Identification of Two Molecular and Clinical Distinct Entities of Posterior Fossa Ependymoma

H Witt; SC Mack; M Ryzhova; S Bender; M Sill; R Isserlin; A Benner; T Hielscher; T Milde; M Remke; DTW Jones; PA Northcott; L Garzia; KC Bertrand; A Wittmann; A von Deimling; AE Kulozik; O Witt; GD Bader; JT Rutka; P Lichter; A Korshunov; MD Taylor; SM Pfister

doi:10.1055/s-0031-1292598

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Klin Padiatr 2011; 223 - A17
DOI: 10.1055/s-0031-1292598

Identification of Two Molecular and Clinical Distinct Entities of Posterior Fossa Ependymoma

H Witt ¹^,², SC Mack ³^,⁴, M Ryzhova ⁵, S Bender ¹^,², M Sill ⁶, R Isserlin ⁷, A Benner ⁶, T Hielscher ⁶, T Milde ²^,⁸, M Remke ¹^,², DTW Jones ¹, PA Northcott ³^,⁴, L Garzia ³, KC Bertrand ³^,⁴, A Wittmann ¹, A von Deimling ⁹^,¹⁰, AE Kulozik ², O Witt ²^,⁸, GD Bader ⁷, JT Rutka ³^,⁴, P Lichter ¹, A Korshunov ⁷^,⁸, MD Taylor ³^,⁴, SM Pfister ¹^,²

¹Division Molecular Genetics, German Cancer Research Center, Heidelberg, Germany
²Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany
³Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada
⁴Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
⁵Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow, Russia
⁶Division Biostatistics, German Cancer Research Center, Heidelberg, Germany
⁷Department of Molecular Genetics, Banting and Best Department of Medical Research, The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada
⁸Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center, Heidelberg, Germany
⁹Department of Neuropathology, University of Heidelberg, Heidelberg, Germany
¹⁰Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany

Congress Abstract

Ependymoma is the third most common brain tumor in children, and remains incurable for as many as 45% of patients even after therapy currently consisting of maximal safe resection and radiotherapy. Despite the histological similarity of ependymomas from throughout the neuraxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis.

We examined two non-overlapping cohorts of 102 and 75 ependymomas by mRNA expression profiling, on two different array platforms (Affymetrix Exon 1.0 ST, Agilent 4×44K). Multiple statistical clustering methods (unsupervised consensus NMF and consensus HCL) consistently revealed three major subgroups, including two subgroups of posterior fossa (PF) ependymoma in both data sets. Subgroup-specific chromosome aberrations of PF tumors were detected by aCGH. To identify biological signaling pathways distinguishing PF subgroups we performed gene set enrichment analysis visualized by Cytoscape. Most significant subgroup markers were selected by Goeman's global test statistic. Identified subgroup markers could be validated by immunohistochemical staining of 265 PF ependymomas on a tissue microarray.

We identified two subgroups (group A and group B) of PF ependymoma, which are demographically, transcriptionally, genetically, and clinically distinct ependymoma entities. Group A patients are younger, have laterally located tumors with a balanced genome, and are much more likely to exhibit recurrence, secondary metastasis, and death as compared to group B patients. The identification of two distinct subgroups of PF ependymoma, and markers applicable for their clinical distinction, will allow better prognostication of individual cases, and stratification in future ependymoma clinical trials.