AT-10ATYPICAL TERATOID RHABDOID TUMORS AND POORLY DIFFERENTIATED CHORDOMAS: DISTINCT MOLECULAR ENTITIES WITH SMARCB1/INI1 LOSS AND DISMAL PROGNOSIS
Authors: Christian Thomas, Volker Hovestadt, Daniel Schrimpf, Pascal Johann, Susanne Bens, Florian Oyen, Hannes Vogel, Felice Giangaspero, Manila Antonelli, Markus Riemenschneider, Marie Christine Bernardo, Caterina Giannini, Nasir Ud Din, Arie Perry, Kathy Keyvani, Frank van Landeghem, David Sumerauer, Peter Hauser, David Capper, Andrey Korshunov, David T.W. Jones, Stefan Pfister, Reinhard Schneppenheim, Reiner Siebert, Michael C. Frühwald, Marcel Kool, Martin Hasselblatt
Journal: Neuro-Oncology (2016)

AT-10. ATYPICAL TERATOID RHABDOID TUMORS AND POORLY DIFFERENTIATED CHORDOMAS: DISTINCT MOLECULAR ENTITIES WITH SMARCB1/INI1 LOSS AND DISMAL PROGNOSIS Christian Thomas1, Volker Hovestadt2,3, Daniel Schrimpf2,3, Pascal Johann2,4, Susanne Bens5, Florian Oyen6, Hannes Vogel7, Felice Giangaspero8, Manila Antonelli8, Markus Riemenschneider9, Marie Christine Bernardo10, Caterina Giannini11, Nasir Ud Din12, Arie Perry13, Kathy Keyvani14, Frank van Landeghem15, David Sumerauer16, Peter Hauser17, David Capper3,4, Andrey Korshunov3,4, David T.W. Jones2,3, Stefan Pfister2,3, Reinhard Schneppenheim6, Reiner Siebert5, Michael C. Fruhwald18, Marcel Kool2,3, and Martin Hasselblatt1; University Hospital Munster, Munster, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; University Hospital Heidelberg, Heidelberg, Germany; Christian-Albrechts-University Kiel, Kiel, Germany; University Medical CenterHamburg-Eppendorf,Hamburg,Germany;StanfordUniversitySchool of Medicine, Palo Alto, CA, USA; Sapienza University, Rome, Italy; Regensburg University Hospital, Regensburg, Germany; St. Lukes Medical Center, Quezon City, The Philippines; Mayo Clinic, Rochester, MN, USA; Aga Khan University Hospital, Karachi, Pakistan; UCSF Medical Center, San Francisco, CA, USA; University of Duisburg-Essen, Essen, Germany; University of Alberta, Edmonton, Canada; Charles University, Prague, Czech Republic; Semmelweis University, Budapest, Hungary; Childrens’ Hospital Augsburg and EU-RHAB Registry, Augsburg, Germany Chordomasare tumorsof the skull base and spine thought to arise fromremnants of the notochord. Pediatric chordomas showing atypia, increased mitotic activity, unstructured growth pattern and loss of SMARCB1/INI1 expression have been designated as “poorly differentiated chordomas”. It remains uncertain, however, if poorly differentiated chordoma represents a distinct entity or part of the AT/RT spectrum. Therefore, seven poorly differentiated chordomas, 14 conventional chordomas as well as 10 AT/RT of each of three molecular subgroups (i.e. TYR, MYC and SHH) were molecularly characterized including Illumina Infinium Human Methylation 450k Bead Chip profiling. Median age of the four boys and three girls harboring poorly differentiated chordomas was 7 years (range 1-11 years); median overall survival accounted for only 9 months (95% confidence interval 6-12 months). On histopathological examination, all poorly differentiated chordomas lacked SMARCB1/INI1 expression but showed nuclear brachyury expression. Brachyury expression was also observed in 2/30 AT/RT. Unsupervised clusteranalysis identified five methylation groups, including two distinct chordoma clusters, representing the poorly differentiated chordomas and the conventional chordomas, respectively, both clustering apart from the AT/RT subgroups. Losses of 22q affecting the SMARCB1 region were the only recurrentalteration inpoorlydifferentiatedchordomas andthevastmajorityofAT/ RT. Heterozygous or homozygous deletions affecting the SMARCB1 region could be confirmed on FISH and/or MLPA, while SMARCB1 point mutations were absent on sequencing. In conclusion, poorly differentiated chordoma represents a molecularly distinct entity with dismal prognosis, which can be reliably separated from conventional chordoma and AT/RT by a distinct methylation profile. Neuro-Oncology 18:iii1–iii6, 2016. doi:10.1093/neuonc/now065.9 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.