title: Transcriptomic analysis of aggressive meningiomas identifies PTTG1 and LEPR as prognostic biomarkers independent of WHO grade.
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<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.
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Melissa
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mock
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Jungk
authors.affiliation: Department of Neuropathology, Heidelberg University Hospital, CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Sahm
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Anna Theresa
authors.initials: AT
authors.lastname: Ull
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Warta
authors.affiliation: Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Lamszus
authors.affiliation: Department of Neurosurgery, University Hospital Bonn, Bonn, Germany.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Gousias
authors.affiliation: Department of Neurosurgery, Saarland University, Medical School, Homburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Ketter
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Roesch
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Rapp
authors.affiliation: Department of Neuropathology, Heidelberg University Hospital, CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schefzyk
authors.affiliation: Department of Neurosurgery, Saarland University, Medical School, Homburg, Germany.
authors.forename: Steffi
authors.initials: S
authors.lastname: Urbschat
authors.affiliation: Bioquant, Medical Oncology, National Center for Tumor Diseases, Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Lahrmann
authors.affiliation: Department of Neurosurgery, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Almuth F
authors.initials: AF
authors.lastname: Kessler
authors.affiliation: Department of Neurosurgery, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Löhr
authors.affiliation: Department of Neurosurgery, University of Frankfurt, Frankfurt, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Senft
authors.affiliation: Bioquant, Medical Oncology, National Center for Tumor Diseases, Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
authors.affiliation: Department of Neuropathology, Heidelberg University Hospital, CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Reuss
authors.affiliation: Regensburg Center for Interventional Immunology, RCI and University Medical Center of Regensburg, Regensburg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
authors.affiliation: Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Westphal
authors.affiliation: Department of Neuropathology, Heidelberg University Hospital, CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Unterberg
authors.affiliation: Department of Neurosurgery, University Hospital Bonn, Bonn, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Simon
authors.affiliation: Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008577:Meningeal Neoplasms / Q000235:genetics / Q000556:secondary*; D008579:Meningioma / Q000235:genetics / Q000473:pathology*; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology*; D054411:Receptors, Leptin / Q000235:genetics*; D064249:Securin / Q000235:genetics*; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C515448:LEPR protein, human; D054411:Receptors, Leptin; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human
keywords: anaplastic; biomarker; meningioma; recurrent; transcriptomic analysis