Research Papers:

Transcriptomic analysis of aggressive meningiomas identifies PTTG1 and LEPR as prognostic biomarkers independent of WHO grade

Melissa Schmidt _, Andreas Mock, Christine Jungk, Felix Sahm, Anna Theresa Ull, Rolf Warta, Katrin Lamszus, Konstantinos Gousias, Ralf Ketter, Saskia Roesch, Carmen Rapp, Sebastian Schefzyk, Steffi Urbschat, Bernd Lahrmann, Almuth F. Kessler, Mario Löhr, Christian Senft, Niels Grabe, David Reuss, Philipp Beckhove, Manfred Westphal, Andreas von Deimling, Andreas Unterberg, Matthias Simon and Christel Herold-Mende

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Oncotarget. 2016; 7:14551-14568. https://doi.org/10.18632/oncotarget.7396

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Melissa Schmidt1,*, Andreas Mock1,*, Christine Jungk1, Felix Sahm2, Anna Theresa Ull1, Rolf Warta1, Katrin Lamszus3, Konstantinos Gousias4, Ralf Ketter5, Saskia Roesch1, Carmen Rapp1, Sebastian Schefzyk2, Steffi Urbschat5, Bernd Lahrmann6, Almuth F. Kessler7, Mario Löhr7, Christian Senft8, Niels Grabe6, David Reuss2, Philipp Beckhove9, Manfred Westphal3, Andreas von Deimling2, Andreas Unterberg1, Matthias Simon4,*, Christel Herold-Mende1,*

1Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany

2Department of Neuropathology, Heidelberg University Hospital, CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

3Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4Department of Neurosurgery, University Hospital Bonn, Bonn, Germany

5Department of Neurosurgery, Saarland University, Medical School, Homburg, Germany

6Bioquant, Medical Oncology, National Center for Tumor Diseases, Heidelberg, Germany

7Department of Neurosurgery, University Hospital of Würzburg, Würzburg, Germany

8Department of Neurosurgery, University of Frankfurt, Frankfurt, Germany

9Regensburg Center for Interventional Immunology, RCI and University Medical Center of Regensburg, Regensburg, Germany

*These authors have contributed equally to this work

Correspondence to:

Christel Herold-Mende, e-mail: [email protected]

Keywords: meningioma, anaplastic, recurrent, transcriptomic analysis, biomarker

Received: October 26, 2015    Accepted: January 27, 2016    Published: February 15, 2016


Meningiomas are frequent central nervous system tumors. Although most meningiomas are benign (WHO grade I) and curable by surgery, WHO grade II and III tumors remain therapeutically challenging due to frequent recurrence. Interestingly, relapse also occurs in some WHO grade I meningiomas. Hence, we investigated the transcriptional features defining aggressive (recurrent, malignantly progressing or WHO grade III) meningiomas in 144 cases. Meningiomas were categorized into non-recurrent (NR), recurrent (R), and tumors undergoing malignant progression (M) in addition to their WHO grade. Unsupervised transcriptomic analysis in 62 meningiomas revealed transcriptional profiles lining up according to WHO grade and clinical subgroup. Notably aggressive subgroups (R+M tumors and WHO grade III) shared a large set of differentially expressed genes (n=332; p<0.01, FC>1.25). In an independent multicenter validation set (n=82), differential expression of 10 genes between WHO grades was confirmed. Additionally, among WHO grade I tumors differential expression between NR and aggressive R+M tumors was affirmed for PTTG1, AURKB, ECT2, UBE2C and PRC1, while MN1 and LEPR discriminated between NR and R+M WHO grade II tumors. Univariate survival analysis revealed a significant association with progression-free survival for PTTG1, LEPR, MN1, ECT2, PRC1, COX10, UBE2C expression, while multivariate analysis identified a prediction for PTTG1 and LEPR mRNA expression independent of gender, WHO grade and extent of resection. Finally, stainings of PTTG1 and LEPR confirmed malignancy-associated protein expression changes. In conclusion, based on the so far largest study sample of WHO grade III and recurrent meningiomas we report a comprehensive transcriptional landscape and two prognostic markers.

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