Christian Thomas1, Patrick Soschinski1, Melissa Zwaig2, Spyridon Oikonomopoulos2, Konstantin Okonechnikov3,4, Kristian W Pajtler3,4,5, Martin Sill3, Leonille Schweizer6,7,8, Arend Koch6,7,8, Julia Neumann9, Ulrich Schüller9,10,11, Felix Sahm12,13, Laurèl Rauschenbach14,15, Kathy Keyvani16, Martin Proescholdt4,17, Markus J Riemenschneider18, Jochen Segewiß19, Christian Ruckert19, Oliver Grauer20, Camelia-Maria Monoranu21, Katrin Lamszus22, Annarita Patrizi23, Uwe Kordes10, Reiner Siebert24, Marcel Kool3,4,25, Jiannis Ragoussis2, William D Foulkes26, Werner Paulus1, Barbara Rivera27,28, Martin Hasselblatt1. 1. Institute of Neuropathology, University Hospital Münster, Münster, Germany. 2. McGill University Genome Centre, Department of Human Genetics, McGill University, Montreal, Canada. 3. Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany. 4. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Heidelberg, Germany. 5. Department of Pediatric Oncology, Hematology and Immunology, University Hospital, Heidelberg, Germany. 6. Department of Neuropathology, Charité - Universitätsmedizin Berlin, Germany. 7. German Cancer Consortium (DKTK), Heidelberg, Germany, Partner Site Charité Berlin, Berlin, Germany. 8. Berlin Institute of Health (BIH), Berlin, Germany. 9. Department of Neuropathology, University Hospital Hamburg-Eppendorf, Hamburg, Germany. 10. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 11. Research Institute Children's Cancer Center Hamburg, Hamburg, Germany. 12. Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. 13. Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 14. Department of Neurosurgery and Spine Surgery, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 15. DKFZ Division Translational Neurooncology, DKTK partner site, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 16. Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany. 17. Department of Neurosurgery, Regensburg University Hospital, Regensburg, Germany. 18. Department of Neuropathology, Regensburg University Hospital, Regensburg, Germany. 19. Institute of Human Genetics, University Hospital Münster, Münster, Germany. 20. Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany. 21. Department of Neuropathology, Institute of Pathology, University of Würzburg, Germany. 22. Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 23. Schaller Research Group Leader at the German Cancer Research Center (DKFZ), Heidelberg, Germany. 24. Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany. 25. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands. 26. Department of Human Genetics, McGill University, Montreal, QC, Canada. 27. Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. 28. Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada.
Abstract
BACKGROUND: Choroid plexus tumors (CPTs) are intraventricular brain tumors predominantly arising in children but also affecting adults. In most cases, driver mutations have not been identified, although there are reports of frequent chromosome-wide copy-number alterations and TP53 mutations, especially in choroid plexus carcinomas (CPCs). METHODS: DNA methylation profiling and RNA-sequencing was performed in a series of 47 CPTs. Samples comprised 35 choroid plexus papillomas (CPPs), 6 atypical choroid plexus papillomas (aCPPs) and 6 CPCs plus three recurrences thereof. Targeted TP53 and TERT promotor sequencing was performed in all samples. Whole exome sequencing (WES) and linked-read whole genome sequencing (WGS) was performed in 25 and 4 samples, respectively. RESULTS: Tumors comprised the molecular subgroups "pediatric A" (N=11), "pediatric B" (N=12) and "adult" (N=27). Copy-number alterations mainly represented whole-chromosomal alterations with subgroup-specific enrichments (gains of Chr1, 2 and 21q in "pediatric B" and gains of Chr5 and 9 and loss of Chr21q in "adult"). RNA sequencing yielded a novel CCDC47-PRKCA fusion transcript in one adult choroid plexus papilloma patient with aggressive clinical course; an underlying Chr17 inversion was demonstrated by linked-read WGS. WES and targeted sequencing showed TP53 mutations in 7/47 CPTs (15%), five of which were children. On the contrary, TERT promoter mutations were encountered in 7/28 adult patients (25%) and associated with shorter progression-free survival (log-rank test, p=0.015). CONCLUSION: Pediatric CPTs lack recurrent driver alterations except for TP53, whereas CPTs in adults show TERT promoter mutations or a novel CCDC47-PRKCA gene fusion, being associated with a more unfavorable clinical course.
BACKGROUND:Choroid plexus tumors (CPTs) are intraventricular brain tumors predominantly arising in children but also affecting adults. In most cases, driver mutations have not been identified, although there are reports of frequent chromosome-wide copy-number alterations and TP53 mutations, especially in choroid plexus carcinomas (CPCs). METHODS: DNA methylation profiling and RNA-sequencing was performed in a series of 47 CPTs. Samples comprised 35 choroid plexus papillomas (CPPs), 6 atypical choroid plexus papillomas (aCPPs) and 6 CPCs plus three recurrences thereof. Targeted TP53 and TERT promotor sequencing was performed in all samples. Whole exome sequencing (WES) and linked-read whole genome sequencing (WGS) was performed in 25 and 4 samples, respectively. RESULTS:Tumors comprised the molecular subgroups "pediatric A" (N=11), "pediatric B" (N=12) and "adult" (N=27). Copy-number alterations mainly represented whole-chromosomal alterations with subgroup-specific enrichments (gains of Chr1, 2 and 21q in "pediatric B" and gains of Chr5 and 9 and loss of Chr21q in "adult"). RNA sequencing yielded a novel CCDC47-PRKCA fusion transcript in one adult choroid plexus papillomapatient with aggressive clinical course; an underlying Chr17 inversion was demonstrated by linked-read WGS. WES and targeted sequencing showed TP53 mutations in 7/47 CPTs (15%), five of which were children. On the contrary, TERT promoter mutations were encountered in 7/28 adult patients (25%) and associated with shorter progression-free survival (log-rank test, p=0.015). CONCLUSION: Pediatric CPTs lack recurrent driver alterations except for TP53, whereas CPTs in adults show TERT promoter mutations or a novel CCDC47-PRKCA gene fusion, being associated with a more unfavorable clinical course.
Authors: Christian Koelsche; Felix Sahm; David Capper; David Reuss; Dominik Sturm; David T W Jones; Marcel Kool; Paul A Northcott; Benedikt Wiestler; Katja Böhmer; Jochen Meyer; Christian Mawrin; Christian Hartmann; Michel Mittelbronn; Michael Platten; Benjamin Brokinkel; Marcel Seiz; Christel Herold-Mende; Andreas Unterberg; Jens Schittenhelm; Michael Weller; Stefan Pfister; Wolfgang Wick; Andrey Korshunov; Andreas von Deimling Journal: Acta Neuropathol Date: 2013-10-24 Impact factor: 17.088
Authors: Astrid Jeibmann; Martin Hasselblatt; Joachim Gerss; Brigitte Wrede; Rupert Egensperger; Rudi Beschorner; Volkmar H J Hans; Christian H Rickert; Johannes E Wolff; Werner Paulus Journal: J Neuropathol Exp Neurol Date: 2006-11 Impact factor: 3.685
Authors: Franklin W Huang; Eran Hodis; Mary Jue Xu; Gregory V Kryukov; Lynda Chin; Levi A Garraway Journal: Science Date: 2013-01-24 Impact factor: 47.728
Authors: Sarah Sandmann; Mohsen Karimi; Aniek O de Graaf; Christian Rohde; Stefanie Göllner; Julian Varghese; Jan Ernsting; Gunilla Walldin; Bert A van der Reijden; Carsten Müller-Tidow; Luca Malcovati; Eva Hellström-Lindberg; Joop H Jansen; Martin Dugas Journal: Bioinformatics Date: 2018-12-15 Impact factor: 6.937