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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; [...]

PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum

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  • Media type: E-Article
  • Title: PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum
  • Contributor: 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; [...]
  • imprint: Springer Science and Business Media LLC, 2021
  • Published in: Acta Neuropathologica
  • Language: English
  • DOI: 10.1007/s00401-021-02354-8
  • ISSN: 0001-6322; 1432-0533
  • Keywords: Cellular and Molecular Neuroscience ; Neurology (clinical) ; Pathology and Forensic Medicine
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>n</jats:italic> = 60) that harbor <jats:italic>PATZ1</jats:italic> 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 <jats:italic>PATZ1</jats:italic>-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent <jats:italic>MN1</jats:italic>:<jats:italic>PATZ1</jats:italic> or <jats:italic>EWSR1</jats:italic>:<jats:italic>PATZ1</jats:italic> fusions related to (often extensive) copy number variations on chromosome 22, where <jats:italic>PATZ1</jats:italic> 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 <jats:italic>PAX2</jats:italic>, <jats:italic>GATA2</jats:italic> and <jats:italic>IGF2</jats:italic>. Drug screening performed on the <jats:italic>MN1</jats:italic>:<jats:italic>PATZ1</jats:italic> fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, <jats:italic>PATZ1</jats:italic> fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.</jats:p>