PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum
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Published:2021-08-21
Issue:5
Volume:142
Page:841-857
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ISSN:0001-6322
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Container-title:Acta Neuropathologica
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language:en
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Short-container-title:Acta Neuropathol
Author:
Alhalabi Karam T., Stichel Damian, Sievers Philipp, Peterziel Heike, Sommerkamp Alexander C., Sturm Dominik, Wittmann Andrea, Sill Martin, Jäger Natalie, Beck Pengbo, Pajtler Kristian W., Snuderl Matija, Jour George, Delorenzo Michael, Martin Allison M., Levy Adam, Dalvi Nagma, Hansford Jordan R., Gottardo Nicholas G., Uro-Coste Emmanuelle, Maurage Claude-Alain, Godfraind Catherine, Vandenbos Fanny, Pietsch Torsten, Kramm Christof, Filippidou Maria, Kattamis Antonis, Jones Chris, Øra Ingrid, Mikkelsen Torben Stamm, Zapotocky Michal, Sumerauer David, Scheie David, McCabe Martin, Wesseling Pieter, Tops Bastiaan B. J., Kranendonk Mariëtte E. G., Karajannis Matthias A., Bouvier Nancy, Papaemmanuil Elli, Dohmen Hildegard, Acker Till, von Hoff Katja, Schmid Simone, Miele Evelina, Filipski Katharina, Kitanovski Lidija, Krskova Lenka, Gojo Johannes, Haberler Christine, Alvaro Frank, Ecker Jonas, Selt Florian, Milde Till, Witt Olaf, Oehme Ina, Kool Marcel, von Deimling Andreas, Korshunov Andrey, Pfister Stefan M., Sahm Felix, Jones David T. W.ORCID
Abstract
AbstractLarge-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.
Funder
Deutsche Kinderkrebsstiftung Brain Tumour Charity Bundesministerium für Bildung und Forschung Deutsches Krebsforschungszentrum (DKFZ)
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology (clinical),Pathology and Forensic Medicine
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