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

// Melissa Schmidt 1, * , Andreas Mock 1, * , Christine Jungk 1 , Felix Sahm 2 , Anna Theresa Ull 1 , Rolf Warta 1 , Katrin Lamszus 3 , Konstantinos Gousias 4 , Ralf Ketter 5 , Saskia Roesch 1 , Carmen Rapp 1 , Sebastian Schefzyk 2 , Steffi Urbschat 5 , Bernd Lahrmann 6 , Almuth F. Kessler 7 , Mario Lohr 7 , Christian Senft 8 , Niels Grabe 6 , David Reuss 2 , Philipp Beckhove 9 , Manfred Westphal 3 , Andreas von Deimling 2 , Andreas Unterberg 1 , Matthias Simon 4, * , Christel Herold-Mende 1,* 1 Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany 2 Department of Neuropathology, Heidelberg University Hospital, CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany 3 Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 4 Department of Neurosurgery, University Hospital Bonn, Bonn, Germany 5 Department of Neurosurgery, Saarland University, Medical School, Homburg, Germany 6 Bioquant, Medical Oncology, National Center for Tumor Diseases, Heidelberg, Germany 7 Department of Neurosurgery, University Hospital of Wurzburg, Wurzburg, Germany 8 Department of Neurosurgery, University of Frankfurt, Frankfurt, Germany 9 Regensburg 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: h.mende@med.uni-heidelberg.de Keywords: meningioma, anaplastic, recurrent, transcriptomic analysis, biomarker Received: October 26, 2015 Accepted: January 27, 2016 Published: February 15, 2016 ABSTRACT 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 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.