Molecular characterization of CNS paragangliomas identifies cauda equina paragangliomas as a distinct tumor entity
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ORIGINAL PAPER
Molecular characterization of CNS paragangliomas identifies cauda equina paragangliomas as a distinct tumor entity Leonille Schweizer1,2 · Felix Thierfelder1,2 · Christian Thomas3 · Patrick Soschinski3 · Abigail Suwala4,5 · Damian Stichel4,5 · Annika K. Wefers4,5,6 · Lars Wessels7 · Martin Misch7 · Hee‑yeong Kim1,2 · Ruben Jödicke1 · Daniel Teichmann1 · David Kaul8 · Johannes Kahn9 · Michael Bockmayr10,11,12 · Martin Hasselblatt3 · Alexander Younsi13 · Andreas Unterberg13 · Bettina Knie14 · Jan Walter15 · Diaa Al Safatli15 · Sven‑Axel May16 · Andreas Jödicke17 · Georgios Ntoulias17 · Dag Moskopp14 · Peter Vajkoczy7 · Frank L. Heppner1,2,20,21 · David Capper1,2 · Wolfgang Hartmann18 · Christian Hartmann19 · Andreas von Deimling4,5 · David E. Reuss4,5 · Anne Schöler1,2 · Arend Koch1,2 Received: 15 July 2020 / Revised: 26 August 2020 / Accepted: 27 August 2020 © The Author(s) 2020
Abstract Paragangliomas/pheochromocytomas are rare neuroendocrine tumors that arise from the adrenal gland or ganglia at various sites throughout the body. They display a remarkable diversity of driver alterations and are associated with germline mutations in up to 40% of the cases. Comprehensive molecular profiling of abdomino-thoracic paragangliomas revealed four molecularly defined and clinically relevant subtypes. Paragangliomas of the cauda equina region are considered to belong to one of the defined molecular subtypes, but a systematic molecular analysis has not yet been performed. In this study, we analyzed genome-wide DNA methylation profiles of 57 cauda equina paragangliomas and show that these tumors are epigenetically distinct from non-spinal paragangliomas and other tumors. In contrast to paragangliomas of other sites, chromosomal imbalances are widely lacking in cauda equina paragangliomas. Furthermore, RNA and DNA exome sequencing revealed that frequent genetic alterations found in non-spinal paragangliomas—including the prognostically relevant SDH mutations—are absent in cauda equina paragangliomas. Histologically, cauda equina paragangliomas show frequently gangliocytic differentiation and strong immunoreactivity to pan-cytokeratin and cytokeratin 18, which is not common in paragangliomas of other sites. None of our cases had a familial paraganglioma syndrome. Tumors rarely recurred (9%) or presented with multiple lesions within the spinal compartment (7%), but did not metastasize outside the CNS. In summary, we show that cauda equina paragangliomas represent a distinct, sporadic tumor entity defined by a unique clinical and morpho-molecular profile. Keywords Paraganglioma · Cauda equina · Head and neck · SDHB · GATA3 · DNA methylation
Introduction Paragangliomas and pheochromocytomas are rare, neuroendocrine tumors developing from the autonomous nervous system. Arising in the adrenal medulla, tumors are called pheochromocytomas (PCC), whereas tumors in Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00401-020-02218-7) contains supplementary material, whi
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