2,532 results on '"Pfister, Stefan M."'
Search Results
2. Multiomic profiling of medulloblastoma reveals subtype-specific targetable alterations at the proteome and N-glycan level
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Godbole, Shweta, Voß, Hannah, Gocke, Antonia, Schlumbohm, Simon, Schumann, Yannis, Peng, Bojia, Mynarek, Martin, Rutkowski, Stefan, Dottermusch, Matthias, Dorostkar, Mario M., Korshunov, Andrey, Mair, Thomas, Pfister, Stefan M., Kwiatkowski, Marcel, Hotze, Madlen, Neumann, Philipp, Hartmann, Christian, Weis, Joachim, Liesche-Starnecker, Friederike, Guan, Yudong, Moritz, Manuela, Siebels, Bente, Struve, Nina, Schlüter, Hartmut, Schüller, Ulrich, Krisp, Christoph, and Neumann, Julia E.
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- 2024
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3. Capmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy
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Zuckermann, Marc, He, Chen, Andrews, Jared, Bagchi, Aditi, Sloan-Henry, Roketa, Bianski, Brandon, Xie, Jia, Wang, Yingzhe, Twarog, Nathaniel, Onar-Thomas, Arzu, Ernst, Kati J., Yang, Lei, Li, Yong, Zhu, Xiaoyan, Ocasio, Jennifer K., Budd, Kaitlin M., Dalton, James, Li, Xiaoyu, Chepyala, Divyabharathi, Zhang, Junyuan, Xu, Ke, Hover, Laura, Roach, Jordan T., Chan, Kenneth Chun-Ho, Hofmann, Nina, McKinnon, Peter J., Pfister, Stefan M., Shelat, Anang A., Rankovic, Zoran, Freeman, III, Burgess B., Chiang, Jason, Jones, David T. W., Tinkle, Christopher L., and Baker, Suzanne J.
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- 2024
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4. Compartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage
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Ghasemi, David R., Okonechnikov, Konstantin, Rademacher, Anne, Tirier, Stephan, Maass, Kendra K., Schumacher, Hanna, Joshi, Piyush, Gold, Maxwell P., Sundheimer, Julia, Statz, Britta, Rifaioglu, Ahmet S., Bauer, Katharina, Schumacher, Sabrina, Bortolomeazzi, Michele, Giangaspero, Felice, Ernst, Kati J., Clifford, Steven C., Saez-Rodriguez, Julio, Jones, David T. W., Kawauchi, Daisuke, Fraenkel, Ernest, Mallm, Jan-Philipp, Rippe, Karsten, Korshunov, Andrey, Pfister, Stefan M., and Pajtler, Kristian W.
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- 2024
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5. Clinically unfavorable transcriptome subtypes of non-WNT/non-SHH medulloblastomas are associated with a predominance in proliferating and progenitor-like cell subpopulations
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Okonechnikov, Konstantin, Schrimpf, Daniel, Koster, Jan, Sievers, Philipp, Milde, Till, Sahm, Felix, Jones, David T. W., von Deimling, Andreas, Pfister, Stefan M., Kool, Marcel, and Korshunov, Andrey
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- 2024
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6. Loss of phosphatase CTDNEP1 potentiates aggressive medulloblastoma by triggering MYC amplification and genomic instability.
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Luo, Zaili, Xin, Dazhuan, Liao, Yunfei, Berry, Kalen, Ogurek, Sean, Zhang, Feng, Zhang, Liguo, Zhao, Chuntao, Rao, Rohit, Dong, Xinran, Li, Hao, Yu, Jianzhong, Lin, Yifeng, Huang, Guoying, Xu, Lingli, Xin, Mei, Nishinakamura, Ryuichi, Yu, Jiyang, Kool, Marcel, Pfister, Stefan M, Roussel, Martine F, Zhou, Wenhao, Weiss, William A, Andreassen, Paul, and Lu, Q Richard
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Animals ,Humans ,Mice ,Medulloblastoma ,Brain Neoplasms ,Cerebellar Neoplasms ,Cell Transformation ,Neoplastic ,Genomic Instability ,Phosphoric Monoester Hydrolases ,Proto-Oncogene Proteins c-myc ,Child ,Phosphoprotein Phosphatases ,Pediatric Cancer ,Genetics ,Human Genome ,Brain Cancer ,Pediatric ,Rare Diseases ,Brain Disorders ,Cancer ,Neurosciences ,Development of treatments and therapeutic interventions ,2.1 Biological and endogenous factors ,Aetiology ,5.1 Pharmaceuticals - Abstract
MYC-driven medulloblastomas are highly aggressive childhood brain tumors, however, the molecular and genetic events triggering MYC amplification and malignant transformation remain elusive. Here we report that mutations in CTDNEP1, a CTD nuclear-envelope-phosphatase, are the most significantly enriched recurrent alterations in MYC-driven medulloblastomas, and define high-risk subsets with poorer prognosis. Ctdnep1 ablation promotes the transformation of murine cerebellar progenitors into Myc-amplified medulloblastomas, resembling their human counterparts. CTDNEP1 deficiency stabilizes and activates MYC activity by elevating MYC serine-62 phosphorylation, and triggers chromosomal instability to induce p53 loss and Myc amplifications. Further, phosphoproteomics reveals that CTDNEP1 post-translationally modulates the activities of key regulators for chromosome segregation and mitotic checkpoint regulators including topoisomerase TOP2A and checkpoint kinase CHEK1. Co-targeting MYC and CHEK1 activities synergistically inhibits CTDNEP1-deficient MYC-amplified tumor growth and prolongs animal survival. Together, our studies demonstrate that CTDNEP1 is a tumor suppressor in highly aggressive MYC-driven medulloblastomas by controlling MYC activity and mitotic fidelity, pointing to a CTDNEP1-dependent targetable therapeutic vulnerability.
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- 2023
7. Cellular development and evolution of the mammalian cerebellum
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Sepp, Mari, Leiss, Kevin, Murat, Florent, Okonechnikov, Konstantin, Joshi, Piyush, Leushkin, Evgeny, Spänig, Lisa, Mbengue, Noe, Schneider, Céline, Schmidt, Julia, Trost, Nils, Schauer, Maria, Khaitovich, Philipp, Lisgo, Steven, Palkovits, Miklós, Giere, Peter, Kutscher, Lena M., Anders, Simon, Cardoso-Moreira, Margarida, Sarropoulos, Ioannis, Pfister, Stefan M., and Kaessmann, Henrik
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- 2024
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8. Pineal anlage tumor: clinical and diagnostic features, and rationales for treatment
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Obrecht-Sturm, Denise, Pfaff, Elke, Mynarek, Martin, Bison, Brigitte, Rodehüser, Martina, Becker, Martina, Kietz, Silke, Pfister, Stefan M., Jones, David T., Sturm, Dominik, von Deimling, Andreas, Sahm, Felix, Kortmann, Rolf-Dieter, Schwarz, Rudolf, Pietsch, Torsten, Fleischhack, Gudrun, and Rutkowski, Stefan
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- 2024
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9. Generation of patient-derived pediatric pilocytic astrocytoma in-vitro models using SV40 large T: evaluation of a modeling workflow
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Selt, Florian, El Damaty, Ahmed, Schuhmann, Martin U., Sigaud, Romain, Ecker, Jonas, Sievers, Philipp, Kocher, Daniela, Herold-Mende, Christel, Oehme, Ina, von Deimling, Andreas, Pfister, Stefan M., Sahm, Felix, Jones, David T. W., Witt, Olaf, and Milde, Till
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- 2023
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10. Genetical and epigenetical profiling identifies two subgroups of pineal parenchymal tumors of intermediate differentiation (PPTID) with distinct molecular, histological and clinical characteristics
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Rahmanzade, Ramin, Pfaff, Elke, Banan, Rouzbeh, Sievers, Philipp, Suwala, Abigail K., Hinz, Felix, Bogumil, Henri, Cherkezov, Asan, Kaan, Aras Fuat, Schrimpf, Daniel, Friedel, Dennis, Göbel, Kirsten, Keller, Felix, Saenz-Sardà, Xavier, Lossos, Alexander, Sill, Martin, Witt, Olaf, Sakowitz, Oliver W., Korshunov, Andrey, Reuss, David E., Etminan, Nima, Unterberg, Andreas, Ratliff, Miriam, Herold-Mende, Christel, Wick, Wolfgang, Pfister, Stefan M., von Deimling, Andreas, Jones, David T. W., and Sahm, Felix
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- 2023
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11. 3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma
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Okonechnikov, Konstantin, Camgöz, Aylin, Chapman, Owen, Wani, Sameena, Park, Donglim Esther, Hübner, Jens-Martin, Chakraborty, Abhijit, Pagadala, Meghana, Bump, Rosalind, Chandran, Sahaana, Kraft, Katerina, Acuna-Hidalgo, Rocio, Reid, Derek, Sikkink, Kristin, Mauermann, Monika, Juarez, Edwin F, Jenseit, Anne, Robinson, James T, Pajtler, Kristian W, Milde, Till, Jäger, Natalie, Fiesel, Petra, Morgan, Ling, Sridhar, Sunita, Coufal, Nicole G, Levy, Michael, Malicki, Denise, Hobbs, Charlotte, Kingsmore, Stephen, Nahas, Shareef, Snuderl, Matija, Crawford, John, Wechsler-Reya, Robert J, Davidson, Tom Belle, Cotter, Jennifer, Michaiel, George, Fleischhack, Gudrun, Mundlos, Stefan, Schmitt, Anthony, Carter, Hannah, Michealraj, Kulandaimanuvel Antony, Kumar, Sachin A, Taylor, Michael D, Rich, Jeremy, Buchholz, Frank, Mesirov, Jill P, Pfister, Stefan M, Ay, Ferhat, Dixon, Jesse R, Kool, Marcel, and Chavez, Lukas
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Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Pediatric ,Orphan Drug ,Pediatric Cancer ,Brain Disorders ,Cancer ,Rare Diseases ,Human Genome ,Brain Cancer ,Neurosciences ,Child ,Humans ,Child ,Preschool ,Neoplasm Recurrence ,Local ,Chromosomes ,Chromosome Mapping ,Ependymoma ,Genome ,Chromatin - Abstract
Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains ('neo-TADs') caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.
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- 2023
12. Amplification of the PLAG-family genes—PLAGL1 and PLAGL2—is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification
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Keck, Michaela-Kristina, Sill, Martin, Wittmann, Andrea, Joshi, Piyush, Stichel, Damian, Beck, Pengbo, Okonechnikow, Konstantin, Sievers, Philipp, Wefers, Annika K, Roncaroli, Federico, Avula, Shivaram, McCabe, Martin G, Hayden, James T, Wesseling, Pieter, Øra, Ingrid, Nistér, Monica, Kranendonk, Mariëtte EG, Tops, Bastiaan BJ, Zapotocky, Michal, Zamecnik, Josef, Vasiljevic, Alexandre, Fenouil, Tanguy, Meyronet, David, von Hoff, Katja, Schüller, Ulrich, Loiseau, Hugues, Figarella-Branger, Dominique, Kramm, Christof M, Sturm, Dominik, Scheie, David, Rauramaa, Tuomas, Pesola, Jouni, Gojo, Johannes, Haberler, Christine, Brandner, Sebastian, Jacques, Tom, Sexton Oates, Alexandra, Saffery, Richard, Koscielniak, Ewa, Baker, Suzanne J, Yip, Stephen, Snuderl, Matija, Ud Din, Nasir, Samuel, David, Schramm, Kathrin, Blattner-Johnson, Mirjam, Selt, Florian, Ecker, Jonas, Milde, Till, von Deimling, Andreas, Korshunov, Andrey, Perry, Arie, Pfister, Stefan M, Sahm, Felix, Solomon, David A, and Jones, David TW
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Pediatric ,Genetics ,Rare Diseases ,Pediatric Cancer ,Cancer ,Pediatric Research Initiative ,Neurosciences ,Brain Cancer ,Brain Disorders ,Child ,Child ,Preschool ,Female ,Humans ,Infant ,Male ,Cell Cycle Proteins ,Central Nervous System Neoplasms ,DNA Methylation ,DNA-Binding Proteins ,Neuroectodermal Tumors ,Primitive ,RNA-Binding Proteins ,Transcription Factors ,Tumor Suppressor Proteins ,Wnt Signaling Pathway ,PLAGL1 ,PLAGL2 ,Molecular neuro-oncology ,Pediatric cancer ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.
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- 2023
13. Failure of human rhombic lip differentiation underlies medulloblastoma formation
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Hendrikse, Liam D, Haldipur, Parthiv, Saulnier, Olivier, Millman, Jake, Sjoboen, Alexandria H, Erickson, Anders W, Ong, Winnie, Gordon, Victor, Coudière-Morrison, Ludivine, Mercier, Audrey L, Shokouhian, Mohammad, Suárez, Raúl A, Ly, Michelle, Borlase, Stephanie, Scott, David S, Vladoiu, Maria C, Farooq, Hamza, Sirbu, Olga, Nakashima, Takuma, Nambu, Shohei, Funakoshi, Yusuke, Bahcheli, Alec, Diaz-Mejia, J Javier, Golser, Joseph, Bach, Kathleen, Phuong-Bao, Tram, Skowron, Patryk, Wang, Evan Y, Kumar, Sachin A, Balin, Polina, Visvanathan, Abhirami, Lee, John JY, Ayoub, Ramy, Chen, Xin, Chen, Xiaodi, Mungall, Karen L, Luu, Betty, Bérubé, Pierre, Wang, Yu C, Pfister, Stefan M, Kim, Seung-Ki, Delattre, Olivier, Bourdeaut, Franck, Doz, François, Masliah-Planchon, Julien, Grajkowska, Wieslawa A, Loukides, James, Dirks, Peter, Fèvre-Montange, Michelle, Jouvet, Anne, French, Pim J, Kros, Johan M, Zitterbart, Karel, Bailey, Swneke D, Eberhart, Charles G, Rao, Amulya AN, Giannini, Caterina, Olson, James M, Garami, Miklós, Hauser, Peter, Phillips, Joanna J, Ra, Young S, de Torres, Carmen, Mora, Jaume, Li, Kay KW, Ng, Ho-Keung, Poon, Wai S, Pollack, Ian F, López-Aguilar, Enrique, Gillespie, G Yancey, Van Meter, Timothy E, Shofuda, Tomoko, Vibhakar, Rajeev, Thompson, Reid C, Cooper, Michael K, Rubin, Joshua B, Kumabe, Toshihiro, Jung, Shin, Lach, Boleslaw, Iolascon, Achille, Ferrucci, Veronica, de Antonellis, Pasqualino, Zollo, Massimo, Cinalli, Giuseppe, Robinson, Shenandoah, Stearns, Duncan S, Van Meir, Erwin G, Porrati, Paola, Finocchiaro, Gaetano, Massimino, Maura, Carlotti, Carlos G, Faria, Claudia C, Roussel, Martine F, Boop, Frederick, Chan, Jennifer A, Aldinger, Kimberly A, Razavi, Ferechte, Silvestri, Evelina, McLendon, Roger E, and Thompson, Eric M
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Stem Cell Research ,Brain Disorders ,Neurosciences ,Rare Diseases ,Stem Cell Research - Nonembryonic - Non-Human ,Aetiology ,1.1 Normal biological development and functioning ,Underpinning research ,2.1 Biological and endogenous factors ,Cell Differentiation ,Cell Lineage ,Cerebellar Neoplasms ,Cerebellum ,Core Binding Factor alpha Subunits ,Hedgehog Proteins ,Histone Demethylases ,Humans ,Ki-67 Antigen ,Medulloblastoma ,Metencephalon ,Muscle Proteins ,Mutation ,Otx Transcription Factors ,Repressor Proteins ,T-Box Domain Proteins ,Transcription Factors ,General Science & Technology - Abstract
Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.
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- 2022
14. Cancer-specific epigenome identifies oncogenic hijacking by nuclear factor I family proteins for medulloblastoma progression
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Shiraishi, Ryo, Cancila, Gabriele, Kumegawa, Kohei, Torrejon, Jacob, Basili, Irene, Bernardi, Flavia, Silva, Patricia Benites Goncalves da, Wang, Wanchen, Chapman, Owen, Yang, Liying, Jami, Maki, Nishitani, Kayo, Arai, Yukimi, Xiao, Zhize, Yu, Hua, Lo Re, Valentina, Marsaud, Véronique, Talbot, Julie, Lombard, Bérangère, Loew, Damarys, Jingu, Maho, Okonechnikov, Konstantin, Sone, Masaki, Motohashi, Norio, Aoki, Yoshitsugu, Pfister, Stefan M., Chavez, Lukas, Hoshino, Mikio, Maruyama, Reo, Ayrault, Olivier, and Kawauchi, Daisuke
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- 2024
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15. Overview of European standard clinical practice recommendations for multidiscplinary teams involved in the treatment of central nervous system tumours in children and adolescents – SIOPE Brain Tumour Group
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Otth, Maria, Scheinemann, Katrin, Ajithkumar, Thankamma, Aquilina, Kristian, Avula, Shivaram, Gan, Hoong-Wei, Janssens, Geert O., Lemiere, Jurgen, Morana, Giovanni, Opocher, Enrico, Pfister, Stefan M., Porro, Giorgio, Sahm, Felix, Thomale, Ulrich-Wilhelm, van Egmond-Ebbeling, Michelle, van Santen, Hanneke M., Pizer, Barry, and Rutkowski, Stefan
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- 2024
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16. Transcriptional immunogenomic analysis reveals distinct immunological clusters in paediatric nervous system tumours
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Nabbi, Arash, Beck, Pengbo, Delaidelli, Alberto, Oldridge, Derek A., Sudhaman, Sumedha, Zhu, Kelsey, Yang, S. Y. Cindy, Mulder, David T., Bruce, Jeffrey P., Paulson, Joseph N., Raman, Pichai, Zhu, Yuankun, Resnick, Adam C., Sorensen, Poul H., Sill, Martin, Brabetz, Sebastian, Lambo, Sander, Malkin, David, Johann, Pascal D., Kool, Marcel, Jones, David T. W., Pfister, Stefan M., Jäger, Natalie, and Pugh, Trevor J.
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- 2023
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17. MAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas
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Sigaud, Romain, Albert, Thomas K., Hess, Caroline, Hielscher, Thomas, Winkler, Nadine, Kocher, Daniela, Walter, Carolin, Münter, Daniel, Selt, Florian, Usta, Diren, Ecker, Jonas, Brentrup, Angela, Hasselblatt, Martin, Thomas, Christian, Varghese, Julian, Capper, David, Thomale, Ulrich W., Hernáiz Driever, Pablo, Simon, Michèle, Horn, Svea, Herz, Nina Annika, Koch, Arend, Sahm, Felix, Hamelmann, Stefan, Faria-Andrade, Augusto, Jabado, Nada, Schuhmann, Martin U., Schouten-van Meeteren, Antoinette Y. N., Hoving, Eelco, Brummer, Tilman, van Tilburg, Cornelis M., Pfister, Stefan M., Witt, Olaf, Jones, David T. W., Kerl, Kornelius, and Milde, Till
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- 2023
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18. Mitochondrial DNA mutations in Medulloblastoma
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Funke, Viktoria L. E., Sandmann, Sarah, Melcher, Viktoria, Seggewiss, Jochen, Horvath, Judit, Jäger, Natalie, Kool, Marcel, Jones, David T. W., Pfister, Stefan M., Milde, Till, Rutkowski, Stefan, Mynarek, Martin, Varghese, Julian, Sträter, Ronald, Rust, Stephan, Seelhöfer, Anja, Reunert, Janine, Fiedler, Barbara, Schüller, Ulrich, Marquardt, Thorsten, and Kerl, Kornelius
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- 2023
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19. BRCA1/2 potential founder variants in the Jordanian population: an opportunity for a customized screening panel
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Ahmad, Olfat, Sutter, Christian, Hirsch, Steffen, Pfister, Stefan M., and Schaaf, Christian P.
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- 2023
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20. Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature
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Sievers, Philipp, Sill, Martin, Schrimpf, Daniel, Abdullaev, Zied, Donson, Andrew M., Lake, Jessica A., Friedel, Dennis, Scheie, David, Tynninen, Olli, Rauramaa, Tuomas, Vepsäläinen, Kaisa L., Samuel, David, Chapman, Rebecca, Grundy, Richard G., Pajtler, Kristian W., Tauziède-Espariat, Arnault, Métais, Alice, Varlet, Pascale, Snuderl, Matija, Jacques, Thomas S., Aldape, Kenneth, Reuss, David E., Korshunov, Andrey, Wick, Wolfgang, Pfister, Stefan M., von Deimling, Andreas, Sahm, Felix, and Jones, David T. W.
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- 2023
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21. Comparison of transcriptome profiles between medulloblastoma primary and recurrent tumors uncovers novel variance effects in relapses
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Okonechnikov, Konstantin, Federico, Aniello, Schrimpf, Daniel, Sievers, Philipp, Sahm, Felix, Koster, Jan, Jones, David T. W., von Deimling, Andreas, Pfister, Stefan M., Kool, Marcel, and Korshunov, Andrey
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- 2023
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22. Transcriptome analysis stratifies second-generation non-WNT/non-SHH medulloblastoma subgroups into clinically tractable subtypes
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Korshunov, Andrey, Okonechnikov, Konstantin, Schrimpf, Daniel, Tonn, Svenja, Mynarek, Martin, Koster, Jan, Sievers, Philipp, Milde, Till, Sahm, Felix, Jones, David T. W., von Deimling, Andreas, Pfister, Stefan M., and Kool, Marcel
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- 2023
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23. Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA): a molecularly distinct brain tumor type with recurrent NTRK gene fusions
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Bogumil, Henri, Sill, Martin, Schrimpf, Daniel, Ismer, Britta, Blume, Christina, Rahmanzade, Ramin, Hinz, Felix, Cherkezov, Asan, Banan, Rouzbeh, Friedel, Dennis, Reuss, David E., Selt, Florian, Ecker, Jonas, Milde, Till, Pajtler, Kristian W., Schittenhelm, Jens, Hench, Jürgen, Frank, Stephan, Boldt, Henning B., Kristensen, Bjarne Winther, Scheie, David, Melchior, Linea C., Olesen, Viola, Sehested, Astrid, Boué, Daniel R., Abdullaev, Zied, Satgunaseelan, Laveniya, Kurth, Ina, Seidlitz, Annekatrin, White, Christine L., Ng, Ho-Keung, Shi, Zhi-Feng, Haberler, Christine, Deckert, Martina, Timmer, Marco, Goldbrunner, Roland, Tauziède-Espariat, Arnault, Varlet, Pascale, Brandner, Sebastian, Alexandrescu, Sanda, Snuderl, Matija, Aldape, Kenneth, Korshunov, Andrey, Witt, Olaf, Herold-Mende, Christel, Unterberg, Andreas, Wick, Wolfgang, Pfister, Stefan M., von Deimling, Andreas, Jones, David T. W., Sahm, Felix, and Sievers, Philipp
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- 2023
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24. Molecular characterisation defines clinically-actionable heterogeneity within Group 4 medulloblastoma and improves disease risk-stratification
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Goddard, Jack, Castle, Jemma, Southworth, Emily, Fletcher, Anya, Crosier, Stephen, Martin-Guerrero, Idoia, García-Ariza, Miguel, Navajas, Aurora, Masliah-Planchon, Julien, Bourdeaut, Franck, Dufour, Christelle, Ayrault, Olivier, Goschzik, Tobias, Pietsch, Torsten, Sill, Martin, Pfister, Stefan M., Rutkowski, Stefan, Richardson, Stacey, Hill, Rebecca M., Williamson, Daniel, Bailey, Simon, Schwalbe, Edward C., Clifford, Steven C., and Hicks, Debbie
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- 2023
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25. Genetic and epigenetic characterization of posterior pituitary tumors
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Schmid, Simone, Solomon, David A, Perez, Eilis, Thieme, Anne, Kleinschmidt-DeMasters, Bette K, Giannini, Caterina, Reinhardt, Annekathrin, Asa, Sylvia L, Mete, Ozgur, Stichel, Damian, Siewert, Christin, Dittmayer, Carsten, Hasselblatt, Martin, Paulus, Werner, Nagel, Christoph, Harter, Patrick N, Schittenhelm, Jens, Honegger, Jürgen, Rushing, Elisabeth, Coras, Roland, Pfister, Stefan M, Buslei, Rolf, Koch, Arend, Perry, Arie, Jones, David TW, von Deimling, Andreas, Capper, David, and Lopes, M Beatriz
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Genetics ,Human Genome ,Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Adenoma ,Oxyphilic ,Epigenesis ,Genetic ,Granular Cell Tumor ,Humans ,Pituitary Neoplasms ,Pituicytoma ,Spindle cell oncocytoma ,Granular cell tumor ,Posterior pituitary gland neoplasms ,Molecular neuropathology ,Brain tumor ,Clinical Sciences ,Neurosciences ,Neurology & Neurosurgery - Abstract
Pituicytoma (PITUI), granular cell tumor (GCT), and spindle cell oncocytoma (SCO) are rare tumors of the posterior pituitary. Histologically, they may be challenging to distinguish and have been proposed to represent a histological spectrum of a single entity. We performed targeted next-generation sequencing, DNA methylation profiling, and copy number analysis on 47 tumors (14 PITUI; 12 GCT; 21 SCO) to investigate molecular features and explore possibilities of clinically meaningful tumor subclassification. We detected two main epigenomic subgroups by unsupervised clustering of DNA methylation data, though the overall methylation differences were subtle. The largest group (n = 23) contained most PITUIs and a subset of SCOs and was enriched for pathogenic mutations within genes in the MAPK/PI3K pathways (12/17 [71%] of sequenced tumors: FGFR1 (3), HRAS (3), BRAF (2), NF1 (2), CBL (1), MAP2K2 (1), PTEN (1)) and two with accompanying TERT promoter mutation. The second group (n = 16) contained most GCTs and a subset of SCOs, all of which mostly lacked identifiable genetic drivers. Outcome analysis demonstrated that the presence of chromosomal imbalances was significantly associated with reduced progression-free survival especially within the combined PITUI and SCO group (p = 0.031). In summary, we observed only subtle DNA methylation differences between posterior pituitary tumors, indicating that these tumors may be best classified as subtypes of a single entity. Nevertheless, our data indicate differences in mutation patterns and clinical outcome. For a clinically meaningful subclassification, we propose a combined histo-molecular approach into three subtypes: one subtype is defined by granular cell histology, scarcity of identifiable oncogenic mutations, and favorable outcome. The other two subtypes have either SCO or PITUI histology but are segregated by chromosomal copy number profile into a favorable group (no copy number changes) and a less favorable group (copy number imbalances present). Both of the latter groups have recurrent MAPK/PI3K genetic alterations that represent potential therapeutic targets.
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- 2021
26. Molecular profiling of pediatric meningiomas shows tumor characteristics distinct from adult meningiomas
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Kirches, Elmar, Sahm, Felix, Korshunov, Andrey, Bluecher, Christina, Waldt, Natalie, Kropf, Siegfried, Schrimpf, Daniel, Sievers, Philipp, Stichel, Damian, Schüller, Ulrich, Schittenhelm, Jens, Riemenschneider, Markus J, Karajannis, Matthias A, Perry, Arie, Pietsch, Torsten, Boekhoff, Svenja, Capper, David, Beck, Katja, Paramasivam, Nagarajan, Schlesner, Matthias, Brastianos, Priscilla K, Müller, Hermann L, Pfister, Stefan M, and Mawrin, Christian
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Cancer ,Pediatric ,Human Genome ,Brain Cancer ,Pediatric Research Initiative ,Rare Diseases ,Brain Disorders ,Genetics ,Adolescent ,Adult ,Child ,Child ,Preschool ,Female ,Gene Expression Profiling ,Humans ,Male ,Meningeal Neoplasms ,Meningioma ,Transcriptome ,Methylation profile ,Targeted sequencing ,NF2 ,Clinical Sciences ,Neurosciences ,Neurology & Neurosurgery - Abstract
In contrast to adults, meningiomas are uncommon tumors in childhood and adolescence. Whether adult and pediatric meningiomas differ on a molecular level is unclear. Here we report detailed genomic analyses of 37 pediatric meningiomas by sequencing and DNA methylation profiling. Histologically, the series was dominated by meningioma subtypes with aggressive behavior, with 70% of patients suffering from WHO grade II or III meningiomas. The most frequent cytogenetic aberrations were loss of chromosomes 22 (23/37 [62%]), 1 (9/37 [24%]), 18 (7/37 [19%]), and 14 (5/37 [14%]). Tumors with NF2 alterations exhibited overall increased chromosomal instability. Unsupervised clustering of DNA methylation profiles revealed separation into three groups: designated group 1 composed of clear cell and papillary meningiomas, whereas group 2A comprised predominantly atypical meningiomas and group 2B enriched for rare high-grade subtypes (rhabdoid, chordoid). Meningiomas from NF2 patients clustered exclusively within groups 1 and 2A. When compared with a dataset of 105 adult meningiomas, the pediatric meningiomas largely grouped separately. Targeted panel DNA sequencing of 34 tumors revealed frequent NF2 alterations, while other typical alterations found in adult non-NF2 tumors were absent. These data demonstrate that pediatric meningiomas are characterized by molecular features distinct from adult tumors.
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- 2021
27. Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas
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Panwalkar, Pooja, Tamrazi, Benita, Dang, Derek, Chung, Chan, Sweha, Stefan, Natarajan, Siva Kumar, Pun, Matthew, Bayliss, Jill, Ogrodzinski, Martin P, Pratt, Drew, Mullan, Brendan, Hawes, Debra, Yang, Fusheng, Lu, Chao, Sabari, Benjamin R, Achreja, Abhinav, Heon, Jin, Animasahun, Olamide, Cieslik, Marcin, Dunham, Christopher, Yip, Stephen, Hukin, Juliette, Phillips, Joanna J, Bornhorst, Miriam, Griesinger, Andrea M, Donson, Andrew M, Foreman, Nicholas K, Garton, Hugh JL, Heth, Jason, Muraszko, Karin, Nazarian, Javad, Koschmann, Carl, Jiang, Li, Filbin, Mariella G, Nagrath, Deepak, Kool, Marcel, Korshunov, Andrey, Pfister, Stefan M, Gilbertson, Richard J, Allis, C David, Chinnaiyan, Arul M, Lunt, Sophia Y, Blüml, Stefan, Judkins, Alexander R, and Venneti, Sriram
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Cancer ,Biotechnology ,Genetics ,Rare Diseases ,Orphan Drug ,Neurosciences ,Brain Disorders ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Animals ,Child ,Ependymoma ,Epigenesis ,Genetic ,Epigenomics ,Histones ,Humans ,Metabolic Networks and Pathways ,Mice ,Biological Sciences ,Medical and Health Sciences - Abstract
Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle–related genes including hexokinase-2 and pyruvate dehydrogenase. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase, accompanied by enhanced glycolysis and TCA cycle metabolism. AMPKα-2, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT–expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.
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- 2021
28. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary
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Louis, David N, Perry, Arie, Wesseling, Pieter, Brat, Daniel J, Cree, Ian A, Figarella-Branger, Dominique, Hawkins, Cynthia, Ng, HK, Pfister, Stefan M, Reifenberger, Guido, Soffietti, Riccardo, von Deimling, Andreas, and Ellison, David W
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Brain Disorders ,Cancer ,Brain Cancer ,Rare Diseases ,Neurosciences ,Brain ,Central Nervous System ,Central Nervous System Neoplasms ,Humans ,Pathology ,Molecular ,World Health Organization ,brian tumor ,central nervous system ,classification ,diagnosis ,brain tumor ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.
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- 2021
29. Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology
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Sturm, Dominik, Capper, David, Andreiuolo, Felipe, Gessi, Marco, Kölsche, Christian, Reinhardt, Annekathrin, Sievers, Philipp, Wefers, Annika K., Ebrahimi, Azadeh, Suwala, Abigail K., Gielen, Gerrit H., Sill, Martin, Schrimpf, Daniel, Stichel, Damian, Hovestadt, Volker, Daenekas, Bjarne, Rode, Agata, Hamelmann, Stefan, Previti, Christopher, Jäger, Natalie, Buchhalter, Ivo, Blattner-Johnson, Mirjam, Jones, Barbara C., Warmuth-Metz, Monika, Bison, Brigitte, Grund, Kerstin, Sutter, Christian, Hirsch, Steffen, Dikow, Nicola, Hasselblatt, Martin, Schüller, Ulrich, Koch, Arend, Gerber, Nicolas U., White, Christine L., Buntine, Molly K., Kinross, Kathryn, Algar, Elizabeth M., Hansford, Jordan R., Gottardo, Nicholas G., Schuhmann, Martin U., Thomale, Ulrich W., Hernáiz Driever, Pablo, Gnekow, Astrid, Witt, Olaf, Müller, Hermann L., Calaminus, Gabriele, Fleischhack, Gudrun, Kordes, Uwe, Mynarek, Martin, Rutkowski, Stefan, Frühwald, Michael C., Kramm, Christof M., von Deimling, Andreas, Pietsch, Torsten, Sahm, Felix, Pfister, Stefan M., and Jones, David. T. W.
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- 2023
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30. Correction to: Amplification of the PLAG-family genes—PLAGL1 and PLAGL2—is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification
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Keck, Michaela-Kristina, Sill, Martin, Wittmann, Andrea, Joshi, Piyush, Stichel, Damian, Beck, Pengbo, Okonechnikow, Konstantin, Sievers, Philipp, Wefers, Annika K., Roncaroli, Federico, Avula, Shivaram, McCabe, Martin G., Hayden, James T., Wesseling, Pieter, Øra, Ingrid, Nistér, Monica, Kranendonk, Mariëtte E. G., Tops, Bastiaan B. J., Zapotocky, Michal, Zamecnik, Josef, Vasiljevic, Alexandre, Fenouil, Tanguy, Meyronet, David, von Hoff, Katja, Schüller, Ulrich, Loiseau, Hugues, Figarella-Branger, Dominique, Kramm, Christof M., Sturm, Dominik, Scheie, David, Rauramaa, Tuomas, Pesola, Jouni, Gojo, Johannes, Haberler, Christine, Brandner, Sebastian, Jacques, Tom, Sexton Oates, Alexandra, Saffery, Richard, Koscielniak, Ewa, Baker, Suzanne J., Yip, Stephen, Snuderl, Matija, Ud Din, Nasir, Samuel, David, Schramm, Kathrin, Blattner-Johnson, Mirjam, Selt, Florian, Ecker, Jonas, Milde, Till, von Deimling, Andreas, Korshunov, Andrey, Perry, Arie, Pfister, Stefan M., Sahm, Felix, Solomon, David A., and Jones, David T. W.
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- 2023
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31. Comprehensive analysis of mutational signatures reveals distinct patterns and molecular processes across 27 pediatric cancers
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Thatikonda, Venu, Islam, S. M. Ashiqul, Autry, Robert J., Jones, Barbara C., Gröbner, Susanne N., Warsow, Gregor, Hutter, Barbara, Huebschmann, Daniel, Fröhling, Stefan, Kool, Marcel, Blattner-Johnson, Mirjam, Jones, David T. W., Alexandrov, Ludmil B., Pfister, Stefan M., and Jäger, Natalie
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- 2023
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32. Glioblastomas with primitive neuronal component harbor a distinct methylation and copy-number profile with inactivation of TP53, PTEN, and RB1
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Suwala, Abigail K, Stichel, Damian, Schrimpf, Daniel, Maas, Sybren LN, Sill, Martin, Dohmen, Hildegard, Banan, Rouzbeh, Reinhardt, Annekathrin, Sievers, Philipp, Hinz, Felix, Blattner-Johnson, Mirjam, Hartmann, Christian, Schweizer, Leonille, Boldt, Henning B, Kristensen, Bjarne Winther, Schittenhelm, Jens, Wood, Matthew D, Chotard, Guillaume, Bjergvig, Rolf, Das, Anirban, Tabori, Uri, Hasselblatt, Martin, Korshunov, Andrey, Abdullaev, Zied, Quezado, Martha, Aldape, Kenneth, Harter, Patrick N, Snuderl, Matija, Hench, Jürgen, Frank, Stephan, Acker, Till, Brandner, Sebastian, Winkler, Frank, Wesseling, Pieter, Pfister, Stefan M, Reuss, David E, Wick, Wolfgang, von Deimling, Andreas, Jones, David TW, and Sahm, Felix
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Brain Disorders ,Human Genome ,Brain Cancer ,Neurosciences ,Cancer ,Rare Diseases ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Brain Neoplasms ,Chromosomes ,Human ,Pair 1 ,Chromosomes ,Human ,Pair 7 ,Cohort Studies ,Cyclin-Dependent Kinase Inhibitor p16 ,DNA Copy Number Variations ,DNA Methylation ,Female ,Gene Deletion ,Glial Fibrillary Acidic Protein ,Glioblastoma ,Humans ,Male ,Middle Aged ,Neuroectodermal Tumors ,Primitive ,PTEN Phosphohydrolase ,Retinoblastoma Binding Proteins ,Tumor Suppressor Protein p53 ,Ubiquitin-Protein Ligases ,GBM ,PNET ,DNA methylation ,Phenotype ,Classification ,Plasticity ,Neurology & Neurosurgery - Abstract
Glioblastoma IDH-wildtype presents with a wide histological spectrum. Some features are so distinctive that they are considered as separate histological variants or patterns for the purpose of classification. However, these usually lack defined (epi-)genetic alterations or profiles correlating with this histology. Here, we describe a molecular subtype with overlap to the unique histological pattern of glioblastoma with primitive neuronal component. Our cohort consists of 63 IDH-wildtype glioblastomas that harbor a characteristic DNA methylation profile. Median age at diagnosis was 59.5 years. Copy-number variations and genetic sequencing revealed frequent alterations in TP53, RB1 and PTEN, with fewer gains of chromosome 7 and homozygous CDKN2A/B deletions than usually described for IDH-wildtype glioblastoma. Gains of chromosome 1 were detected in more than half of the cases. A poorly differentiated phenotype with frequent absence of GFAP expression, high proliferation index and strong staining for p53 and TTF1 often caused misleading histological classification as carcinoma metastasis or primitive neuroectodermal tumor. Clinically, many patients presented with leptomeningeal dissemination and spinal metastasis. Outcome was poor with a median overall survival of only 12 months. Overall, we describe a new molecular subtype of IDH-wildtype glioblastoma with a distinct histological appearance and genetic signature.
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- 2021
33. Clear cell meningiomas are defined by a highly distinct DNA methylation profile and mutations in SMARCE1
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Sievers, Philipp, Sill, Martin, Blume, Christina, Tauziede-Espariat, Arnault, Schrimpf, Daniel, Stichel, Damian, Reuss, David E, Dogan, Helin, Hartmann, Christian, Mawrin, Christian, Hasselblatt, Martin, Stummer, Walter, Schick, Uta, Hench, Jürgen, Frank, Stephan, Ketter, Ralf, Schweizer, Leonille, Schittenhelm, Jens, Puget, Stéphanie, Brandner, Sebastian, Jaunmuktane, Zane, Küsters, Benno, Abdullaev, Zied, Pekmezci, Melike, Snuderl, Matija, Ratliff, Miriam, Herold-Mende, Christel, Unterberg, Andreas, Aldape, Kenneth, Ellison, David W, Wesseling, Pieter, Reifenberger, Guido, Wick, Wolfgang, Perry, Arie, Varlet, Pascale, Pfister, Stefan M, Jones, David TW, von Deimling, Andreas, and Sahm, Felix
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Human Genome ,Brain Disorders ,Pediatric ,Cancer ,Genetics ,Rare Diseases ,Brain Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Brain Neoplasms ,Child ,Chromosomal Proteins ,Non-Histone ,Cohort Studies ,DNA Methylation ,DNA Mutational Analysis ,DNA ,Neoplasm ,DNA-Binding Proteins ,Disease Progression ,Epigenesis ,Genetic ,Female ,Genome-Wide Association Study ,Humans ,Immunohistochemistry ,Male ,Meningioma ,Mutation ,Neoplasm Recurrence ,Local ,Treatment Outcome ,Young Adult ,Brain tumor ,Clear cell ,SMARCE1 ,DNA methylation profile ,German Consortium “Aggressive Meningiomas” ,Clinical Sciences ,Neurosciences ,Neurology & Neurosurgery - Abstract
Clear cell meningioma represents an uncommon variant of meningioma that typically affects children and young adults. Although an enrichment of loss-of-function mutations in the SMARCE1 gene has been reported for this subtype, comprehensive molecular investigations are lacking. Here we describe a molecularly distinct subset of tumors (n = 31), initially identified through genome-wide DNA methylation screening among a cohort of 3093 meningiomas, of which most were diagnosed histologically as clear cell meningioma. This cohort was further supplemented by an additional 11 histologically diagnosed clear cell meningiomas for analysis (n = 42). Targeted DNA sequencing revealed SMARCE1 mutations in 33/34 analyzed samples, accompanied by a nuclear loss of expression determined via immunohistochemistry and a decreased SMARCE1 transcript expression in the tumor cells. Analysis of time to progression or recurrence of patients within the clear cell meningioma group (n = 14) in comparison to those with meningioma WHO grade 2 (n = 220) revealed a similar outcome and support the assignment of WHO grade 2 to these tumors. Our findings indicate the existence of a highly distinct epigenetic signature of clear cell meningiomas, separate from all other variants of meningiomas, with recurrent mutations in the SMARCE1 gene. This suggests that these tumors may arise from a different precursor cell population than the broad spectrum of the other meningioma subtypes.
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- 2021
34. A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR.
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Sievers, Philipp, Sill, Martin, Schrimpf, Daniel, Stichel, Damian, Reuss, David E, Sturm, Dominik, Hench, Jürgen, Frank, Stephan, Krskova, Lenka, Vicha, Ales, Zapotocky, Michal, Bison, Brigitte, Castel, David, Grill, Jacques, Debily, Marie-Anne, Harter, Patrick N, Snuderl, Matija, Kramm, Christof M, Reifenberger, Guido, Korshunov, Andrey, Jabado, Nada, Wesseling, Pieter, Wick, Wolfgang, Solomon, David A, Perry, Arie, Jacques, Thomas S, Jones, Chris, Witt, Olaf, Pfister, Stefan M, von Deimling, Andreas, Jones, David TW, and Sahm, Felix
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Brain Disorders ,Pediatric Cancer ,Cancer ,Pediatric ,Brain Cancer ,Rare Diseases ,Genetics ,Neurosciences ,Brain Neoplasms ,Child ,DNA Methylation ,ErbB Receptors ,Genes ,erbB-1 ,Glioma ,Histones ,Humans ,Mutation ,Thalamus ,(bi)thalamic ,EGFR mutation ,H3 K27M mutation ,K27me3 ,pediatric-type high-grade glioma ,EGFR mutation ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
BackgroundMalignant astrocytic gliomas in children show a remarkable biological and clinical diversity. Small in-frame insertions or missense mutations in the epidermal growth factor receptor gene (EGFR) have recently been identified in a distinct subset of pediatric-type bithalamic gliomas with a unique DNA methylation pattern.MethodsHere, we investigated an epigenetically homogeneous cohort of malignant gliomas (n = 58) distinct from other subtypes and enriched for pediatric cases and thalamic location, in comparison with this recently identified subtype of pediatric bithalamic gliomas.ResultsEGFR gene amplification was detected in 16/58 (27%) tumors, and missense mutations or small in-frame insertions in EGFR were found in 20/30 tumors with available sequencing data (67%; 5 of them co-occurring with EGFR amplification). Additionally, 8 of the 30 tumors (27%) harbored an H3.1 or H3.3 K27M mutation (6 of them with a concomitant EGFR alteration). All tumors tested showed loss of H3K27me3 staining, with evidence of overexpression of the EZH inhibitory protein (EZHIP) in the H3 wildtype cases. Although some tumors indeed showed a bithalamic growth pattern, a significant proportion of tumors occurred in the unilateral thalamus or in other (predominantly midline) locations.ConclusionsOur findings present a distinct molecular class of pediatric-type malignant gliomas largely overlapping with the recently reported bithalamic gliomas characterized by EGFR alteration, but additionally showing a broader spectrum of EGFR alterations and tumor localization. Global H3K27me3 loss in this group appears to be mediated by either H3 K27 mutation or EZHIP overexpression. EGFR inhibition may represent a potential therapeutic strategy in these highly aggressive gliomas.
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- 2021
35. Author Correction: Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology
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Sturm, Dominik, Capper, David, Andreiuolo, Felipe, Gessi, Marco, Kölsche, Christian, Reinhardt, Annekathrin, Sievers, Philipp, Wefers, Annika K., Ebrahimi, Azadeh, Suwala, Abigail K., Gielen, Gerrit H., Sill, Martin, Schrimpf, Daniel, Stichel, Damian, Hovestadt, Volker, Daenekas, Bjarne, Rode, Agata, Hamelmann, Stefan, Previti, Christopher, Jäger, Natalie, Buchhalter, Ivo, Blattner-Johnson, Mirjam, Jones, Barbara C., Warmuth-Metz, Monika, Bison, Brigitte, Grund, Kerstin, Sutter, Christian, Hirsch, Steffen, Dikow, Nicola, Hasselblatt, Martin, Schüller, Ulrich, Koch, Arend, Gerber, Nicolas U., White, Christine L., Buntine, Molly K., Kinross, Kathryn, Algar, Elizabeth M., Hansford, Jordan R., Gottardo, Nicholas G., Schuhmann, Martin U., Thomale, Ulrich W., Hernáiz Driever, Pablo, Gnekow, Astrid, Witt, Olaf, Müller, Hermann L., Calaminus, Gabriele, Fleischhack, Gudrun, Kordes, Uwe, Mynarek, Martin, Rutkowski, Stefan, Frühwald, Michael C., Kramm, Christof M., von Deimling, Andreas, Pietsch, Torsten, Sahm, Felix, Pfister, Stefan M., and Jones, David. T. W.
- Published
- 2024
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36. Identification of low and very high-risk patients with non-WNT/non-SHH medulloblastoma by improved clinico-molecular stratification of the HIT2000 and I-HIT-MED cohorts
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Mynarek, Martin, Obrecht, Denise, Sill, Martin, Sturm, Dominik, Kloth-Stachnau, Katja, Selt, Florian, Ecker, Jonas, von Hoff, Katja, Juhnke, Björn-Ole, Goschzik, Tobias, Pietsch, Torsten, Bockmayr, Michael, Kool, Marcel, von Deimling, Andreas, Witt, Olaf, Schüller, Ulrich, Benesch, Martin, Gerber, Nicolas U., Sahm, Felix, Jones, David T. W., Korshunov, Andrey, Pfister, Stefan M., Rutkowski, Stefan, and Milde, Till
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- 2023
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37. Functional Precision Medicine Identifies New Therapeutic Candidates for Medulloblastoma
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Rusert, Jessica M, Juarez, Edwin F, Brabetz, Sebastian, Jensen, James, Garancher, Alexandra, Chau, Lianne Q, Tacheva-Grigorova, Silvia K, Wahab, Sameerah, Udaka, Yoko T, Finlay, Darren, Seker-Cin, Huriye, Reardon, Brendan, Gröbner, Susanne, Serrano, Jonathan, Ecker, Jonas, Qi, Lin, Kogiso, Mari, Du, Yuchen, Baxter, Patricia A, Henderson, Jacob J, Berens, Michael E, Vuori, Kristiina, Milde, Till, Cho, Yoon-Jae, Li, Xiao-Nan, Olson, James M, Reyes, Iris, Snuderl, Matija, Wong, Terence C, Dimmock, David P, Nahas, Shareef A, Malicki, Denise, Crawford, John R, Levy, Michael L, Van Allen, Eliezer M, Pfister, Stefan M, Tamayo, Pablo, Kool, Marcel, Mesirov, Jill P, and Wechsler-Reya, Robert J
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Clinical Sciences ,Oncology and Carcinogenesis ,Brain Disorders ,Neurosciences ,Pediatric ,Orphan Drug ,Biotechnology ,Genetic Testing ,Cancer ,Human Genome ,Pediatric Research Initiative ,Rare Diseases ,Brain Cancer ,Pediatric Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Generic health relevance ,Good Health and Well Being ,Animals ,Antineoplastic Agents ,Cell Line ,Tumor ,Cerebellar Neoplasms ,Child ,Dactinomycin ,Gene Expression Regulation ,Neoplastic ,High-Throughput Screening Assays ,Humans ,Male ,Medulloblastoma ,Mice ,Inbred NOD ,Mutation ,Polymorphism ,Single Nucleotide ,Precision Medicine ,Exome Sequencing ,Xenograft Model Antitumor Assays ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each patient with medulloblastoma is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patients' tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most medulloblastomas do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provided valuable information about potential therapies for every tumor. For example, drug screening demonstrated that actinomycin D, which is used for treatment of sarcoma but rarely for medulloblastoma, was active against PDXs representing Group 3 medulloblastoma, the most aggressive form of the disease. Functional analysis of tumor cells was successfully used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor. SIGNIFICANCE: These findings show that high-throughput drug screening identifies therapies for medulloblastoma that cannot be predicted by genomic or transcriptomic analysis.
- Published
- 2020
38. Epigenetic profiling reveals a subset of pediatric-type glioneuronal tumors characterized by oncogenic gene fusions involving several targetable kinases
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Sievers, Philipp, Sill, Martin, Schrimpf, Daniel, Friedel, Dennis, Sturm, Dominik, Gardberg, Maria, Kurian, Kathreena M., Krskova, Lenka, Vicha, Ales, Schaller, Tina, Hagel, Christian, Abdullaev, Zied, Aldape, Kenneth, Jacques, Thomas S., Korshunov, Andrey, Wick, Wolfgang, Pfister, Stefan M., von Deimling, Andreas, Jones, David T. W., and Sahm, Felix
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- 2022
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39. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials
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Hong, David S, DuBois, Steven G, Kummar, Shivaani, Farago, Anna F, Albert, Catherine M, Rohrberg, Kristoffer S, van Tilburg, Cornelis M, Nagasubramanian, Ramamoorthy, Berlin, Jordan D, Federman, Noah, Mascarenhas, Leo, Geoerger, Birgit, Dowlati, Afshin, Pappo, Alberto S, Bielack, Stefan, Doz, François, McDermott, Ray, Patel, Jyoti D, Schilder, Russell J, Tahara, Makoto, Pfister, Stefan M, Witt, Olaf, Ladanyi, Marc, Rudzinski, Erin R, Nanda, Shivani, Childs, Barrett H, Laetsch, Theodore W, Hyman, David M, and Drilon, Alexander
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Trials and Supportive Activities ,Clinical Research ,Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Good Health and Well Being ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Child ,Child ,Preschool ,Female ,Humans ,Infant ,Infant ,Newborn ,Male ,Middle Aged ,Neoplasms ,Proteins ,Pyrazoles ,Pyrimidines ,Young Adult ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundThe selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours.MethodsPatients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m2 (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov, NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting).FindingsBetween May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72-85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [
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- 2020
40. Molecular diagnostics enables detection of actionable targets: the Pediatric Targeted Therapy 2.0 registry
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Ecker, Jonas, Selt, Florian, Sturm, Dominik, Sill, Martin, Korshunov, Andrey, Hirsch, Steffen, Capper, David, Dikow, Nicola, Sutter, Christian, Müller, Carina, Sigaud, Romain, Eggert, Angelika, Simon, Thorsten, Niehues, Tim, von Deimling, Andreas, Pajtler, Kristian W., van Tilburg, Cornelis M., Jones, David T.W., Sahm, Felix, Pfister, Stefan M., Witt, Olaf, and Milde, Till
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- 2023
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41. Gene expression profiling of Group 3 medulloblastomas defines a clinically tractable stratification based on KIRREL2 expression
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Korshunov, Andrey, Okonechnikov, Konstantin, Stichel, Damian, Schrimpf, Daniel, Delaidelli, Alberto, Tonn, Svenja, Mynarek, Martin, Sievers, Philipp, Sahm, Felix, Jones, David T. W., von Deimling, Andreas, Pfister, Stefan M., and Kool, Marcel
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- 2022
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42. Implementation of DNA Methylation Array Profiling in Pediatric Central Nervous System Tumors: The AIM BRAIN Project: An Australian and New Zealand Children's Hematology and Oncology Group Study
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White, Christine L., Kinross, Kathryn M., Buntine, Molly K., Rasouli, Elnaz, Strong, Robyn, Jones, Janelle M., Cain, Jason E., Sturm, Dominik, Sahm, Felix, Jones, David T.W., Pfister, Stefan M., Robertson, Thomas, D'Arcy, Colleen, Rodriguez, Michael L., Dyke, Jason M., Junckerstorff, Reimar, Bhuva, Dharmesh D., Davis, Melissa J., Wood, Paul, Hassall, Tim, Ziegler, David S., Kellie, Stewart, McCowage, Geoffrey, Alvaro, Frank, Kirby, Maria, Heath, John A., Tsui, Karen, Dodgshun, Andrew, Eisenstat, David D., Khuong-Quang, Dong-Anh, Wall, Meaghan, Algar, Elizabeth M., Gottardo, Nicholas G., and Hansford, Jordan R.
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- 2023
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43. Risk factors for domain-specific neurocognitive outcome in pediatric survivors of a brain tumor in the posterior fossa – Results of the HIT 2000 trial
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Mynarek, Martin, primary, Rossius, Anne, additional, Guiard, Anika, additional, Ottensmeier, Holger, additional, von Hoff, Katja, additional, Obrecht-Sturm, Denise, additional, Bußenius, Lisa, additional, Friedrich, Carsten, additional, von Bueren, Andre O, additional, Gerber, Nicolas U, additional, Traunwieser, Thomas, additional, Kortmann, Rolf-Dieter, additional, Warmuth-Metz, Monika, additional, Bison, Brigitte, additional, Thomale, Ulrich-W, additional, Krauss, Juergen, additional, Pietsch, Torsten, additional, Clifford, Steven C, additional, Pfister, Stefan M, additional, Sturm, Dominik, additional, Sahm, Felix, additional, Tischler, Tanja, additional, and Rutkowski, Stefan, additional
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- 2024
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44. Radiotherapy for Recurrent Medulloblastoma in Children and Adolescents: Survival after Re-Irradiation and First-Time Irradiation
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Adolph, Jonas E., primary, Fleischhack, Gudrun, additional, Tschirner, Sebastian, additional, Rink, Lydia, additional, Dittes, Christine, additional, Mikasch, Ruth, additional, Dammann, Philipp, additional, Mynarek, Martin, additional, Obrecht-Sturm, Denise, additional, Rutkowski, Stefan, additional, Bison, Brigitte, additional, Warmuth-Metz, Monika, additional, Pietsch, Torsten, additional, Pfister, Stefan M., additional, Pajtler, Kristian W., additional, Milde, Till, additional, Kortmann, Rolf-Dieter, additional, Dietzsch, Stefan, additional, Timmermann, Beate, additional, and Tippelt, Stephan, additional
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- 2024
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45. Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile
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Nussbaumer, Gunther, primary, Benesch, Martin, additional, Grabovska, Yura, additional, Mackay, Alan, additional, Castel, David, additional, Grill, Jacques, additional, Alonso, Marta M, additional, Antonelli, Manila, additional, Bailey, Simon, additional, Baugh, Joshua N, additional, Biassoni, Veronica, additional, Blattner Johnson, Mirjam, additional, Broniscer, Alberto, additional, Carai, Andrea, additional, Colafati, Giovanna Stefania, additional, Colditz, Niclas, additional, Corbacioglu, Selim, additional, Crampsie, Shauna, additional, Entz-Werle, Natacha, additional, Eyrich, Matthias, additional, Friker, Lea L, additional, Frühwald, Michael C, additional, Garrè, Maria Luisa, additional, Gerber, Nicolas U, additional, Giangaspero, Felice, additional, Gil-da-Costa, Maria J, additional, Graf, Norbert, additional, Hargrave, Darren, additional, Hauser, Peter, additional, Herrlinger, Ulrich, additional, Hoffmann, Marion, additional, Hulleman, Esther, additional, Izquierdo, Elisa, additional, Jacobs, Sandra, additional, Karremann, Michael, additional, Kattamis, Antonis, additional, Kebudi, Rejin, additional, Kortmann, Rolf-Dieter, additional, Kwiecien, Robert, additional, Massimino, Maura, additional, Mastronuzzi, Angela, additional, Miele, Evelina, additional, Morana, Giovanni, additional, Noack, Claudia M, additional, Pentikainen, Virve, additional, Perwein, Thomas, additional, Pfister, Stefan M, additional, Pietsch, Torsten, additional, Roka, Kleoniki, additional, Rossi, Sabrina, additional, Rutkowski, Stefan, additional, Schiavello, Elisabetta, additional, Seidel, Clemens, additional, Štěrba, Jaroslav, additional, Sturm, Dominik, additional, Sumerauer, David, additional, Tacke, Anna, additional, Temelso, Sara, additional, Valentini, Chiara, additional, van Vuurden, Dannis, additional, Varlet, Pascale, additional, Veldhuijzen van Zanten, Sophie E M, additional, Vinci, Maria, additional, von Bueren, André O, additional, Warmuth-Metz, Monika, additional, Wesseling, Pieter, additional, Wiese, Maria, additional, Wolff, Johannes E A, additional, Zamecnik, Josef, additional, Morales La Madrid, Andrés, additional, Bison, Brigitte, additional, Gielen, Gerrit H, additional, Jones, David T W, additional, Jones, Chris, additional, and Kramm, Christof M, additional
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- 2024
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46. Pediatric T-ALL type-1 and type-2 relapses develop along distinct pathways of clonal evolution
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Richter-Pechańska, Paulina, Kunz, Joachim B., Rausch, Tobias, Erarslan-Uysal, Büşra, Bornhauser, Beat, Frismantas, Viktoras, Assenov, Yassen, Zimmermann, Martin, Happich, Margit, von Knebel-Doeberitz, Caroline, von Neuhoff, Nils, Köhler, Rolf, Stanulla, Martin, Schrappe, Martin, Cario, Gunnar, Escherich, Gabriele, Kirschner-Schwabe, Renate, Eckert, Cornelia, Avigad, Smadar, Pfister, Stefan M., Muckenthaler, Martina U., Bourquin, Jean-Pierre, Korbel, Jan O., and Kulozik, Andreas E.
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- 2022
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47. Rapid-CNS2: rapid comprehensive adaptive nanopore-sequencing of CNS tumors, a proof-of-concept study
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Patel, Areeba, Dogan, Helin, Payne, Alexander, Krause, Elena, Sievers, Philipp, Schoebe, Natalie, Schrimpf, Daniel, Blume, Christina, Stichel, Damian, Holmes, Nadine, Euskirchen, Philipp, Hench, Jürgen, Frank, Stephan, Rosenstiel-Goidts, Violaine, Ratliff, Miriam, Etminan, Nima, Unterberg, Andreas, Dieterich, Christoph, Herold-Mende, Christel, Pfister, Stefan M., Wick, Wolfgang, Loose, Matthew, von Deimling, Andreas, Sill, Martin, Jones, David T. W., Schlesner, Matthias, and Sahm, Felix
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- 2022
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48. Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis
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Huang, Miller, Tailor, Jignesh, Zhen, Qiqi, Gillmor, Aaron H, Miller, Matthew L, Weishaupt, Holger, Chen, Justin, Zheng, Tina, Nash, Emily K, McHenry, Lauren K, An, Zhenyi, Ye, Fubaiyang, Takashima, Yasuhiro, Clarke, James, Ayetey, Harold, Cavalli, Florence MG, Luu, Betty, Moriarity, Branden S, Ilkhanizadeh, Shirin, Chavez, Lukas, Yu, Chunying, Kurian, Kathreena M, Magnaldo, Thierry, Sevenet, Nicolas, Koch, Philipp, Pollard, Steven M, Dirks, Peter, Snyder, Michael P, Largaespada, David A, Cho, Yoon Jae, Phillips, Joanna J, Swartling, Fredrik J, Morrissy, A Sorana, Kool, Marcel, Pfister, Stefan M, Taylor, Michael D, Smith, Austin, and Weiss, William A
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Medical Biotechnology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Genetics ,Human Genome ,Brain Disorders ,Regenerative Medicine ,Pediatric ,Pediatric Cancer ,Stem Cell Research ,Transplantation ,Biotechnology ,Rare Diseases ,Stem Cell Research - Nonembryonic - Human ,Cancer ,Neurosciences ,Stem Cell Research - Nonembryonic - Non-Human ,Brain Cancer ,Development of treatments and therapeutic interventions ,5.2 Cellular and gene therapies ,Animals ,Basal Cell Nevus Syndrome ,Brain Neoplasms ,Carcinogenesis ,DEAD-box RNA Helicases ,Disease Models ,Animal ,Genetic Engineering ,Genetic Predisposition to Disease ,Humans ,Medulloblastoma ,Mice ,Mice ,SCID ,N-Myc Proto-Oncogene Protein ,Neoplasm Proteins ,Neural Stem Cells ,Neuroepithelial Cells ,Patched-1 Receptor ,Pluripotent Stem Cells ,Stem Cell Transplantation ,Transplantation ,Heterologous ,SHH ,human pluripotent stem cells ,medulloblastoma ,neuroepithelial stem cells ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predisposed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.
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- 2019
49. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial
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Fangusaro, Jason, Onar-Thomas, Arzu, Young Poussaint, Tina, Wu, Shengjie, Ligon, Azra H, Lindeman, Neal, Banerjee, Anuradha, Packer, Roger J, Kilburn, Lindsay B, Goldman, Stewart, Pollack, Ian F, Qaddoumi, Ibrahim, Jakacki, Regina I, Fisher, Paul G, Dhall, Girish, Baxter, Patricia, Kreissman, Susan G, Stewart, Clinton F, Jones, David TW, Pfister, Stefan M, Vezina, Gilbert, Stern, Jessica S, Panigrahy, Ashok, Patay, Zoltan, Tamrazi, Benita, Jones, Jeremy Y, Haque, Sofia S, Enterline, David S, Cha, Soonmee, Fisher, Michael J, Doyle, Laurence Austin, Smith, Malcolm, Dunkel, Ira J, and Fouladi, Maryam
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Clinical Trials and Supportive Activities ,Pediatric Cancer ,Brain Cancer ,Rare Diseases ,Brain Disorders ,Clinical Research ,Cancer ,Pediatric ,Neurosciences ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adolescent ,Benzimidazoles ,Central Nervous System Neoplasms ,Child ,Child ,Preschool ,Disease Progression ,Female ,Glioma ,Humans ,Male ,Neoplasm Grading ,Neoplasms ,Multiple Primary ,Neurofibromatosis 1 ,Proto-Oncogene Proteins B-raf ,Young Adult ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
BackgroundPaediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients.MethodsThe Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3-21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAFV600E [Val600Glu] mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101.FindingsBetween July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14-51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No treatment-realted deaths were reported.InterpretationSelumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1.FundingNational Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.
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- 2019
50. Lsd1 as a therapeutic target in Gfi1-activated medulloblastoma.
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Lee, Catherine, Rudneva, Vasilisa A, Erkek, Serap, Zapatka, Marc, Chau, Lianne Q, Tacheva-Grigorova, Silvia K, Garancher, Alexandra, Rusert, Jessica M, Aksoy, Ozlem, Lea, Robin, Mohammad, Helai P, Wang, Jianxun, Weiss, William A, Grimes, H Leighton, Pfister, Stefan M, Northcott, Paul A, and Wechsler-Reya, Robert J
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NIH 3T3 Cells ,Animals ,Mice ,Inbred C57BL ,Mice ,Knockout ,Humans ,Mice ,Mice ,SCID ,Retroviridae ,Oncogenic Viruses ,Medulloblastoma ,Cerebellar Neoplasms ,Doxorubicin ,DNA-Binding Proteins ,Transcription Factors ,Antibiotics ,Antineoplastic ,Neoplasm Transplantation ,Cell Proliferation ,Gene Expression Regulation ,Neoplastic ,Histone Demethylases ,HEK293 Cells ,Carcinogenesis ,Antibiotics ,Antineoplastic ,Gene Expression Regulation ,Neoplastic ,Inbred C57BL ,Knockout ,SCID - Abstract
Drugs that modify the epigenome are powerful tools for treating cancer, but these drugs often have pleiotropic effects, and identifying patients who will benefit from them remains a major clinical challenge. Here we show that medulloblastomas driven by the transcription factor Gfi1 are exquisitely dependent on the enzyme lysine demethylase 1 (Kdm1a/Lsd1). We demonstrate that Lsd1 physically associates with Gfi1, and that these proteins cooperate to inhibit genes involved in neuronal commitment and differentiation. We also show that Lsd1 is essential for Gfi1-mediated transformation: Gfi1 proteins that cannot recruit Lsd1 are unable to drive tumorigenesis, and genetic ablation of Lsd1 markedly impairs tumor growth in vivo. Finally, pharmacological inhibitors of Lsd1 potently inhibit growth of Gfi1-driven tumors. These studies provide important insight into the mechanisms by which Gfi1 contributes to tumorigenesis, and identify Lsd1 inhibitors as promising therapeutic agents for Gfi1-driven medulloblastoma.
- Published
- 2019
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