Open Access

Karam T. Alhalabi, Damian Stichel, Philipp Sievers, Heike Peterziel, Alexander C. Sommerkamp, Dominik Sturm, Andrea Wittmann, Martin Sill, Natalie Jäger, Pengbo Beck, Kristian Wilfried Pajtler, Matija Snuderl, George Jour, Michael Delorenzo, Allison M. Martin, Adam Levy, Nagma Dalvi, Jordan R. Hansford, Nicholas G. Gottardo, Emmanuelle Uro-Coste, Claude-Alain Maurage, Catherine Godfraind, Fanny Vandenbos, Torsten Pietsch, Christof M. Kramm, Maria Filippidou, Antonis Kattamis, Chris Jones, Ingrid Øra, Torben Stamm Mikkelsen, Michal Zapotocky, David Sumerauer, David Scheie, Martin McCabe, Pieter Wesseling, Bastiaan B. J. Tops, Mariëtte E. G. Kranendonk, Matthias A. Karajannis, Nancy Bouvier, Elli Papaemmanuil, Hildegard Dohmen, Till Acker, Katja von Hoff, Simone Schmid, Evelina Miele, Katharina Johanna Filipski, Lidija Kitanovski, Lenka Krskova, Johannes Gojo, Christine Haberler, Frank Alvaro, Jonas Ecker, Florian Selt, Till Milde, Olaf Witt, Ina Oehme, Marcel Kool, Andreas von Deimling, Andrey Korshunov, Stefan Pfister, Felix Sahm, David T. W. Jones

• Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.