferrante, Clara Viberti, Anna Aspesi, Marika Sculco, Chiara Pirazzini, Roberta Libener, Dario Mirabelli, Corrado Magnani, Irma Dianzani, and Giuseppe Matullo. 2020. "DNA Methylation of FKBP5 as Predictor of Overall Survival in Malignant Pleural Mesothelioma" Cancers 12, no. 11: 3470. https://doi.org/10.3390/cancers12113470

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