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1. Genetical and epigenetical profiling identifies two subgroups of pineal parenchymal tumors of intermediate differentiation (PPTID) with distinct molecular, histological and clinical characteristics

Author

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

Published
2023
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2. Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature

Author

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.

Published
2023
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3. Oligosarcomas, IDH-mutant are distinct and aggressive

Author

Suwala, Abigail K, Felix, Marius, Friedel, Dennis, Stichel, Damian, Schrimpf, Daniel, Hinz, Felix, Hewer, Ekkehard, Schweizer, Leonille, Dohmen, Hildegard, Pohl, Ute, Staszewski, Ori, Korshunov, Andrey, Stein, Marco, Wongsurawat, Thidathip, Cheunsuacchon, Pornsuk, Sathornsumetee, Sith, Koelsche, Christian, Turner, Clinton, Le Rhun, Emilie, Mühlebner, Angelika, Schucht, Philippe, Özduman, Koray, Ono, Takahiro, Shimizu, Hiroaki, Prinz, Marco, Acker, Till, Herold-Mende, Christel, Kessler, Tobias, Wick, Wolfgang, Capper, David, Wesseling, Pieter, Sahm, Felix, von Deimling, Andreas, Hartmann, Christian, and Reuss, David E

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Brain Cancer, Cancer, Brain Disorders, Clinical Research, Pediatric Research Initiative, Genetics, 2.1 Biological and endogenous factors, Aetiology, Adult, Aged, Brain Neoplasms, Female, Humans, Isocitrate Dehydrogenase, Male, Middle Aged, Mutation, Oligodendroglioma, Sarcoma, Oligosarcoma, Gliosarcoma, 1p, 19q, Codeletion, SMA, YAP1, NF1, TP53, TERT, DNA methylation, Type, Subtype, Variant, Prognosis, 1p/19q, Clinical Sciences, Neurosciences, Neurology & Neurosurgery
Abstract

Oligodendrogliomas are defined at the molecular level by the presence of an IDH mutation and codeletion of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 24 IDH-mutant oligosarcomas from 23 patients forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 12 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dense network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA and CALD1, loss of OLIG2 and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Copy number neutral LOH was determined as underlying mechanism. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent CDKN2A/B deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional CNS WHO grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in NF1 and TP53 along with IDH1/2 and TERT promoter mutations. Survival of patients was significantly poorer for oligosarcomas as first recurrence than for grade 3 oligodendrogliomas as first recurrence. These results establish oligosarcomas as a distinct group of IDH-mutant gliomas differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. The diagnosis can be based on the combined presence of (a) sarcomatous histology, (b) IDH-mutation and (c) TERT promoter mutation and/or 1p/19q codeletion, or, in unresolved cases, on its characteristic DNA methylation profile.

Published
2022

4. Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA): a molecularly distinct brain tumor type with recurrent NTRK gene fusions

Author

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

Published
2023
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5. Glioblastomas with primitive neuronal component harbor a distinct methylation and copy-number profile with inactivation of TP53, PTEN, and RB1

Author

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

Subjects
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.

Published
2021

6. Clear cell meningiomas are defined by a highly distinct DNA methylation profile and mutations in SMARCE1

Author

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

Subjects
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.

Published
2021

7. A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR.

Author

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

Subjects
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.

Published
2021

8. Molecular matched targeted therapies for primary brain tumors—a single center retrospective analysis

Author

Luger, Anna-Luisa, König, Sven, Samp, Patrick Felix, Urban, Hans, Divé, Iris, Burger, Michael C., Voss, Martin, Franz, Kea, Fokas, Emmanouil, Filipski, Katharina, Demes, Melanie-Christin, Stenzinger, Albrecht, Sahm, Felix, Reuss, David E., Harter, Patrick N., Wagner, Sebastian, Hattingen, Elke, Wichert, Jennifer, Lapa, Constantin, Fröhling, Stefan, Steinbach, Joachim P., and Ronellenfitsch, Michael W.

Published
2022
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9. Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival

Author

Ebrahimi, Azadeh, Korshunov, Andrey, Reifenberger, Guido, Capper, David, Felsberg, Joerg, Trisolini, Elena, Pollo, Bianca, Calatozzolo, Chiara, Prinz, Marco, Staszewski, Ori, Schweizer, Leonille, Schittenhelm, Jens, Harter, Patrick N., Paulus, Werner, Thomas, Christian, Kohlhof-Meinecke, Patricia, Seiz-Rosenhagen, Marcel, Milde, Till, Casalini, Belén M., Suwala, Abigail, Wefers, Annika K., Reinhardt, Annekathrin, Sievers, Philipp, Kramm, Christof M., Etminam, Nima, Unterberg, Andreas, Wick, Wolfgang, Herold-Mende, Christel, Sturm, Dominik, Pfister, Stefan M., Sill, Martin, Jones, David T. W., Schrimpf, Daniel, Reuss, David E., Aldape, Ken, Abdullaev, Zied, Sahm, Felix, von Deimling, Andreas, and Stichel, Damian

Published
2022
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10. DNA methylation-based classification of central nervous system tumours.

Author

Capper, David, Jones, David TW, 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, Hölsken, 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, Jürgen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brück, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Hänggi, 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, Mühleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G, Driever, Pablo Hernáiz, Kramm, Christof M, Müller, Hermann L, Rutkowski, Stefan, von Hoff, Katja, Frühwald, Michael C, Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia-Maria, Perry, Arie, and Jones, Chris

Subjects
Humans, Central Nervous System Neoplasms, Cohort Studies, Reproducibility of Results, DNA Methylation, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, Child, Child, Preschool, Infant, Female, Male, Young Adult, Unsupervised Machine Learning, and over, Preschool, General Science & Technology
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 challenging-with 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

11. Spatial single-cell profiling of deeply matched extreme long-term surviving glioblastoma patients reveals a distinct immune and stem cell driven ecosystem

Author

Decraene, Brecht, primary, Antoranz, Asier, additional, Vanmechelen, Maxime, additional, Coppens, Grégoire, additional, Shankar, Gautam, additional, Spans, Lien, additional, Verbeke, Tatjana, additional, Solie, Lien, additional, Dubroja, Nikolina, additional, Nazari, Pouya, additional, Derweduwe, Marleen, additional, Sciot, Raf, additional, De Visser, Yanti, additional, Andhari, Madhavi, additional, Hecke, Manon Van, additional, Bempt, Isabelle Vanden, additional, Loon, Joannes van, additional, Agostinis, Patrizia, additional, Bamps, Sven, additional, Gijtenbeek, Anja, additional, Noens, Bonny, additional, Duerinck, Johnny, additional, De Mulder, Gert, additional, Weyns, Frank, additional, Broekman, Marike, additional, Govaere, Olivier, additional, Reuss, David E, additional, De Smet, Frederik, additional, and De Vleeschouwer, Steven, additional

Published
2024
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12. Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis

Author

Suwala, Abigail K., Stichel, Damian, Schrimpf, Daniel, Kloor, Matthias, Wefers, Annika K., Reinhardt, Annekathrin, Maas, Sybren L. N., Kratz, Christian P., Schweizer, Leonille, Hasselblatt, Martin, Snuderl, Matija, Abedalthagafi, Malak Sameer J., Abdullaev, Zied, Monoranu, Camelia M., Bergmann, Markus, Pekrun, Arnulf, Freyschlag, Christian, Aronica, Eleonora, Kramm, Christof M., Hinz, Felix, Sievers, Philipp, Korshunov, Andrey, Kool, Marcel, Pfister, Stefan M., Sturm, Dominik, Jones, David T. W., Wick, Wolfgang, Unterberg, Andreas, Hartmann, Christian, Dodgshun, Andrew, Tabori, Uri, Wesseling, Pieter, Sahm, Felix, von Deimling, Andreas, and Reuss, David E.

Published
2021
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13. Protein Analysis of Glioblastoma Primary and Posttreatment Pairs Suggests a Mesenchymal Shift at Recurrence

Author

Wood, Matthew D, Reis, Gerald F, Reuss, David E, and Phillips, Joanna J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Neurosciences, Brain Disorders, Brain Cancer, Rare Diseases, Cancer, Glioblastoma, Glioblastoma molecular subtype, Immunohistochemistry, Mesenchymal transition, Neurofibromin, Recurrent glioblastoma, Recurrent glioblastoma., Clinical Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

Glioblastomas (GBM) are aggressive brain tumors that inevitably recur despite surgical resection, chemotherapy, and radiation. The degree to which recurrent GBM retains its initial immunophenotype is incompletely understood. We generated tissue microarrays of paired initial and posttreatment GBM (3 pairs positive and 17 negative for IDH1R132H) from the same patients and made comparisons in the IDH1R132H-negative group for immunohistochemical and gene expression differences between primary and recurrent tumors. In initial tumors, immunopositivity for Ki-67 in > 20% of tumor cells was associated with shorter progression-free and overall survival. Recurrent tumors showed decreased staining for CD34 suggesting lower vessel density. A subset of tumors showed increased staining for markers associated with the mesenchymal gene expression pattern, including CD44, phosphorylated STAT3, and YKL40. Recurrent tumors with the greatest increase in mesenchymal marker expression had rapid clinical progression, but no difference in overall survival after second surgery. Comparison of protein and gene expression data from the same samples revealed a poor correlation. A subset of tumors (15%) showed loss of neurofibromin protein in both initial and recurrent tumors. These data support the notion that GBM progression is associated with a shift toward a mesenchymal phenotype in a subset of tumors and this may portend a more aggressive behavior.

Published
2016

14. Molecular characterization of CNS paragangliomas identifies cauda equina paragangliomas as a distinct tumor entity

Author

Schweizer, Leonille, Thierfelder, Felix, Thomas, Christian, Soschinski, Patrick, Suwala, Abigail, Stichel, Damian, Wefers, Annika K., Wessels, Lars, Misch, Martin, Kim, Hee-yeong, Jödicke, Ruben, Teichmann, Daniel, Kaul, David, Kahn, Johannes, Bockmayr, Michael, Hasselblatt, Martin, Younsi, Alexander, Unterberg, Andreas, Knie, Bettina, Walter, Jan, Al Safatli, Diaa, May, Sven-Axel, Jödicke, Andreas, Ntoulias, Georgios, Moskopp, Dag, Vajkoczy, Peter, Heppner, Frank L., Capper, David, Hartmann, Wolfgang, Hartmann, Christian, von Deimling, Andreas, Reuss, David E., Schöler, Anne, and Koch, Arend

Published
2020
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15. Molecular analysis of pediatric CNS-PNET revealed nosologic heterogeneity and potent diagnostic markers for CNS neuroblastoma with FOXR2-activation

Author

Korshunov, Andrey, Okonechnikov, Konstantin, Schmitt-Hoffner, Felix, Ryzhova, Marina, Sahm, Felix, Stichel, Damian, Schrimpf, Daniel, Reuss, David E., Sievers, Philipp, Suwala, Abigail Kora, Kumirova, Ella, Zheludkova, Olga, Golanov, Andrey, Jones, David T. W., Pfister, Stefan M., Kool, Marcel, and von Deimling, Andreas

Published
2021
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16. 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, Fernández-Klett, Francisco, Casalini, Belén, 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-Pérez, Laura, Grünewald, Thomas G. P., Kirchner, Thomas, Wick, Wolfgang, Platten, Michael, Unterberg, Andreas, Uhl, Matthias, Abdollahi, Amir, Debus, Jürgen, Lehner, Burkhard, Thomas, Christian, Hasselblatt, Martin, Paulus, Werner, Hartmann, Christian, Staszewski, Ori, Prinz, Marco, Hench, Jürgen, Frank, Stephan, Versleijen-Jonkers, Yvonne M. H., Weidema, Marije E., Mentzel, Thomas, Griewank, Klaus, de Álava, Enrique, Martín, Juan Díaz, Gastearena, Miguel A. Idoate, Chang, Kenneth Tou-En, Low, Sharon Yin Yee, Cuevas-Bourdier, Adrian, Mittelbronn, Michel, Mynarek, Martin, Rutkowski, Stefan, Schüller, Ulrich, Mautner, Viktor F., Schittenhelm, Jens, Serrano, Jonathan, Snuderl, Matija, Büttner, Reinhard, Klingebiel, Thomas, Buslei, Rolf, Gessler, Manfred, Wesseling, Pieter, Dinjens, Winand N. M., Brandner, Sebastian, Jaunmuktane, Zane, Lyskjær, Iben, Schirmacher, Peter, Stenzinger, Albrecht, Brors, Benedikt, Glimm, Hanno, Heining, Christoph, Tirado, Oscar M., Sáinz-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., Fröhling, Stefan, Pfister, Stefan M., and von Deimling, Andreas

Published
2021
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17. Targetable ERBB2 mutations identified in neurofibroma/schwannoma hybrid nerve sheath tumors

Author

Ronellenfitsch, Michael W., Harter, Patrick N., Kirchner, Martina, Heining, Christoph, Hutter, Barbara, Gieldon, Laura, Schittenhelm, Jens, Schuhmann, Martin U., Tatagiba, Marcos, Wagner, Gerhard Marquard Marlies, Endris, Volker, Brandts, Christian H., Mautner, Victor-Felix, Schrock, Evelin, Weicher, Wilko, Brors, Benedikt, von Deimling, Andreas, Mittelbronn, Michel, Steinbach, Joachim P., Reuss, David E., Glimm, Hanno, Stenzinger, Albrecht, and Frohling, Stefan

Subjects
Merck & Company Inc., Thermo Fisher Scientific Inc., Bayer AG, Bristol-Myers Squibb Co., Novartis AG, AstraZeneca PLC, Lapatinib, Cancer -- Care and treatment -- Genetic aspects, Methylation, Tyrosine -- Genetic aspects, Pharmaceutical industry, Genomics -- Genetic aspects, Neratinib, Scientific equipment industry -- Genetic aspects, Criminal investigation, Cancer research, Neurofibromatosis, Phenols (Class of compounds), Tumors, DNA, Scientists, Research funding, Health care industry
Abstract

BACKGROUND. Neurofibroma/schwannoma hybrid nerve sheath tumors (N/S HNSTs) are neoplasms associated with larger nerves that occur sporadically and in the context of schwannomatosis or neurofibromatosis type 2 or 1. Clinical management of N/S HNSTs is challenging, especially for large tumors, and established systemic treatments are lacking. METHODS. We used next-generation sequencing and array-based DNA methylation profiling to determine the clinically actionable genomic and epigenomic landscapes of N/S HNSTs. RESULTS. Whole-exome sequencing within a precision oncology program identified an activating mutation (p.Asp769Tyr) in the catalytic domain of the ERBB2 receptor tyrosine kinase in a patient with schwannomatosis-associated N/S HNST, and targeted treatment with the small-molecule ERBB inhibitor lapatinib led to prolonged clinical benefit and a lasting radiographic and metabolic response. Analysis of a multicenter validation cohort revealed recurrent ERBB2 mutations (p.Leu755Ser, p.Asp769Tyr, p.Val777Leu) in N/S HNSTs occurring in patients who met diagnostic criteria for sporadic schwannomatosis (3 of 7 patients), but not in N/S HNSTs arising in the context of neurofibromatosis (6 patients) or outside a tumor syndrome (1 patient), and showed that ERBB2-mutant N/S HNSTs cluster in a distinct subgroup of peripheral nerve sheath tumors based on genome-wide DNA methylation patterns. CONCLUSION. These findings uncover a key biological feature of N/S HNSTs that may have important diagnostic and therapeutic implications. FUNDING. This work was supported by grant H021 from DKFZ-HIPO, the University Cancer Center Frankfurt, and the Frankfurt Research Funding Clinician Scientist Program., Introduction Neurofibroma/schwannoma hybrid nerve sheath tumors (N/S HNSTs) are peripheral nerve sheath tumors that are recognized as a distinct entity by the 2016 update of the World Health Organization (WHO) [...]

Published
2020
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18. Infratentorial IDH-mutant astrocytoma is a distinct subtype

Author

Banan, Rouzbeh, Stichel, Damian, Bleck, Anja, Hong, Bujung, Lehmann, Ulrich, Suwala, Abigail, Reinhardt, Annekathrin, Schrimpf, Daniel, Buslei, Rolf, Stadelmann, Christine, Ehlert, Karoline, Prinz, Marco, Acker, Till, Schittenhelm, Jens, Kaul, David, Schweizer, Leonille, Capper, David, Harter, Patrick N., Etminan, Nima, Jones, David T. W., Pfister, Stefan M., Herold-Mende, Christel, Wick, Wolfgang, Sahm, Felix, von Deimling, Andreas, Hartmann, Christian, and Reuss, David E.

Published
2020
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19. CDKN2A/B homozygous deletion is associated with early recurrence in meningiomas

Author

Sievers, Philipp, Hielscher, Thomas, Schrimpf, Daniel, Stichel, Damian, Reuss, David E., Berghoff, Anna S., Neidert, Marian C., Wirsching, Hans-Georg, Mawrin, Christian, Ketter, Ralf, Paulus, Werner, Reifenberger, Guido, Lamszus, Katrin, Westphal, Manfred, Etminan, Nima, Ratliff, Miriam, Herold-Mende, Christel, Pfister, Stefan M., Jones, David T. W., Weller, Michael, Harter, Patrick N., Wick, Wolfgang, Preusser, Matthias, von Deimling, Andreas, and Sahm, Felix

Published
2020
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21. YAP1-fusions in pediatric NF2-wildtype meningioma

Author

Sievers, Philipp, Chiang, Jason, Schrimpf, Daniel, Stichel, Damian, Paramasivam, Nagarajan, Sill, Martin, Gayden, Tenzin, Casalini, Belen, Reuss, David E., Dalton, James, Pajtler, Kristian W., Hänggi, Daniel, Herold-Mende, Christel, Rushing, Elisabeth, Korshunov, Andrey, Mawrin, Christian, Weller, Michael, Schlesner, Matthias, Wick, Wolfgang, Jabado, Nada, Jones, David T. W., Pfister, Stefan M., von Deimling, Andreas, Ellison, David W., and Sahm, Felix

Published
2020
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22. Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course

Author

Wefers, Annika K., Stichel, Damian, Schrimpf, Daniel, Coras, Roland, Pages, Mélanie, Tauziède-Espariat, Arnault, Varlet, Pascale, Schwarz, Daniel, Söylemezoglu, Figen, Pohl, Ute, Pimentel, José, Meyer, Jochen, Hewer, Ekkehard, Japp, Anna, Joshi, Abhijit, Reuss, David E., Reinhardt, Annekathrin, Sievers, Philipp, Casalini, M. Belén, Ebrahimi, Azadeh, Huang, Kristin, Koelsche, Christian, Low, Hu Liang, Rebelo, Olinda, Marnoto, Dina, Becker, Albert J., Staszewski, Ori, Mittelbronn, Michel, Hasselblatt, Martin, Schittenhelm, Jens, Cheesman, Edmund, de Oliveira, Ricardo Santos, Queiroz, Rosane Gomes P., Valera, Elvis Terci, Hans, Volkmar H., Korshunov, Andrey, Olar, Adriana, Ligon, Keith L., Pfister, Stefan M., Jaunmuktane, Zane, Brandner, Sebastian, Tatevossian, Ruth G., Ellison, David W., Jacques, Thomas S., Honavar, Mrinalini, Aronica, Eleonora, Thom, Maria, Sahm, Felix, von Deimling, Andreas, Jones, David T. W., Blumcke, Ingmar, and Capper, David

Published
2020
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23. Morphologic and immunohistochemical features of malignant peripheral nerve sheath tumors and cellular schwannomas

Author

Pekmezci, Melike, Reuss, David E, Hirbe, Angela C, Dahiya, Sonika, Gutmann, David H, von Deimling, Andreas, Horvai, Andrew E, and Perry, Arie

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Cancer, Neurosciences, Brain Cancer, Brain Disorders, Rare Diseases, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Adult, Biomarkers, Tumor, Diagnosis, Differential, Disease-Free Survival, Female, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Male, Middle Aged, Nerve Sheath Neoplasms, Neurilemmoma, Sensitivity and Specificity, Medical and Health Sciences, Pathology, Clinical sciences
Abstract

Cellular schwannoma is an uncommon, but well-recognized, benign peripheral nerve sheath tumor, which can be misdiagnosed as malignant peripheral nerve sheath tumor. To develop consensus diagnostic criteria for cellular schwannoma, we reviewed 115 malignant peripheral nerve sheath tumor and 26 cellular schwannoma cases from two institutions. Clinical data were retrieved from the electronic medical records, and morphologic features, maximal mitotic counts, Ki67 labeling indices, and immunohistochemical profiles (SOX10, SOX2, p75NTR, p16, p53, EGFR, and neurofibromin) were assessed. Several features distinguish cellular schwannoma from malignant peripheral nerve sheath tumor. First, in contrast to patients with malignant peripheral nerve sheath tumor, no metastases or disease-specific deaths were found in patients with cellular schwannoma. More specifically, 5-year progression-free survival rates were 100 and 18%, and 5-year disease-specific survival rates were 100 and 32% for cellular schwannoma and malignant peripheral nerve sheath tumor, respectively. Second, the presence of Schwannian whorls, a peritumoral capsule, subcapsular lymphocytes, macrophage-rich infiltrates, and the absence of fascicles favored the diagnosis of cellular schwannoma, while the presence of perivascular hypercellularity, tumor herniation into vascular lumens, and necrosis favor malignant peripheral nerve sheath tumor. Third, complete loss of SOX10, neurofibromin or p16 expression, or the presence of EGFR immunoreactivity was specific for malignant peripheral nerve sheath tumor (P

Published
2015

24. MYCN amplification drives an aggressive form of spinal ependymoma

Author

Ghasemi, David R., Sill, Martin, Okonechnikov, Konstantin, Korshunov, Andrey, Yip, Stephen, Schutz, Peter W., Scheie, David, Kruse, Anders, Harter, Patrick N., Kastelan, Marina, Wagner, Marlies, Hartmann, Christian, Benzel, Julia, Maass, Kendra K., Khasraw, Mustafa, Sträter, Ronald, Thomas, Christian, Paulus, Werner, Kratz, Christian P., Witt, Hendrik, Kawauchi, Daisuke, Herold-Mende, Christel, Sahm, Felix, Brandner, Sebastian, Kool, Marcel, Jones, David T. W., von Deimling, Andreas, Pfister, Stefan M., Reuss, David E., and Pajtler, Kristian W.

Published
2019
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25. Survey of NF1 inactivation by surrogate immunohistochemistry in ovarian carcinomas

Author

Köbel, Martin, primary, Yang, Rui Zhe, additional, Kang, Eun Young, additional, Al-Shamma, Zainab, additional, Cook, Linda S., additional, Kinloch, Mary, additional, Carey, Mark S., additional, Hopkins, Laura, additional, Nelson, Gregg S., additional, McManus, Kirk J., additional, Vizeacoumar, Frederick S., additional, Vizeacoumar, Franco J., additional, Freywald, Andrew, additional, Fu, YangXin, additional, Reuss, David E., additional, and Lee, Cheng-Han, additional

Published
2023
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26. Array-based DNA-methylation profiling in sarcomas with small blue round cell histology provides valuable diagnostic information

Author

Koelsche, Christian, Hartmann, Wolfgang, Schrimpf, Daniel, Stichel, Damian, Jabar, Susanne, Ranft, Andreas, Reuss, David E., Sahm, Felix, Jones, David T.W., Bewerunge-Hudler, Melanie, Trautmann, Marcel, Klingebiel, Thomas, Vokuhl, Christian, Gessler, Manfred, Wardelmann, Eva, Petersen, Iver, Baumhoer, Daniel, Flucke, Uta, Antonescu, Cristina, Esteller, Manel, Fröhling, Stefan, Kool, Marcel, Pfister, Stefan M., Mechtersheimer, Gunhild, Dirksen, Uta, and von Deimling, Andreas

Published
2018
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28. Routine RNA sequencing of formalin-fixed paraffin-embedded specimens in neuropathology diagnostics identifies diagnostically and therapeutically relevant gene fusions

Author

Stichel, Damian, Schrimpf, Daniel, Casalini, Belén, Meyer, Jochen, Wefers, Annika K., Sievers, Philipp, Korshunov, Andrey, Koelsche, Christian, Reuss, David E., Reinhardt, Annekathrin, Ebrahimi, Azadeh, Fernández-Klett, Francisco, Kessler, Tobias, Sturm, Dominik, Ecker, Jonas, Milde, Till, Herold-Mende, Christel, Witt, Olaf, Pfister, Stefan M., Wick, Wolfgang, Jones, David T. W., von Deimling, Andreas, and Sahm, Felix

Published
2019
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29. Rosette-forming glioneuronal tumors share a distinct DNA methylation profile and mutations in FGFR1, with recurrent co-mutation of PIK3CA and NF1

Author

Sievers, Philipp, Appay, Romain, Schrimpf, Daniel, Stichel, Damian, Reuss, David E., Wefers, Annika K., Reinhardt, Annekathrin, Coras, Roland, Ruf, Viktoria C., Schmid, Simone, de Stricker, Karin, Boldt, Henning B., Kristensen, Bjarne Winther, Petersen, Jeanette Krogh, Ulhøi, Benedicte P., Gardberg, Maria, Aronica, Eleonora, Hasselblatt, Martin, Brück, Wolfgang, Bielle, Franck, Mokhtari, Karima, Lhermitte, Benoît, Wick, Wolfgang, Herold-Mende, Christel, Hänggi, Daniel, Brandner, Sebastian, Giangaspero, Felice, Capper, David, Rushing, Elisabeth, Wesseling, Pieter, Pfister, Stefan M., Figarella-Branger, Dominique, von Deimling, Andreas, Sahm, Felix, and Jones, David T. W.

Published
2019
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30. Papillary glioneuronal tumor (PGNT) exhibits a characteristic methylation profile and fusions involving PRKCA

Author

Hou, Yanghao, Pinheiro, Jorge, Sahm, Felix, Reuss, David E., Schrimpf, Daniel, Stichel, Damian, Casalini, Belén, Koelsche, Christian, Sievers, Philipp, Wefers, Annika K., Reinhardt, Annekathrin, Ebrahimi, Azadeh, Fernández-Klett, Francisco, Pusch, Stefan, Meier, Jochen, Schweizer, Leonille, Paulus, Werner, Prinz, Marco, Hartmann, Christian, Plate, Karl H., Reifenberger, Guido, Pietsch, Torsten, Varlet, Pascale, Pagès, Mélanie, Schüller, Ulrich, Scheie, David, de Stricker, Karin, Frank, Stephan, Hench, Jürgen, Pollo, Bianca, Brandner, Sebastian, Unterberg, Andreas, Pfister, Stefan M., Jones, David T. W., Korshunov, Andrey, Wick, Wolfgang, Capper, David, Blümcke, Ingmar, von Deimling, Andreas, and Bertero, Luca

Published
2019
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31. The molecular landscape of glioma in patients with Neurofibromatosis 1

Author

D’Angelo, Fulvio, Ceccarelli, Michele, Tala, Garofano, Luciano, Zhang, Jing, Frattini, Véronique, Caruso, Francesca P., Lewis, Genevieve, Alfaro, Kristin D., Bauchet, Luc, Berzero, Giulia, Cachia, David, Cangiano, Mario, Capelle, Laurent, de Groot, John, DiMeco, Francesco, Ducray, François, Farah, Walid, Finocchiaro, Gaetano, Goutagny, Stéphane, Kamiya-Matsuoka, Carlos, Lavarino, Cinzia, Loiseau, Hugues, Lorgis, Véronique, Marras, Carlo E., McCutcheon, Ian, Nam, Do-Hyun, Ronchi, Susanna, Saletti, Veronica, Seizeur, Romuald, Slopis, John, Suñol, Mariona, Vandenbos, Fanny, Varlet, Pascale, Vidaud, Dominique, Watts, Colin, Tabar, Viviane, Reuss, David E., Kim, Seung-Ki, Meyronet, David, Mokhtari, Karima, Salvador, Hector, Bhat, Krishna P., Eoli, Marica, Sanson, Marc, Lasorella, Anna, and Iavarone, Antonio

Published
2019
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32. Simultaneous Nbs1 and p53 inactivation in neural progenitors triggers high‐grade gliomas

Author

Reuss, David E., primary, Downing, Susanna M., additional, Camacho, Cristel V., additional, Wang, Yong‐Dong, additional, Piro, Rosario M., additional, Herold‐Mende, Christel, additional, Wang, Zhao‐Qi, additional, Hofmann, Thomas G., additional, Sahm, Felix, additional, von Deimling, Andreas, additional, McKinnon, Peter J., additional, and Frappart, Pierre‐Olivier, additional

Published
2023
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33. DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis

Author

Sahm, Felix, Schrimpf, Daniel, Stichel, Damian, Jones, David T W, Hielscher, Thomas, Schefzyk, Sebastian, Okonechnikov, Konstantin, Koelsche, Christian, Reuss, David E, Capper, David, Sturm, Dominik, Wirsching, Hans-Georg, Berghoff, Anna Sophie, Baumgarten, Peter, Kratz, Annekathrin, Huang, Kristin, Wefers, Annika K, Hovestadt, Volker, Sill, Martin, Ellis, Hayley P, Kurian, Kathreena M, Okuducu, Ali Fuat, Jungk, Christine, Drueschler, Katharina, Schick, Matthias, Bewerunge-Hudler, Melanie, Mawrin, Christian, Seiz-Rosenhagen, Marcel, Ketter, Ralf, Simon, Matthias, Westphal, Manfred, Lamszus, Katrin, Becker, Albert, Koch, Arend, Schittenhelm, Jens, Rushing, Elisabeth J, Collins, V Peter, Brehmer, Stefanie, Chavez, Lukas, Platten, Michael, Hänggi, Daniel, Unterberg, Andreas, Paulus, Werner, Wick, Wolfgang, Pfister, Stefan M, Mittelbronn, Michel, Preusser, Matthias, Herold-Mende, Christel, Weller, Michael, and von Deimling, Andreas

Published
2017
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34. Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience

Author

Capper, David, Stichel, Damian, Sahm, Felix, Jones, David T. W., Schrimpf, Daniel, Sill, Martin, Schmid, Simone, Hovestadt, Volker, Reuss, David E., Koelsche, Christian, Reinhardt, Annekathrin, Wefers, Annika K., Huang, Kristin, Sievers, Philipp, Ebrahimi, Azadeh, Schöler, Anne, Teichmann, Daniel, Koch, Arend, Hänggi, Daniel, Unterberg, Andreas, Platten, Michael, Wick, Wolfgang, Witt, Olaf, Milde, Till, Korshunov, Andrey, Pfister, Stefan M., and von Deimling, Andreas

Published
2018
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35. Primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features share a highly distinct methylation profile and DICER1 mutations

Author

Koelsche, Christian, Mynarek, Martin, Schrimpf, Daniel, Bertero, Luca, Serrano, Jonathan, Sahm, Felix, Reuss, David E., Hou, Yanghao, Baumhoer, Daniel, Vokuhl, Christian, Flucke, Uta, Petersen, Iver, Brück, Wolfgang, Rutkowski, Stefan, Zambrano, Sandro Casavilca, Garcia Leon, Juan Luis, Diaz Coronado, Rosdali Yesenia, Gessler, Manfred, Tirado, Oscar M., Mora, Jaume, Alonso, Javier, Garcia del Muro, Xavier, Esteller, Manel, Sturm, Dominik, Ecker, Jonas, Milde, Till, Pfister, Stefan M., Korshunov, Andrey, Snuderl, Matija, Mechtersheimer, Gunhild, Schüller, Ulrich, Jones, David T. W., and von Deimling, Andreas

Published
2018
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36. Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA):a molecularly distinct brain tumor type with recurrent NTRK gene fusions

Author

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, Sievers, Philipp, 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

Abstract

Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors—distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors.

Published
2023

37. Tumors diagnosed as cerebellar glioblastoma comprise distinct molecular entities

Author

Reinhardt, Annekathrin, Stichel, Damian, Schrimpf, Daniel, Koelsche, Christian, Wefers, Annika K., Ebrahimi, Azadeh, Sievers, Philipp, Huang, Kristin, Casalini, M. Belén, Fernández-Klett, Francisco, Suwala, Abigail, Weller, Michael, Gramatzki, Dorothee, Felsberg, Joerg, Reifenberger, Guido, Becker, Albert, Hans, Volkmar H., Prinz, Marco, Staszewski, Ori, Acker, Till, Dohmen, Hildegard, Hartmann, Christian, Paulus, Werner, Heß, Katharina, Brokinkel, Benjamin, Schittenhelm, Jens, Buslei, Rolf, Deckert, Martina, Mawrin, Christian, Hewer, Ekkehard, Pohl, Ute, Jaunmuktane, Zane, Brandner, Sebastian, Unterberg, Andreas, Hänggi, Daniel, Platten, Michael, Pfister, Stefan M., Wick, Wolfgang, Herold-Mende, Christel, Korshunov, Andrey, Reuss, David E., Sahm, Felix, Jones, David T. W., Capper, David, and von Deimling, Andreas

Published
2019
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38. Genome-wide methylation profiling and copy number analysis in atypical fibroxanthomas and pleomorphic dermal sarcomas indicate a similar molecular phenotype

Author

Koelsche, Christian, Stichel, Damian, Griewank, Klaus G., Schrimpf, Daniel, Reuss, David E., Bewerunge-Hudler, Melanie, Vokuhl, Christian, Dinjens, Winand N. M., Petersen, Iver, Mittelbronn, Michel, Cuevas-Bourdier, Adrian, Buslei, Rolf, Pfister, Stefan M., Flucke, Uta, Mechtersheimer, Gunhild, Mentzel, Thomas, and von Deimling, Andreas

Published
2019
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39. Anaplastic ganglioglioma—A diagnosis comprising several distinct tumour types

Author

Reinhardt, Annekathrin, primary, Pfister, Kristin, additional, Schrimpf, Daniel, additional, Stichel, Damian, additional, Sahm, Felix, additional, Reuss, David E., additional, Capper, David, additional, Wefers, Annika K., additional, Ebrahimi, Azadeh, additional, Sill, Martin, additional, Felsberg, Joerg, additional, Reifenberger, Guido, additional, Becker, Albert, additional, Prinz, Marco, additional, Staszewski, Ori, additional, Hartmann, Christian, additional, Schittenhelm, Jens, additional, Gramatzki, Dorothee, additional, Weller, Michael, additional, Olar, Adriana, additional, Rushing, Elisabeth Jane, additional, Bergmann, Markus, additional, Farrell, Michael A., additional, Blümcke, Ingmar, additional, Coras, Roland, additional, Beckervordersandforth, Jan, additional, Kim, Se Hoon, additional, Rogerio, Fabio, additional, Dimova, Petia S., additional, Niehusmann, Pitt, additional, Unterberg, Andreas, additional, Platten, Michael, additional, Pfister, Stefan M., additional, Wick, Wolfgang, additional, Herold‐Mende, Christel, additional, and von Deimling, Andreas, additional

Published
2022
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41. Methylation-based classification of benign and malignant peripheral nerve sheath tumors

Author

Röhrich, Manuel, Koelsche, Christian, Schrimpf, Daniel, Capper, David, Sahm, Felix, Kratz, Annekathrin, Reuss, Jana, Hovestadt, Volker, Jones, David T. W., Bewerunge-Hudler, Melanie, Becker, Albert, Weis, Joachim, Mawrin, Christian, Mittelbronn, Michel, Perry, Arie, Mautner, Victor-Felix, Mechtersheimer, Gunhild, Hartmann, Christian, Okuducu, Ali Fuat, Arp, Mirko, Seiz-Rosenhagen, Marcel, Hänggi, Daniel, Heim, Stefanie, Paulus, Werner, Schittenhelm, Jens, Ahmadi, Rezvan, Herold-Mende, Christel, Unterberg, Andreas, Pfister, Stefan M., von Deimling, Andreas, and Reuss, David E.

Published
2016
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42. Oligosarcomas, IDH‑mutant are distinct and aggressive

Author

Suwala, Abigail K., Felix, Marius, Friedel, Dennis, Stichel, Damian, Schrimpf, Daniel, Hinz, Felix, Hewer, Ekkehard, Schweizer, Leonille, Dohmen, Hildegard, Pohl, Ute, Staszewski, Ori, Korshunov, Andrey, Stein, Marco, Wongsurawat, Thidathip, Cheunsuacchon, Pornsuk, Sathornsumetee, Sith, Koelsche, Christian, Turner, Clinton, Rhun, Emilie Le, Mühlebner, Angelika, Schucht, Philippe, Özduman, Koray, Ono, Takahiro, Shimizu, Hiroaki, Prinz, Marco, Acker, Till, Herold‑Mende, Christel, Kessler, Tobias, Wick, Wolfgang, Capper, David, Wesseling, Pieter, Sahm, Felix, von Deimling, Andreas, Hartmann, Christian, Reuss, David E., Suwala, Abigail K., Felix, Marius, Friedel, Dennis, Stichel, Damian, Schrimpf, Daniel, Hinz, Felix, Hewer, Ekkehard, Schweizer, Leonille, Dohmen, Hildegard, Pohl, Ute, Staszewski, Ori, Korshunov, Andrey, Stein, Marco, Wongsurawat, Thidathip, Cheunsuacchon, Pornsuk, Sathornsumetee, Sith, Koelsche, Christian, Turner, Clinton, Rhun, Emilie Le, Mühlebner, Angelika, Schucht, Philippe, Özduman, Koray, Ono, Takahiro, Shimizu, Hiroaki, Prinz, Marco, Acker, Till, Herold‑Mende, Christel, Kessler, Tobias, Wick, Wolfgang, Capper, David, Wesseling, Pieter, Sahm, Felix, von Deimling, Andreas, Hartmann, Christian, and Reuss, David E.

Abstract

Oligodendrogliomas are defined at the molecular level by the presence of an IDH mutation and codeletion of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 24 IDH-mutant oligosarcomas from 23 patients forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 12 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dense network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA and CALD1, loss of OLIG2 and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Copy number neutral LOH was determined as underlying mechanism. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent CDKN2A/B deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional CNS WHO grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in NF1 and TP53 along with IDH1/2 and TERT promoter mutations. Survival of patients was significantly poorer for oligosarcomas as first recurrence than for grade 3 oligodendrogliomas as first recurrence. These results establish oligosarcomas as a distinct group of IDH-mutant gliomas differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. The diagnosis can be based on the combined presence of (a) sarcomatous histology, (b) IDH-mutation and

Published
2022

43. Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities

Author

Reuss, David E., Kratz, Annekathrin, Sahm, Felix, Capper, David, Schrimpf, Daniel, Koelsche, Christian, Hovestadt, Volker, Bewerunge-Hudler, Melanie, Jones, David T. W., Schittenhelm, Jens, Mittelbronn, Michel, Rushing, Elisabeth, Simon, Matthias, Westphal, Manfred, Unterberg, Andreas, Platten, Michael, Paulus, Werner, Reifenberger, Guido, Tonn, Joerg-Christian, Aldape, Kenneth, Pfister, Stefan M., Korshunov, Andrey, Weller, Michael, Herold-Mende, Christel, Wick, Wolfgang, Brandner, Sebastian, and von Deimling, Andreas

Published
2015
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44. IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO

Author

Reuss, David E., Mamatjan, Yasin, Schrimpf, Daniel, Capper, David, Hovestadt, Volker, Kratz, Annekathrin, Sahm, Felix, Koelsche, Christian, Korshunov, Andrey, Olar, Adriana, Hartmann, Christian, Reijneveld, Jaap C., Wesseling, Pieter, Unterberg, Andreas, Platten, Michael, Wick, Wolfgang, Herold-Mende, Christel, Aldape, Kenneth, and von Deimling, Andreas

Published
2015
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45. ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an “integrated” diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma

Author

Reuss, David E., Sahm, Felix, Schrimpf, Daniel, Wiestler, Benedikt, Capper, David, Koelsche, Christian, Schweizer, Leonille, Korshunov, Andrey, Jones, David T. W., Hovestadt, Volker, Mittelbronn, Michel, Schittenhelm, Jens, Herold-Mende, Christel, Unterberg, Andreas, Platten, Michael, Weller, Michael, Wick, Wolfgang, Pfister, Stefan M., and von Deimling, Andreas

Published
2015
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46. HIP1R and vimentin immunohistochemistry predict 1p/19q status in IDH-mutant glioma

Author

Felix, Marius, primary, Friedel, Dennis, additional, Jayavelu, Ashok Kumar, additional, Filipski, Katharina, additional, Reinhardt, Annekathrin, additional, Warnken, Uwe, additional, Stichel, Damian, additional, Schrimpf, Daniel, additional, Korshunov, Andrey, additional, Wang, Yueting, additional, Kessler, Tobias, additional, Etminan, Nima, additional, Unterberg, Andreas, additional, Herold-Mende, Christel, additional, Heikaus, Laura, additional, Sahm, Felix, additional, Wick, Wolfgang, additional, Harter, Patrick N, additional, von Deimling, Andreas, additional, and Reuss, David E, additional

Published
2022
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47. Additional file 3 of Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival

Author

Ebrahimi, Azadeh, Korshunov, Andrey, Reifenberger, Guido, Capper, David, Felsberg, Joerg, Trisolini, Elena, Pollo, Bianca, Calatozzolo, Chiara, Prinz, Marco, Staszewski, Ori, Schweizer, Leonille, Schittenhelm, Jens, Harter, Patrick N., Paulus, Werner, Thomas, Christian, Kohlhof-Meinecke, Patricia, Seiz-Rosenhagen, Marcel, Milde, Till, Casalini, Bel��n M., Suwala, Abigail, Wefers, Annika K., Reinhardt, Annekathrin, Sievers, Philipp, Kramm, Christof M., Etminam, Nima, Unterberg, Andreas, Wick, Wolfgang, Herold-Mende, Christel, Sturm, Dominik, Pfister, Stefan M., Sill, Martin, Jones, David T. W., Schrimpf, Daniel, Reuss, David E., Aldape, Ken, Abdullaev, Zied, Sahm, Felix, von Deimling, Andreas, and Stichel, Damian

Abstract

Additional file 3. Composition of cohorts mcPXA and histPXA in numbers.

Published
2022
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48. Additional file 5 of Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival

Author

Ebrahimi, Azadeh, Korshunov, Andrey, Reifenberger, Guido, Capper, David, Felsberg, Joerg, Trisolini, Elena, Pollo, Bianca, Calatozzolo, Chiara, Prinz, Marco, Staszewski, Ori, Schweizer, Leonille, Schittenhelm, Jens, Harter, Patrick N., Paulus, Werner, Thomas, Christian, Kohlhof-Meinecke, Patricia, Seiz-Rosenhagen, Marcel, Milde, Till, Casalini, Bel��n M., Suwala, Abigail, Wefers, Annika K., Reinhardt, Annekathrin, Sievers, Philipp, Kramm, Christof M., Etminam, Nima, Unterberg, Andreas, Wick, Wolfgang, Herold-Mende, Christel, Sturm, Dominik, Pfister, Stefan M., Sill, Martin, Jones, David T. W., Schrimpf, Daniel, Reuss, David E., Aldape, Ken, Abdullaev, Zied, Sahm, Felix, von Deimling, Andreas, and Stichel, Damian

Abstract

Additional file 5. Histological features observed in pleomorphic xanthoastrocytomas, (a) classical giant pleomorphic cells with multiple nuclei and prominent nucleolus, (b) extensive perivascular inflammatory infiltrates, (c) endothelial proliferations, (d) extensive myxoid matrix, (e) pseudopalisading necrosis, (f) pseudopapillary growth pattern, (g) biphasic pattern with spindle cell component and giant pleomorphic cell component, (h) extensive calcification, (i) small round blue cell morphology, (j) a thrombosed vessel; all depicted tumors had a maximum calibrated score above 0.9 for mcPXA; Supplementary figure 2 Overall survival (Kaplan-Meier curve) of patients in cohort mcPXA stratified after initial histological diagnosis (a) and BRAF V600E status (b); Supplementary figure 3 Typical copy number profile of mcPXA (upper panel) compared to that of mcGBM (lower panel); Supplementary figure 4 Copy number summary of cohort mcPXA altogether and stratified after WHO grade; Supplementary figure 5: The composition of cohorts histPXA and mcPXA, (a) 220 mcPXA cases with their histological composition, (b) 144 histPXA cases with their methylation class assignments (v11b4).

Published
2022
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49. Additional file 6 of Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival

Author

Ebrahimi, Azadeh, Korshunov, Andrey, Reifenberger, Guido, Capper, David, Felsberg, Joerg, Trisolini, Elena, Pollo, Bianca, Calatozzolo, Chiara, Prinz, Marco, Staszewski, Ori, Schweizer, Leonille, Schittenhelm, Jens, Harter, Patrick N., Paulus, Werner, Thomas, Christian, Kohlhof-Meinecke, Patricia, Seiz-Rosenhagen, Marcel, Milde, Till, Casalini, Bel��n M., Suwala, Abigail, Wefers, Annika K., Reinhardt, Annekathrin, Sievers, Philipp, Kramm, Christof M., Etminam, Nima, Unterberg, Andreas, Wick, Wolfgang, Herold-Mende, Christel, Sturm, Dominik, Pfister, Stefan M., Sill, Martin, Jones, David T. W., Schrimpf, Daniel, Reuss, David E., Aldape, Ken, Abdullaev, Zied, Sahm, Felix, von Deimling, Andreas, and Stichel, Damian

Subjects
TheoryofComputation_MATHEMATICALLOGICANDFORMALLANGUAGES, ComputingMethodologies_SYMBOLICANDALGEBRAICMANIPULATION, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Data_FILES, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries)
Abstract

Additional file 6. List of abbreviations.

Published
2022
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50. Additional file 4 of Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival

Author

Ebrahimi, Azadeh, Korshunov, Andrey, Reifenberger, Guido, Capper, David, Felsberg, Joerg, Trisolini, Elena, Pollo, Bianca, Calatozzolo, Chiara, Prinz, Marco, Staszewski, Ori, Schweizer, Leonille, Schittenhelm, Jens, Harter, Patrick N., Paulus, Werner, Thomas, Christian, Kohlhof-Meinecke, Patricia, Seiz-Rosenhagen, Marcel, Milde, Till, Casalini, Bel��n M., Suwala, Abigail, Wefers, Annika K., Reinhardt, Annekathrin, Sievers, Philipp, Kramm, Christof M., Etminam, Nima, Unterberg, Andreas, Wick, Wolfgang, Herold-Mende, Christel, Sturm, Dominik, Pfister, Stefan M., Sill, Martin, Jones, David T. W., Schrimpf, Daniel, Reuss, David E., Aldape, Ken, Abdullaev, Zied, Sahm, Felix, von Deimling, Andreas, and Stichel, Damian

Abstract

Additional file 4. tSNE plot of histPXA cases with the set of reference samples underlying the classifier version v11b4; ���histPXA a��� represents cases with a calibrated score less than 0.9 in v11b4 classifier, ���histPXA b��� represents cases with a calibrated score of 0.9 or higher in v11b4 classifier.

Published
2022
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