Research Papers: Pathology:
Immunohistochemically detectable metallothionein expression in malignant pleural mesotheliomas is strongly associated with early failure to platin-based chemotherapy
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Fabian D. Mairinger1,*, Jan Schmeller1,*, Sabrina Borchert1, Michael Wessolly1, Elena Mairinger1, Jens Kollmeier2, Thomas Hager1, Thomas Mairinger3, Daniel C. Christoph4,5, Robert F.H. Walter1,6, Wilfried E.E. Eberhardt4,6, Till Plönes7, Jeremias Wohlschlaeger1,8, Bharat Jasani9, Kurt Werner Schmid1 and Agnes Bankfalvi1
1Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
2Department of Pneumology, Helios Klinikum Emil von Behring, Berlin, Germany
3Department of Pathology, Helios Klinikum Emil von Behring, Berlin, Germany
4Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
5Department of Internistic Oncology, Kliniken Essen Mitte, Essen, Germany
6Ruhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
7Department of Thoracic Surgery and Thoracical Endoscopy, Ruhrlandklinik, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
8Department of Pathology, Diakonissenkrankenhaus Flensburg, Flensburg, Germany
9Department of Pathology, Targos Molecular Pathology GmbH, Kassel, Germany
*These authors have contributed equally to this work
Fabian D. Mairinger, email: [email protected]
Keywords: malignant pleural mesothelioma; metallothionein; overall survival; prognostic biomarker; platin-based chemotherapy; Pathology
Received: August 18, 2017 Accepted: March 11, 2018 Published: April 27, 2018
Background: Malignant pleural mesothelioma (MPM) is a biologically highly aggressive tumor arising from the pleura with a dismal prognosis. Cisplatin is the drug of choice for the treatment of MPM, and carboplatin seems to have comparable efficacy. Nevertheless, cisplatin treatment results in a response rate of merely 14% and a median survival of less than seven months. Due to their role in many cellular processes, methallothioneins (MTs) have been widely studied in various cancers. The known heavy metal detoxifying effect of MT-I and MT-II may be the reason for heavy metal drug resistance of various cancers including MPM.
Methods: 105 patients were retrospectively analyzed immunohistochemically for their MT expression levels. Survival analysis was done by Cox-regression, and statistical significance determined using likelihood ratio, Wald test and Score (logrank) tests.
Results: Cox-regression analyses were done in a linear and logarithmic scale revealing a significant association between expression of MT and shortened overall survival (OS) in a linear (p=0.0009) and logarithmic scale (p=0.0003). Reduced progression free survival (PFS) was also observed for MT expressing tumors (linear: p=0.0134, log: p=0.0152).
Conclusion: Since both, overall survival and progression-free survival are negatively correlated with detectable MT expression in MPM, our results indicate a possible resistance to platin-based chemotherapy associated with MT expression upregulation, found exclusively in progressive MPM samples. Initial cell culture studies suggest promoter DNA hypomethylation and expression of miRNA-566 a direct regulator of copper transporter SLC31A1 and a putative regulator of MT1A and MT2A gene expression, to be responsible for the drug resistance.
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