J Cancer 2016; 7(13):1915-1925. doi:10.7150/jca.16390

Research Paper

Screening of Pleural Mesotheliomas for DNA-damage Repair Players by Digital Gene Expression Analysis Can Enhance Clinical Management of Patients Receiving Platin-Based Chemotherapy

Robert Fred Henry Walter1, 2, Claudia Vollbrecht3, Robert Werner4, Thomas Mairinger4, Jan Schmeller2, Elena Flom1, Jeremias Wohlschlaeger2,5, Nikolaos Barbetakis6, Dimitrios Paliouras6, Fotios Chatzinikolaou7, Vasilis Adamidis8, Kosmas Tsakiridis8, Paul Zarogoulidis8✉, Georgia Trakada9, Daniel Christian Christoph2, Kurt Werner Schmid2, Fabian Dominik Mairinger2

1. Ruhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;
2. Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;
3. Institute of Pathology, Division of Molecular Pathology, Charité, Berlin, Germany;
4. Department of Pathology, Helios Klinikum Emil von Behring, Berlin Germany;
5. Institute of Pathology, Ev.-Luth. Diakonissenkrankenhaus Flensburg, Flensburg, Germany;
6. Thoracic Surgery Department, Theagenio Cancer Hospital, Thessaloniki, Greece;
7. Pathology Department, “Theagenio” Cancer Hospital, Thessaloniki, Greece;
8. Pulmonary Department-Oncology Unit, “G. Papanikolaou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece;
9. Division of Pulmonology, Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra Hospital, Athens, Greece;
10. Department of Medical Oncology, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare, predominantly asbestos-related and biologically highly aggressive tumour leading to a dismal prognosis. Multimodality therapy consisting of platinum-based chemotherapy is the treatment of choice. The reasons for the rather poor efficacy of platinum compounds remain largely unknown.

Material and Methods: For this exploratory mRNA study, 24 FFPE tumour specimens were screened by digital gene expression analysis. Based on data from preliminary experiments and recent literature, a total of 366 mRNAs were investigated using a Custom CodeSet from NanoString. All statistical analyses were calculated with the R i386 statistical programming environment.

Results: CDC25A and PARP1 gene expression were correlated with lymph node spread, BRCA1 and TP73 expression levels with higher IMIG stage. NTHL1 and XRCC3 expression was associated with TNM stage. CHECK1 as well as XRCC2 expression levels were correlated with tumour progression in the overall cohort of patients. CDKN2A and MLH1 gene expression influenced overall survival in this collective. In the adjuvant treated cohort only, CDKN2A, CHEK1 as well as ERCC1 were significantly associated with overall survival. Furthermore, TP73 expression was associated with progression in this subgroup.

Conclusion: DNA-damage response plays a crucial role in response to platin-based chemotherapeutic regimes. In particular, CHEK1, XRCC2 and TP73 are strongly associated with tumour progression. ERCC1, MLH1, CDKN2A and most promising CHEK1 are prognostic markers for OS in MPM. TP73, CDKN2A, CHEK1 and ERCC1 seem to be also predictive markers in adjuvant treated MPMs. After a prospective validation, these markers may improve clinical and pathological practice, finally leading to a patients' benefit by an enhanced clinical management.

Keywords: pleural mesothelioma, NanoString nCounter, digital gene expression analysis, DNA-damage repair, platin-based chemotherapy.

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How to cite this article:
Walter RFH, Vollbrecht C, Werner R, Mairinger T, Schmeller J, Flom E, Wohlschlaeger J, Barbetakis N, Paliouras D, Chatzinikolaou F, Adamidis V, Tsakiridis K, Zarogoulidis P, Trakada G, Christoph DC, Schmid KW, Mairinger FD. Screening of Pleural Mesotheliomas for DNA-damage Repair Players by Digital Gene Expression Analysis Can Enhance Clinical Management of Patients Receiving Platin-Based Chemotherapy. J Cancer 2016; 7(13):1915-1925. doi:10.7150/jca.16390. Available from http://www.jcancer.org/v07p1915.htm