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31 results on '"Schueller, Ulrich"'

1. GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant

Author

Liu, Ilon, Alencastro Veiga Cruzeiro, Gustavo, Bjerke, Lynn, Rogers, Rebecca F., Grabovska, Yura, Beck, Alexander, Mackay, Alan, Barron, Tara, Hack, Olivia A., Quezada, Michael A., Molinari, Valeria, Shaw, McKenzie L., Perez-Somarriba, Marta, Temelso, Sara, Raynaud, Florence, Ruddle, Ruth, Panditharatna, Eshini, Englinger, Bernhard, Mire, Hafsa M., Jiang, Li, Nascimento, Andrezza, LaBelle, Jenna, Haase, Rebecca, Rozowsky, Jacob, Neyazi, Sina, Baumgartner, Alicia-Christina, Castellani, Sophia, Hoffman, Samantha E., Cameron, Amy, Morrow, Murry, Nguyen, Quang-De, Pericoli, Giulia, Madlener, Sibylle, Mayr, Lisa, Dorfer, Christian, Geyeregger, Rene, Rota, Christopher, Ricken, Gerda, Ligon, Keith L., Alexandrescu, Sanda, Cartaxo, Rodrigo T., Lau, Benison, Uphadhyaya, Santhosh, Koschmann, Carl, Braun, Emelie, Danan-Gotthold, Miri, Hu, Lijuan, Siletti, Kimberly, Sundström, Erik, Hodge, Rebecca, Lein, Ed, Agnihotri, Sameer, Eisenstat, David D., Stapleton, Simon, King, Andrew, Bleil, Cristina, Mastronuzzi, Angela, Cole, Kristina A., Waanders, Angela J., Montero Carcaboso, Angel, Schüller, Ulrich, Hargrave, Darren, Vinci, Maria, Carceller, Fernando, Haberler, Christine, Slavc, Irene, Linnarsson, Sten, Gojo, Johannes, Monje, Michelle, Jones, Chris, and Filbin, Mariella G.

Published
2024
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3. Multi-Scale Input Strategies for Medulloblastoma Tumor Classification using Deep Transfer Learning

Author

Bengs, Marcel, Pant, Satish, Bockmayr, Michael, Schüller, Ulrich, and Schlaefer, Alexander

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition
Abstract

Medulloblastoma (MB) is a primary central nervous system tumor and the most common malignant brain cancer among children. Neuropathologists perform microscopic inspection of histopathological tissue slides under a microscope to assess the severity of the tumor. This is a time-consuming task and often infused with observer variability. Recently, pre-trained convolutional neural networks (CNN) have shown promising results for MB subtype classification. Typically, high-resolution images are divided into smaller tiles for classification, while the size of the tiles has not been systematically evaluated. We study the impact of tile size and input strategy and classify the two major histopathological subtypes-Classic and Demoplastic/Nodular. To this end, we use recently proposed EfficientNets and evaluate tiles with increasing size combined with various downsampling scales. Our results demonstrate using large input tiles pixels followed by intermediate downsampling and patch cropping significantly improves MB classification performance. Our top-performing method achieves the AUC-ROC value of 90.90\% compared to 84.53\% using the previous approach with smaller input tiles., Comment: Accepted at CURAC 2021

Published
2021

4. Medulloblastoma Tumor Classification using Deep Transfer Learning with Multi-Scale EfficientNets

Author

Bengs, Marcel, Bockmayr, Michael, Schüller, Ulrich, and Schlaefer, Alexander

Subjects
Electrical Engineering and Systems Science - Image and Video Processing, Computer Science - Computer Vision and Pattern Recognition
Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in childhood. The diagnosis is generally based on the microscopic evaluation of histopathological tissue slides. However, visual-only assessment of histopathological patterns is a tedious and time-consuming task and is also affected by observer variability. Hence, automated MB tumor classification could assist pathologists by promoting consistency and robust quantification. Recently, convolutional neural networks (CNNs) have been proposed for this task, while transfer learning has shown promising results. In this work, we propose an end-to-end MB tumor classification and explore transfer learning with various input sizes and matching network dimensions. We focus on differentiating between the histological subtypes classic and desmoplastic/nodular. For this purpose, we systematically evaluate recently proposed EfficientNets, which uniformly scale all dimensions of a CNN. Using a data set with 161 cases, we demonstrate that pre-trained EfficientNets with larger input resolutions lead to significant performance improvements compared to commonly used pre-trained CNN architectures. Also, we highlight the importance of transfer learning, when using such large architectures. Overall, our best performing method achieves an F1-Score of 80.1%., Comment: Accepted at SPIE Medical Imaging 2021 https://www.spiedigitallibrary.org/conference-proceedings-of-spie/11603/116030D/Medulloblastoma-tumor-classification-using-deep-transfer-learning-with-multi-scale/10.1117/12.2580717.full?SSO=1

Published
2021

7. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis

Author

Thompson, Eric M, Hielscher, Thomas, Bouffet, Eric, Remke, Marc, Luu, Betty, Gururangan, Sridharan, McLendon, Roger E, Bigner, Darell D, Lipp, Eric S, Perreault, Sebastien, Cho, Yoon-Jae, Grant, Gerald, Kim, Seung-Ki, Lee, Ji Yeoun, Rao, Amulya A Nageswara, Giannini, Caterina, Li, Kay Ka Wai, Ng, Ho-Keung, Yao, Yu, Kumabe, Toshihiro, Tominaga, Teiji, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Low, David C Y, Seow, Wan Tew, Chang, Kenneth T E, Mora, Jaume, Pollack, Ian F, Hamilton, Ronald L, Leary, Sarah, Moore, Andrew S, Ingram, Wendy J, Hallahan, Andrew R, Jouvet, Anne, Fèvre-Montange, Michelle, Vasiljevic, Alexandre, Faure-Conter, Cecile, Shofuda, Tomoko, Kagawa, Naoki, Hashimoto, Naoya, Jabado, Nada, Weil, Alexander G, Gayden, Tenzin, Wataya, Takafumi, Shalaby, Tarek, Grotzer, Michael, Zitterbart, Karel, Sterba, Jaroslav, Kren, Leos, Hortobágyi, Tibor, Klekner, Almos, László, Bognár, Pócza, Tímea, Hauser, Peter, Schüller, Ulrich, Jung, Shin, Jang, Woo-Youl, French, Pim J, Kros, Johan M, van Veelen, Marie-Lise C, Massimi, Luca, Leonard, Jeffrey R, Rubin, Joshua B, Vibhakar, Rajeev, Chambless, Lola B, Cooper, Michael K, Thompson, Reid C, Faria, Claudia C, Carvalho, Alice, Nunes, Sofia, Pimentel, José, Fan, Xing, Muraszko, Karin M, López-Aguilar, Enrique, Lyden, David, Garzia, Livia, Shih, David J H, Kijima, Noriyuki, Schneider, Christian, Adamski, Jennifer, Northcott, Paul A, Kool, Marcel, Jones, David T W, Chan, Jennifer A, Nikolic, Ana, Garre, Maria Luisa, Van Meir, Erwin G, Osuka, Satoru, Olson, Jeffrey J, Jahangiri, Arman, Castro, Brandyn A, Gupta, Nalin, Weiss, William A, Moxon-Emre, Iska, Mabbott, Donald J, Lassaletta, Alvaro, Hawkins, Cynthia E, Tabori, Uri, Drake, James, Kulkarni, Abhaya, Dirks, Peter, Rutka, James T, Korshunov, Andrey, Pfister, Stefan M, Packer, Roger J, Ramaswamy, Vijay, and Taylor, Michael D

Published
2016
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8. Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis

Author

Torchia, Jonathon, Picard, Daniel, Lafay-Cousin, Lucie, Hawkins, Cynthia E, Kim, Seung-Ki, Letourneau, Louis, Ra, Young-Shin, Ho, King Ching, Chan, Tiffany Sin Yu, Sin-Chan, Patrick, Dunham, Christopher P, Yip, Stephen, Ng, Ho-keung, Lu, Jian-Qiang, Albrecht, Steffen, Pimentel, José, Chan, Jennifer A, Somers, Gino R, Zielenska, Maria, Faria, Claudia C, Roque, Lucia, Baskin, Berivan, Birks, Diane, Foreman, Nick, Strother, Douglas, Klekner, Almos, Garami, Miklos, Hauser, Peter, Hortobágyi, Tibor, Bognár, Laszló, Wilson, Beverly, Hukin, Juliette, Carret, Anne-Sophie, Van Meter, Timothy E, Nakamura, Hideo, Toledano, Helen, Fried, Iris, Fults, Daniel, Wataya, Takafumi, Fryer, Chris, Eisenstat, David D, Scheineman, Katrin, Johnston, Donna, Michaud, Jean, Zelcer, Shayna, Hammond, Robert, Ramsay, David A, Fleming, Adam J, Lulla, Rishi R, Fangusaro, Jason R, Sirachainan, Nongnuch, Larbcharoensub, Noppadol, Hongeng, Suradej, Barakzai, Muhammad Abrar, Montpetit, Alexandre, Stephens, Derek, Grundy, Richard G, Schüller, Ulrich, Nicolaides, Theodore, Tihan, Tarik, Phillips, Joanna, Taylor, Michael D, Rutka, James T, Dirks, Peter, Bader, Gary D, Warmuth-Metz, Monika, Rutkowski, Stefan, Pietsch, Torsten, Judkins, Alexander R, Jabado, Nada, Bouffet, Eric, and Huang, Annie

Published
2015
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9. Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis

Author

Ramaswamy, Vijay, Remke, Marc, Bouffet, Eric, Faria, Claudia C, Perreault, Sebastien, Cho, Yoon-Jae, Shih, David J, Luu, Betty, Dubuc, Adrian M, Northcott, Paul A, Schüller, Ulrich, Gururangan, Sridharan, McLendon, Roger, Bigner, Darell, Fouladi, Maryam, Ligon, Keith L, Pomeroy, Scott L, Dunn, Sandra, Triscott, Joanna, Jabado, Nada, Fontebasso, Adam, Jones, David T W, Kool, Marcel, Karajannis, Matthias A, Gardner, Sharon L, Zagzag, David, Nunes, Sofia, Pimentel, José, Mora, Jaume, Lipp, Eric, Walter, Andrew W, Ryzhova, Marina, Zheludkova, Olga, Kumirova, Ella, Alshami, Jad, Croul, Sidney E, Rutka, James T, Hawkins, Cynthia, Tabori, Uri, Codispoti, Kari-Elise T, Packer, Roger J, Pfister, Stefan M, Korshunov, Andrey, and Taylor, Michael D

Published
2013
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11. Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma

Author

Borgenvik, Anna, Holmberg, Karl O., Bolin, Sara, Zhao, Miao, Savov, Vasil, Rosén, Gabriela, Hutter, Sonja, Garancher, Alexandra, Rahmanto, Aldwin Suryo, Bergström, Tobias, Olsen, Thale Kristin, Mainwaring, Oliver, Sattanino, Damiana, Verbaan, Annemieke D., Rusert, Jessica M., Sundström, Anders, Ballester Bravo, Mar, Dang, Yonglong, Wenz, Amelie S., Richardson, Stacey, Fotaki, Grammatiki, Hill, Rebecca M., Dubuc, Adrian M., Kalushkova, Antonia, Remke, Marc, Čančer, Matko, Jernberg Wiklund, Helena, Giraud, Geraldine, Chen, Xingqi, Taylor, Michael D., Sangfelt, Olle, Clifford, Steven C., Schueller, Ulrich, Wechsler-Reya, Robert J., Weishaupt, Holger, Swartling, Fredrik J., Borgenvik, Anna, Holmberg, Karl O., Bolin, Sara, Zhao, Miao, Savov, Vasil, Rosén, Gabriela, Hutter, Sonja, Garancher, Alexandra, Rahmanto, Aldwin Suryo, Bergström, Tobias, Olsen, Thale Kristin, Mainwaring, Oliver, Sattanino, Damiana, Verbaan, Annemieke D., Rusert, Jessica M., Sundström, Anders, Ballester Bravo, Mar, Dang, Yonglong, Wenz, Amelie S., Richardson, Stacey, Fotaki, Grammatiki, Hill, Rebecca M., Dubuc, Adrian M., Kalushkova, Antonia, Remke, Marc, Čančer, Matko, Jernberg Wiklund, Helena, Giraud, Geraldine, Chen, Xingqi, Taylor, Michael D., Sangfelt, Olle, Clifford, Steven C., Schueller, Ulrich, Wechsler-Reya, Robert J., Weishaupt, Holger, and Swartling, Fredrik J.

Abstract

Relapse is the leading cause of death in patients with medulloblas-toma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC amplification. In paired primary-recurrent patient samples, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected in vivo from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial-mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, whereas MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse.Significance: SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.

Published
2022
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14. Sarcoma classification by DNA methylation profiling

Author

Koelsche, Christian, Schrimpf, Daniel, Stichel, Damian, Sill, Martin, Sahm, Felix, Reuss, David E., Blattner, Mirjam, Worst, Barbara, Heilig, Christoph E., Beck, Katja, Horak, Peter, Kreutzfeldt, Simon, Paff, Elke, Stark, Sebastian, Johann, Pascal, Selt, Florian, Ecker, Jonas, Sturm, Dominik, Pajtler, Kristian W., Reinhardt, Annekathrin, Wefers, Annika K., Sievers, Philipp, Ebrahimi, Azadeh, Suwala, Abigail, Fernandez-Klett, Francisco, Casalini, Belen, Korshunov, Andrey, Hovestadt, Volker, Kommoss, Felix K. F., Kriegsmann, Mark, Schick, Matthias, Bewerunge-Hudler, Melanie, Milde, Till, Witt, Olaf, Kulozik, Andreas E., Kool, Marcel, Romero-Perez, Laura, Gruenewald, Thomas G. P., Kirchner, Thomas, Wick, Wolfgang, Platten, Michael, Unterberg, Andreas, Uhl, Matthias, Abdollahi, Amir, Debus, Juergen, Lehner, Burkhard, Thomas, Christian, Hasselblatt, Martin, Paulus, Werner, Hartmann, Christian, Staszewski, Ori, Prinz, Marco, Hench, Juergen, Frank, Stephan, Versleijen-Jonkers, Yvonne M. H., Weidema, Marije E., Mentzel, Thomas, Griewank, Klaus, de Alava, Enrique, Martin, Juan Diaz, Gastearena, Miguel A. Idoate, Chang, Kenneth Tou-En, Low, Sharon Yin Yee, Cuevas-Bourdier, Adrian, Mittelbronn, Michel, Mynarek, Martin, Rutkowski, Stefan, Schueller, Ulrich, Mautner, Viktor F., Schittenhelm, Jens, Serrano, Jonathan, Snuderl, Matija, Buettner, Reinhard, Klingebiel, Thomas, Buslei, Rolf, Gessler, Manfred, Wesseling, Pieter, Dinjens, Winand N. M., Brandner, Sebastian, Jaunmuktane, Zane, Lyskjaer, Iben, Schirmacher, Peter, Stenzinger, Albrecht, Brors, Benedikt, Glimm, Hanno, Heining, Christoph, Tirado, Oscar M., Sainz-Jaspeado, Miguel, Mora, Jaume, Alonso, Javier, del Muro, Xavier Garcia, Moran, Sebastian, Esteller, Manel, Benhamida, Jamal K., Ladanyi, Marc, Wardelmann, Eva, Antonescu, Cristina, Flanagan, Adrienne, Dirksen, Uta, Hohenberger, Peter, Baumhoer, Daniel, Hartmann, Wolfgang, Vokuhl, Christian, Flucke, Uta, Petersen, Iver, Mechtersheimer, Gunhild, Capper, David, Jones, David T. W., Froehling, Stefan, Pfister, Stefan M., von Deimling, Andreas, Koelsche, Christian, Schrimpf, Daniel, Stichel, Damian, Sill, Martin, Sahm, Felix, Reuss, David E., Blattner, Mirjam, Worst, Barbara, Heilig, Christoph E., Beck, Katja, Horak, Peter, Kreutzfeldt, Simon, Paff, Elke, Stark, Sebastian, Johann, Pascal, Selt, Florian, Ecker, Jonas, Sturm, Dominik, Pajtler, Kristian W., Reinhardt, Annekathrin, Wefers, Annika K., Sievers, Philipp, Ebrahimi, Azadeh, Suwala, Abigail, Fernandez-Klett, Francisco, Casalini, Belen, Korshunov, Andrey, Hovestadt, Volker, Kommoss, Felix K. F., Kriegsmann, Mark, Schick, Matthias, Bewerunge-Hudler, Melanie, Milde, Till, Witt, Olaf, Kulozik, Andreas E., Kool, Marcel, Romero-Perez, Laura, Gruenewald, Thomas G. P., Kirchner, Thomas, Wick, Wolfgang, Platten, Michael, Unterberg, Andreas, Uhl, Matthias, Abdollahi, Amir, Debus, Juergen, Lehner, Burkhard, Thomas, Christian, Hasselblatt, Martin, Paulus, Werner, Hartmann, Christian, Staszewski, Ori, Prinz, Marco, Hench, Juergen, Frank, Stephan, Versleijen-Jonkers, Yvonne M. H., Weidema, Marije E., Mentzel, Thomas, Griewank, Klaus, de Alava, Enrique, Martin, Juan Diaz, Gastearena, Miguel A. Idoate, Chang, Kenneth Tou-En, Low, Sharon Yin Yee, Cuevas-Bourdier, Adrian, Mittelbronn, Michel, Mynarek, Martin, Rutkowski, Stefan, Schueller, Ulrich, Mautner, Viktor F., Schittenhelm, Jens, Serrano, Jonathan, Snuderl, Matija, Buettner, Reinhard, Klingebiel, Thomas, Buslei, Rolf, Gessler, Manfred, Wesseling, Pieter, Dinjens, Winand N. M., Brandner, Sebastian, Jaunmuktane, Zane, Lyskjaer, Iben, Schirmacher, Peter, Stenzinger, Albrecht, Brors, Benedikt, Glimm, Hanno, Heining, Christoph, Tirado, Oscar M., Sainz-Jaspeado, Miguel, Mora, Jaume, Alonso, Javier, del Muro, Xavier Garcia, Moran, Sebastian, Esteller, Manel, Benhamida, Jamal K., Ladanyi, Marc, Wardelmann, Eva, Antonescu, Cristina, Flanagan, Adrienne, Dirksen, Uta, Hohenberger, Peter, Baumhoer, Daniel, Hartmann, Wolfgang, Vokuhl, Christian, Flucke, Uta, Petersen, Iver, Mechtersheimer, Gunhild, Capper, David, Jones, David T. W., Froehling, Stefan, Pfister, Stefan M., and von Deimling, Andreas

Abstract

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications. Sarcomas are morphologically heterogeneous tumours rendering their classification challenging. Here the authors developed a classifier using DNA methylation data from several soft tissue and bone sarcoma subtypes, which has the potential to improve classification for research and clinical purposes.

Published
2021

17. Multicenter Study on Clinical Outcomes of Olfactory Neuroblastoma

Author

Lechner, Matt, additional, Takahashi, Yoko, additional, Hermsen, Mario, additional, Turri-Zanoni, Mario, additional, Schartinger, Volker, additional, Bell, Diana M., additional, Helman, Sam, additional, Varghese, Jordan, additional, Magliocca, Kelly, additional, Dudas, Jozsef, additional, Riechelmann, Herbert, additional, Kaur, Raman, additional, Sprung, Susanne, additional, Howard, David, additional, Engel, Nils, additional, Zhao, Tianna, additional, Liu, Jacklyn, additional, Facchetti, Fabio, additional, Maragliano, Roberta, additional, Battocchio, Simonetta, additional, Franchi, Alessandro, additional, Carnell, Dawn, additional, Capper, David, additional, Schueller, Ulrich, additional, Forster, Martin, additional, Forde, Cillian, additional, Jay, Amrita, additional, Manes, R. Peter, additional, Judson, Benjamin L., additional, Vining, Eugenia, additional, Woods, Robbie, additional, Solares, C. Arturo, additional, O'Neill, James P., additional, Nicolai, Piero, additional, Surda, Pavol, additional, Bossi, Paolo, additional, Rampinelli, Vittorio, additional, Henriquez, Oswaldo A., additional, Hopkins, Claire, additional, Thavaraj, Selbam, additional, Yarbrough, Wendell G., additional, London, Nyall R., additional, Gallia, Gary L., additional, Wise, Sarah K., additional, Llorente, Jose L., additional, Castelnuovo, Paolo, additional, Hanna, Ehab Y., additional, and Lund, Valerie J., additional

Published
2021
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18. Multicenter Analysis of Clinical Outcomes and Biomarkers of Esthesioneuroblastoma

Author

Lechner, Matt, additional, Hermsen, Mario, additional, Turri-Zanoni, Mario, additional, Schartinger, Volker H., additional, Helman, Sam, additional, Varghese, Jordan, additional, Solares, C. Arturo, additional, Magliocca, Kelly, additional, Wang, Simon, additional, Sprung, Susanne, additional, Howard, David, additional, Engel, Nils, additional, Capper, David, additional, Schueller, Ulrich, additional, Forster, Martin, additional, Jay, Amrita, additional, Forde, Cillian, additional, Dudas, Jozsef, additional, Riechelmann, Herbert, additional, Manes, R. Peter, additional, Yarbrough, Wendell G., additional, Llorente, Jose L., additional, Wise, Sarah K., additional, Castelnuovo, Paolo, additional, and Lund, Valerie J., additional

Published
2020
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19. Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma

Author

Merk, Daniel J., Ohli, Jasmin, Merk, Natalie D., Thatikonda, Venu, Morrissy, Sorana, Schoof, Melanie, Schmid, Susanne N., Harrison, Luke, Filser, Severin, Ahlfeld, Julia, Erkek, Serap, Raithatha, Kaamini, Andreska, Thomas, Weisshaar, Marc, Launspach, Michael, Neumann, Julia E., Shakarami, Mehdi, Plenker, Dennis, Marra, Marco A., Li, Yisu, Mungall, Andrew J., Moore, Richard A., Ma, Yussanne, Jones, Steven J. M., Lutz, Beat, Ertl-Wagner, Birgit, Rossi, Andrea, Wagener, Rabea, Siebert, Reiner, Jung, Andreas, Eberhart, Charles G., Lach, Boleslaw, Sendtner, Michael, Pfister, Stefan M., Taylor, Michael D., Chavez, Lukas, Kool, Marcel, Schueller, Ulrich, Merk, Daniel J., Ohli, Jasmin, Merk, Natalie D., Thatikonda, Venu, Morrissy, Sorana, Schoof, Melanie, Schmid, Susanne N., Harrison, Luke, Filser, Severin, Ahlfeld, Julia, Erkek, Serap, Raithatha, Kaamini, Andreska, Thomas, Weisshaar, Marc, Launspach, Michael, Neumann, Julia E., Shakarami, Mehdi, Plenker, Dennis, Marra, Marco A., Li, Yisu, Mungall, Andrew J., Moore, Richard A., Ma, Yussanne, Jones, Steven J. M., Lutz, Beat, Ertl-Wagner, Birgit, Rossi, Andrea, Wagener, Rabea, Siebert, Reiner, Jung, Andreas, Eberhart, Charles G., Lach, Boleslaw, Sendtner, Michael, Pfister, Stefan M., Taylor, Michael D., Chavez, Lukas, Kool, Marcel, and Schueller, Ulrich

Abstract

Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of Crebbp in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor (Bdnf). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mutations of CREBBP. By contrast, loss of Crebbp in GNPs during postnatal development synergizes with oncogenic activation of SHH signaling to drive MB growth, thereby explaining the enrichment of somatic CREBBP mutations in SHH MB of adult patients. Together, our data provide insights into time-sensitive consequences of CREBBP mutations and corresponding associations with human diseases.

Published
2018

20. DNA methylation-based classification of central nervous system tumours

Author

Capper, David, Jones, David T. W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, Hoelsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J., Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Juergen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brueck, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Haenggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R., Kohlhof, Patricia, Kristensen, Bjarne W., Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Muehleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G., Driever, Pablo Hernaiz, Kramm, Christof M., Mueller, Hermann L., Rutkowski, Stefan, von Hoff, Katja, Fruehwald, Michael C., Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia-Maria, Perry, Arie, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Bluemcke, Ingmar, Bendszus, Martin, Debus, Juergen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schueller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, von Deimling, Andreas, Pfister, Stefan M., Capper, David, Jones, David T. W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, Hoelsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J., Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Juergen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brueck, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Haenggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R., Kohlhof, Patricia, Kristensen, Bjarne W., Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Muehleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G., Driever, Pablo Hernaiz, Kramm, Christof M., Mueller, Hermann L., Rutkowski, Stefan, von Hoff, Katja, Fruehwald, Michael C., Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia-Maria, Perry, Arie, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Bluemcke, Ingmar, Bendszus, Martin, Debus, Juergen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schueller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, von Deimling, Andreas, and Pfister, Stefan M.

Abstract

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challengingwith substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.

Published
2018

21. Characterization of Diffuse Gliomas With Histone H3-G34 Mutation by MRI and Dynamic 18F-FET PET

Author

Vettermann, Franziska J., Felsberg, Joerg, Reifenberger, Guido, Hasselblatt, Martin, Forbrig, Robert, Berding, Georg, la Fougere, Christian, Galldiks, Norbert, Schittenhelm, Jens, Weis, Joachim, Albert, Nathalie L., Schueller, Ulrich, Vettermann, Franziska J., Felsberg, Joerg, Reifenberger, Guido, Hasselblatt, Martin, Forbrig, Robert, Berding, Georg, la Fougere, Christian, Galldiks, Norbert, Schittenhelm, Jens, Weis, Joachim, Albert, Nathalie L., and Schueller, Ulrich

Abstract

Background Recent data suggest that diffuse gliomas carrying mutations in codon 34 of the H3 histone family 3A protein represent a very rare, distinct subgroup of IDH-wild type malignant astrocytic gliomas. However, characteristics detectable by MRI and F-18-FET PET in H3-G34-mutant gliomas are unknown. Methods We report on MRI and F-18-FET PET findings in 8 patients from 4 German centers with H3-G34-mutant diffuse gliomas. MRI analyses included multifocality, contrast enhancement, necrosis, cysts, hemorrhages, calcification, and edema. F-18-FET PET characteristics were evaluated on the basis of static F-18-FET PET parameters, such as maximal tumor-to-background ratio (TBRmax) and biological tumor volume (BTV), as well as the minimal time-to-peak (TTPmin) obtained from dynamic F-18-FET PET data. Results MRI showed multifocal lesions in 2 of 8, contrast enhancement in 6 of 8, necrosis in 3 of 8, cysts in 3 of 8, hemorrhage in 1 of 8, and calcifications in 1 of 8 patients. None of the tumors showed marked peritumoral edema. However, all 8 H3-G34-mutant gliomas were characterized by a high uptake intensity on F-18-FET PET with a median TBRmax of 3.4 (range, 2.5-11.7) and a relatively diffuse uptake pattern leading to a large BTV (median, 41.9 mL; range, 7.5-115.6). Dynamic PET data revealed a short median TTPmin of 12.5 minutes. Conclusions MRI features of diffuse gliomas with H3-G34 mutation may present very heterogeneously with some cases not even fulfilling the imaging criteria of high-grade glioma. In contrast, in F-18-FET PET, these tumors show an extensive and diffuse tracer uptake resulting in large BTV with a high TBRmax and a short TTPmin, thus resembling PET characteristics of aggressive high-grade gliomas, namely, glioblastomas.

Published
2018

22. MBCL-21. EARLY CHILDHOOD MEDULLOBLASTOMA: SUBGROUP-SPECIFIC SURVIVAL IN PATIENTS TREATED WITH SYSTEMIC CHEMOTHERAPY AND INTRAVENTRICULAR MTX TO AVOID CRANIOSPINAL RADIOTHERAPY

Author

Mynarek, Martin, primary, Kool, Marcel, additional, Schueller, Ulrich, additional, von Hoff, Katja, additional, Sharma, Tanvi, additional, Rudneva, Vasilisa, additional, Pietsch, Torsten, additional, Northcott, Paul, additional, Juhnke, B -Ole, additional, Meissner, Barbara, additional, Warmuth-Metz, Monica, additional, Kortmann, Rolf D, additional, Robinson, Giles, additional, von Deimling, Andreas, additional, Pfister, Stefan, additional, and Rutkowski, Stefan, additional

Published
2018
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23. Medulloblastoma : experimental models and reality

Author

Neumann, Julia E., Johansson, Fredrik K., Schueller, Ulrich, Neumann, Julia E., Johansson, Fredrik K., and Schueller, Ulrich

Abstract

Medulloblastoma is the most frequent malignant brain tumor in childhood, but it may also affect infants, adolescents, and young adults. Recent advances in the understanding of the disease have shed light on molecular and clinical heterogeneity, which is now reflected in the updated WHO classification of brain tumors. At the same time, it is well accepted that preclinical research and clinical trials have to be subgroup-specific. Hence, valid models have to be generated specifically for every medulloblastoma subgroup to properly mimic molecular fingerprints, clinical features, and responsiveness to targeted therapies. This review summarizes the availability of experimental medulloblastoma models with a particular focus on how well these models reflect the actual disease subgroup. We further describe technical advantages and disadvantages of the models and finally point out how some models have successfully been used to introduce new drugs and why some medulloblastoma subgroups are extraordinary difficult to model.

Published
2017
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24. Adressen

Author

Bernhard, Matthias K., Blank, Rainer, Dulz, Simon, Ebinger, Friedrich, Ebinger, Martin, Friedrich, Reinhard E., Frölich, Jan, Gärtner, Jutta, Hagel, Christian, Häusler, Martin, Hömberg, Volker, Hornung, Dagmar, Jorch, Gerhard, Jaite, Charlotte, Jung, Nikolai, Kammler, Gertrud, Klein, Christine, Kohlschütter, Alfried, Kordes, Uwe, Korinthenberg, Rudolf, Krägeloh-Mann, Ingeborg, Krause, Matthias, Kunde-Trommer, Jutta, Lehmkuhl, Gerd, Lehmkuhl, Ulrike, Linhart, Dieter, Löbel, Ulrike, Mall, Volker, Mautner, Victor-Felix, Mehlan, Juliane, Merkenschlager, Andreas, von Moers, Arpad, Müller, Kristina, Müller-Felber, Wolfgang, Münchau, Alexander, Müther, Silvia, Muschol, Nicole, Nestler, Ulf, Omran, Heymut, Panteliadis, Christos P., Ramantani, Georgia, Roessner, Veit, Röhling, Dagmar, Rosenbaum, Thorsten, Rothenberger, Aribert, Rudolf, Jobst, Rutkowski, Stefan, Rutz, Erich, Salbach, Harriet, Schlößer, Rolf L., Schneider, Markus, Schneider, Susanne A., Schöls, Ludger, Schönweiler, Rainer, Schüller, Ulrich, Sinzig, Judith, Schüttauf, Frank, Spiekerkötter, Ute, Spitzer, Martin, Steinfeld, Robert, Stephani, Ulrich, von Suchodoletz, Waldemar, Synofzik, Matthis, Thiel, Christian, Tischler, Tanja, Trinka, Eugen, Unterberger, Iris, Velthoven, Vera van, and Wilichowski, Ekkehard

Published
2020
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25. Abstract LB-019: FGFR1 abnormalities in seizure-associated familial and sporadic dysembryoplastic neuroepithelial tumors

Author

Rivera, Barbara, primary, Gayden, Tenzin, additional, Zhang, Jian, additional, Nadaf, Javad, additional, Boshari, Talia, additional, Faury, Damien, additional, Zeinieh, Michele, additional, Blanc, Romeo, additional, Burk, David, additional, Fahiminiya, Somayyeh, additional, Bareke, Eric, additional, Schueller, Ulrich, additional, Monoranu, Camelia M., additional, Sträter, Ronald, additional, Kerl, Kornelius, additional, Niederstadt, Thomas, additional, Kurlemann, Gerhard, additional, Ellezam, Benjamin, additional, Michalak, Zuzanna, additional, Thom, Maria, additional, Lockhart, Paul, additional, Leventer, Richard, additional, Ohm, Milou, additional, McGregor, Duncan, additional, Jones, David, additional, Karamchandani, Jason, additional, Greenwood, Celia, additional, Berghuis, Albert, additional, Bens, Susanne, additional, Siebert, Reiner, additional, Zakrzewska, Magdalena, additional, Liberski, Pawel, additional, Zakrzewski, Krzysztof, additional, Sisodiya, Sanjay, additional, Paulus, Werner, additional, Albrecht, Steffen, additional, Hasselblatt, Martin, additional, Jabado, Nada, additional, Foulkes, William D., additional, and Majewski, Jacek, additional

Published
2016
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26. Correlation of IDH mutation, 1p/19q co-deletion and 18FET-PET derived time-to-peak analysis as prognostic markers in glioma

Author

Suchorska, Bogdana, primary, Kraus, Theo, additional, Biczok, Annamaria, additional, Weller, Michael, additional, Unterrainer, Marcus, additional, Schueller, Ulrich, additional, Schmid-Tannwald, Christine, additional, Bartenstein, Peter, additional, Giese, Armin, additional, Tonn, Joerg, additional, and Albert, Nathalie Lisa, additional

Published
2016
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28. Abstract 4591: Whole genome sequencing of SHH medulloblastomas predicts molecular groups of responders and non-responders to SMO-inhibition .

Author

Kool, Marcel, primary, Jones, David TW, additional, Jaeger, Natalie, additional, Northcott, Paul A., additional, Hovestadt, Volker, additional, Schueller, Ulrich, additional, Remke, Marc, additional, Cho, Yoon-Jae, additional, Pomeroy, Scott, additional, Taylor, Michael D., additional, Eils, Roland, additional, Korshunov, Andrey, additional, Lichter, Peter, additional, and Pfister, Stefan M., additional

Published
2013
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29. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Author

Remke, Marc, Ramaswamy, Vijay, Peacock, John, Shih, David J. H., Koelsche, Christian, Northcott, Paul A., Hill, Nadia, Cavalli, Florence M. G., Kool, Marcel, Wang, Xin, Mack, Stephen C., Barszczyk, Mark, Morrissy, A. Sorana, Wu, Xiaochong, Agnihotri, Sameer, Luu, Betty, Jones, David T. W., Garzia, Livia, Dubuc, Adrian M., Zhukova, Nataliya, Vanner, Robert, Kros, Johan M., French, Pim J., Van Meir, Erwin G., Vibhakar, Rajeev, Zitterbart, Karel, Chan, Jennifer A., Bognár, László, Klekner, Almos, Lach, Boleslaw, Jung, Shin, Saad, Ali G., Liau, Linda M., Albrecht, Steffen, Zollo, Massimo, Cooper, Michael K., Thompson, Reid C., Delattre, Oliver O., Bourdeaut, Franck, Doz, François F., Garami, Miklós, Hauser, Peter, Carlotti, Carlos G., Van Meter, Timothy E., Massimi, Luca, Fults, Daniel, Pomeroy, Scott L., Kumabe, Toshiro, Ra, Young Shin, Leonard, Jeffrey R., Elbabaa, Samer K., Mora, Jaume, Rubin, Joshua B., Cho, Yoon-Jae, McLendon, Roger E., Bigner, Darell D., Eberhart, Charles G., Fouladi, Maryam, Wechsler-Reya, Robert J., Faria, Claudia C., Croul, Sidney E., Huang, Annie, Bouffet, Eric, Hawkins, Cynthia E., Dirks, Peter B., Weiss, William A., Schüller, Ulrich, Pollack, Ian F., Rutkowski, Stefan, Meyronet, David, Jouvet, Anne, Fèvre-Montange, Michelle, Jabado, Nada, Perek-Polnik, Marta, Grajkowska, Wieslawa A., Kim, Seung-Ki, Rutka, James T., Malkin, David, Tabori, Uri, Pfister, Stefan M., Korshunov, Andrey, von Deimling, Andreas, and Taylor, Michael D.

Subjects
TERT promoter mutations, SHH pathway, Adult, Medulloblastoma
Abstract

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes. Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1198-2) contains supplementary material, which is available to authorized users.

Published
2013
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30. CROSS-SPECIES GENOMICS IDENTIFIES GLI2 AS AN ONCOGENE OF C11ORF95 FUSION-POSITIVE SUPRATENTORIAL EPENDYMOMA

Author

Zheng, Tuyu, Ghasemi, David R., Okonechnikov, Konstantin, Korshunov, Andrey, Sill, Martin, Huebner, Jens-Martin, Maass, Kendra K., Snuderl, Matija, Gojo, Johannes, Schueller, Ulrich, Gerber, Nicolas U., Hernaiz-Driever, Pablo, Milde, Till, Sturm, Dominik, Chapman, Rebecca, Grundy, Richard G., Deimling, Andreas, Jones, David T. W., Kool, Marcel, Pfister, Stefan M., Felix Sahm, Kawauchi, Daisuke, and Pajtler, Kristian W.

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