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1. Whole tumor analysis reveals early origin of the TERT promoter mutation and intercellular heterogeneity in TERT expression

Author

Appin, Christina L, Hong, Chibo, Suwala, Abigail K, Hilz, Stephanie, Mathur, Radhika, Solomon, David A, Smirnov, Ivan V, Stevers, Nicholas O, Shai, Anny, Wang, Albert, Berger, Mitchel S, Chang, Susan M, Phillips, Joanna J, and Costello, Joseph F

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Brain Cancer, Genetics, Cancer, Neurosciences, Brain Disorders, Human Genome, Rare Diseases, Cancer Genomics, Humans, Brain Neoplasms, Glioma, Glioblastoma, Oligodendroglioma, Mutation, Biomarkers, Tumor, Isocitrate Dehydrogenase, Telomerase, Proto-Oncogene Proteins, Cell Cycle Proteins, glioblastoma, oligodendroglioma, sequencing, TERT, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundThe TERT promoter mutation (TPM) is acquired in most IDH-wildtype glioblastomas (GBM) and IDH-mutant oligodendrogliomas (OD) enabling tumor cell immortality. Previous studies on TPM clonality show conflicting results. This study was performed to determine whether TPM is clonal on a tumor-wide scale.MethodsWe investigated TPM clonality in relation to presumed early events in 19 IDH-wildtype GBM and 10 IDH-mutant OD using 3-dimensional comprehensive tumor sampling. We performed Sanger sequencing on 264 tumor samples and deep amplicon sequencing on 187 tumor samples. We obtained tumor purity and copy number estimates from whole exome sequencing. TERT expression was assessed by RNA-seq and RNAscope.ResultsWe detected TPM in 100% of tumor samples with quantifiable tumor purity (219 samples). Variant allele frequencies (VAF) of TPM correlate positively with chromosome 10 loss in GBM (R = 0.85), IDH1 mutation in OD (R = 0.87), and with tumor purity (R = 0.91 for GBM; R = 0.90 for OD). In comparison, oncogene amplification was tumor-wide for MDM4- and most EGFR-amplified cases but heterogeneous for MYCN and PDGFRA, and strikingly high in low-purity samples. TPM VAF was moderately correlated with TERT expression (R = 0.52 for GBM; R = 0.65 for OD). TERT expression was detected in a subset of cells, solely in TPM-positive samples, including samples equivocal for tumor.ConclusionsOn a tumor-wide scale, TPM is among the earliest events in glioma evolution. Intercellular heterogeneity of TERT expression, however, suggests dynamic regulation during tumor growth. TERT expression may be a tumor cell-specific biomarker.

Published
2024

3. Face Identity-Aware Disentanglement in StyleGAN

Author

Suwała, Adrian, Wójcik, Bartosz, Proszewska, Magdalena, Tabor, Jacek, Spurek, Przemysław, and Śmieja, Marek

Subjects
Computer Science - Computer Vision and Pattern Recognition, Computer Science - Machine Learning
Abstract

Conditional GANs are frequently used for manipulating the attributes of face images, such as expression, hairstyle, pose, or age. Even though the state-of-the-art models successfully modify the requested attributes, they simultaneously modify other important characteristics of the image, such as a person's identity. In this paper, we focus on solving this problem by introducing PluGeN4Faces, a plugin to StyleGAN, which explicitly disentangles face attributes from a person's identity. Our key idea is to perform training on images retrieved from movie frames, where a given person appears in various poses and with different attributes. By applying a type of contrastive loss, we encourage the model to group images of the same person in similar regions of latent space. Our experiments demonstrate that the modifications of face attributes performed by PluGeN4Faces are significantly less invasive on the remaining characteristics of the image than in the existing state-of-the-art models.

Published
2023

4. Novel SOX10 indel mutations drive schwannomas through impaired transactivation of myelination gene programs

Author

Williams, Erik A, Ravindranathan, Ajay, Gupta, Rohit, Stevers, Nicholas O, Suwala, Abigail K, Hong, Chibo, Kim, Somang, Yuan, Jimmy Bo, Wu, Jasper, Barreto, Jairo, Lucas, Calixto-Hope G, Chan, Emily, Pekmezci, Melike, LeBoit, Philip E, Mully, Thaddeus, Perry, Arie, Bollen, Andrew, Van Ziffle, Jessica, Devine, W Patrick, Reddy, Alyssa T, Gupta, Nalin, Basnet, Kristen M, Macaulay, Robert JB, Malafronte, Patrick, Lee, Han, Yong, William H, Williams, Kevin Jon, Juratli, Tareq A, Mata, Douglas A, Huang, Richard SP, Hiemenz, Matthew C, Pavlick, Dean C, Frampton, Garrett M, Janovitz, Tyler, Ross, Jeffrey S, Chang, Susan M, Berger, Mitchel S, Jacques, Line, Song, Jun S, Costello, Joseph F, and Solomon, David A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Cancer, Neurofibromatosis, Cancer Genomics, Genetics, Pediatric, Rare Diseases, Human Genome, Neurosciences, Biotechnology, 2.1 Biological and endogenous factors, Humans, INDEL Mutation, Transcriptional Activation, Neurilemmoma, Neuroma, Acoustic, Mutation, Nerve Sheath Neoplasms, SOXE Transcription Factors, myelination, PMP2, Schwann cell, schwannoma, SOX10, Oncology and Carcinogenesis, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundSchwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas.MethodsWe performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10.ResultsWe identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs.ConclusionsWe thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.

Published
2023

5. Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses

Author

Chen, William C, Choudhury, Abrar, Youngblood, Mark W, Polley, Mei-Yin C, Lucas, Calixto-Hope G, Mirchia, Kanish, Maas, Sybren LN, Suwala, Abigail K, Won, Minhee, Bayley, James C, Harmanci, Akdes S, Harmanci, Arif O, Klisch, Tiemo J, Nguyen, Minh P, Vasudevan, Harish N, McCortney, Kathleen, Yu, Theresa J, Bhave, Varun, Lam, Tai-Chung, Pu, Jenny Kan-Suen, Li, Lai-Fung, Leung, Gilberto Ka-Kit, Chan, Jason W, Perlow, Haley K, Palmer, Joshua D, Haberler, Christine, Berghoff, Anna S, Preusser, Matthias, Nicolaides, Theodore P, Mawrin, Christian, Agnihotri, Sameer, Resnick, Adam, Rood, Brian R, Chew, Jessica, Young, Jacob S, Boreta, Lauren, Braunstein, Steve E, Schulte, Jessica, Butowski, Nicholas, Santagata, Sandro, Spetzler, David, Bush, Nancy Ann Oberheim, Villanueva-Meyer, Javier E, Chandler, James P, Solomon, David A, Rogers, C Leland, Pugh, Stephanie L, Mehta, Minesh P, Sneed, Penny K, Berger, Mitchel S, Horbinski, Craig M, McDermott, Michael W, Perry, Arie, Bi, Wenya Linda, Patel, Akash J, Sahm, Felix, Magill, Stephen T, and Raleigh, David R

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Brain Cancer, Clinical Trials and Supportive Activities, Radiation Oncology, Human Genome, Precision Medicine, Rare Diseases, Cancer, Brain Disorders, Genetics, Humans, Biomarkers, Gene Expression Profiling, Meningeal Neoplasms, Meningioma, Neoplasm Recurrence, Local, Prospective Studies, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P

Published
2023

7. Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation

Author

Neyazi, Sina, Yamazawa, Erika, Hack, Karoline, Tanaka, Shota, Nagae, Genta, Kresbach, Catena, Umeda, Takayoshi, Eckhardt, Alicia, Tatsuno, Kenji, Pohl, Lara, Hana, Taijun, Bockmayr, Michael, Kim, Phyo, Dorostkar, Mario M., Takami, Toshihiro, Obrecht, Denise, Takai, Keisuke, Suwala, Abigail K., Komori, Takashi, Godbole, Shweta, Wefers, Annika K., Otani, Ryohei, Neumann, Julia E., Higuchi, Fumi, Schweizer, Leonille, Nakanishi, Yuta, Monoranu, Camelia-Maria, Takami, Hirokazu, Engertsberger, Lara, Yamada, Keisuke, Ruf, Viktoria, Nomura, Masashi, Mohme, Theresa, Mukasa, Akitake, Herms, Jochen, Takayanagi, Shunsaku, Mynarek, Martin, Matsuura, Reiko, Lamszus, Katrin, Ishii, Kazuhiko, Kluwe, Lan, Imai, Hideaki, von Deimling, Andreas, Koike, Tsukasa, Benesch, Martin, Kushihara, Yoshihiro, Snuderl, Matija, Nambu, Shohei, Frank, Stephan, Omura, Takaki, Hagel, Christian, Kugasawa, Kazuha, Mautner, Viktor F., Ichimura, Koichi, Rutkowski, Stefan, Aburatani, Hiroyuki, Saito, Nobuhito, and Schüller, Ulrich

Published
2024
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9. Characterizing and targeting glioblastoma neuron-tumor networks with retrograde tracing

Author

Tetzlaff, Svenja K., Reyhan, Ekin, Layer, Nikolas, Bengtson, C. Peter, Heuer, Alina, Schroers, Julian, Faymonville, Anton J., Langeroudi, Atefeh Pourkhalili, Drewa, Nina, Keifert, Elijah, Wagner, Julia, Soyka, Stella J., Schubert, Marc C., Sivapalan, Nirosan, Pramatarov, Rangel L., Buchert, Verena, Wageringel, Tim, Grabis, Elena, Wißmann, Niklas, Alhalabi, Obada T., Botz, Michael, Bojcevski, Jovana, Campos, Joaquín, Boztepe, Berin, Scheck, Jonas G., Conic, Sascha Henry, Puschhof, Maria C., Villa, Giulia, Drexler, Richard, Zghaibeh, Yahya, Hausmann, Fabian, Hänzelmann, Sonja, Karreman, Matthia A., Kurz, Felix T., Schröter, Manuel, Thier, Marc, Suwala, Abigail K., Forsberg-Nilsson, Karin, Acuna, Claudio, Saez-Rodriguez, Julio, Abdollahi, Amir, Sahm, Felix, Breckwoldt, Michael O., Suchorska, Bogdana, Ricklefs, Franz L., Heiland, Dieter Henrik, and Venkataramani, Varun

Published
2025
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11. 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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12. Auswahl der Regionen

Author

König, Jonas, Willwacher, Hanna, Ziemer, Torge, Feller, Zarina, Piesker, Axel, Delargy, Colin, Ziekow, Jan, Suwala, Lech, Albers, Hans-Hermann, Merkel, Janet, Porth, Jan, König, Jonas, Willwacher, Hanna, Ziemer, Torge, Feller, Zarina, Piesker, Axel, Delargy, Colin, Ziekow, Jan, Suwala, Lech, Albers, Hans-Hermann, Merkel, Janet, and Porth, Jan

Published
2023
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13. Fokus gleichwertige Lebensverhältnisse und Passgenauigkeit

Author

König, Jonas, Willwacher, Hanna, Ziemer, Torge, Feller, Zarina, Piesker, Axel, Delargy, Colin, Ziekow, Jan, Suwala, Lech, Albers, Hans-Hermann, Merkel, Janet, Porth, Jan, König, Jonas, Willwacher, Hanna, Ziemer, Torge, Feller, Zarina, Piesker, Axel, Delargy, Colin, Ziekow, Jan, Suwala, Lech, Albers, Hans-Hermann, Merkel, Janet, and Porth, Jan

Published
2023
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14. Methodische Vorgehensweise

Author

König, Jonas, Willwacher, Hanna, Ziemer, Torge, Feller, Zarina, Piesker, Axel, Delargy, Colin, Ziekow, Jan, Suwala, Lech, Albers, Hans-Hermann, Merkel, Janet, Porth, Jan, König, Jonas, Willwacher, Hanna, Ziemer, Torge, Feller, Zarina, Piesker, Axel, Delargy, Colin, Ziekow, Jan, Suwala, Lech, Albers, Hans-Hermann, Merkel, Janet, and Porth, Jan

Published
2023
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15. Handlungsempfehlungen

Author

König, Jonas, Willwacher, Hanna, Ziemer, Torge, Feller, Zarina, Piesker, Axel, Delargy, Colin, Ziekow, Jan, Suwala, Lech, Albers, Hans-Hermann, Merkel, Janet, Porth, Jan, König, Jonas, Willwacher, Hanna, Ziemer, Torge, Feller, Zarina, Piesker, Axel, Delargy, Colin, Ziekow, Jan, Suwala, Lech, Albers, Hans-Hermann, Merkel, Janet, and Porth, Jan

Published
2023
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16. Zentrale Untersuchungsergebnisse

Author

König, Jonas, Willwacher, Hanna, Ziemer, Torge, Feller, Zarina, Piesker, Axel, Delargy, Colin, Ziekow, Jan, Suwala, Lech, Albers, Hans-Hermann, Merkel, Janet, Porth, Jan, König, Jonas, Willwacher, Hanna, Ziemer, Torge, Feller, Zarina, Piesker, Axel, Delargy, Colin, Ziekow, Jan, Suwala, Lech, Albers, Hans-Hermann, Merkel, Janet, and Porth, Jan

Published
2023
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17. A H3K27M-targeted vaccine in adults with diffuse midline glioma

Author

Grassl, Niklas, Poschke, Isabel, Lindner, Katharina, Bunse, Lukas, Mildenberger, Iris, Boschert, Tamara, Jähne, Kristine, Green, Edward W., Hülsmeyer, Ingrid, Jünger, Simone, Kessler, Tobias, Suwala, Abigail K., Eisele, Philipp, Breckwoldt, Michael O., Vajkoczy, Peter, Grauer, Oliver M., Herrlinger, Ulrich, Tonn, Joerg-Christian, Denk, Monika, Sahm, Felix, Bendszus, Martin, von Deimling, Andreas, Winkler, Frank, Wick, Wolfgang, Platten, Michael, and Sahm, Katharina

Published
2023
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20. 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

21. Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer

Author

Barger, Carter J, Suwala, Abigail K, Soczek, Katarzyna M, Wang, Albert S, Kim, Min Y, Hong, Chibo, Doudna, Jennifer A, Chang, Susan M, Phillips, Joanna J, Solomon, David A, and Costello, Joseph F

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Genetics, Brain Disorders, 2.1 Biological and endogenous factors, Glioblastoma, Humans, Mutation, Promoter Regions, Genetic, Telomerase
Abstract

Mutations in the TERT promoter represent the genetic underpinnings of tumor cell immortality. Beyond the two most common point mutations, which selectively recruit the ETS factor GABP to activate TERT, the significance of other variants is unknown. In seven cancer types, we identify duplications of wildtype sequence within the core promoter region of TERT that have strikingly similar features including an ETS motif, the duplication length and insertion site. The duplications recruit a GABP tetramer by virtue of the native ETS motif and its precisely spaced duplicated counterpart, activate the promoter and are clonal in a TERT expressing multifocal glioblastoma. We conclude that recurrent TERT promoter duplications are functionally and mechanistically equivalent to the hotspot mutations that confer tumor cell immortality. The shared mechanism of these divergent somatic genetic alterations suggests a strong selective pressure for recruitment of the GABP tetramer to activate TERT.

Published
2022

22. Place-Based Climate-Proofing of Commercial and Industrial Areas: Inventory and Guidelines From a Regional Planning Perspective

Author

Cordula Schwappach, Elke Beyer, and Lech Suwala

Subjects
backcasting analysis, berlin, brandenburg, climate adaptation, climate-proofing, commercial areas, germany, industrial areas, place-based, regional planning, City planning, HT165.5-169.9
Abstract

In spite of all efforts to reduce greenhouse gases, climate change has become a new reality that requires regional planning to provide effective solutions. This article focuses on commercial and industrial areas (Gewerbegebiete), which are important but often overlooked spaces, by means of examples in the Berlin-Brandenburg region. The article investigates whether and how regional planning can help these areas adapt to climate change. Three commercial and industrial areas in different spatial settings are examined, using an inventory of place-based measures, general standards, and regional networking of planning actors. This inventory is based on a backcasting analysis that compares normative future images of climate-adapted commercial and industrial areas with their current local situation. Spatially differentiated guidelines for the adaptation of commercial and industrial areas are then developed from a regional planning perspective by “climate-proofing” regional plans. These guidelines provide both place-based and general solutions for integrating and governing climate adaptation measures and standards into existing frameworks using a hands-on regional planning approach.

Published
2023
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23. Heterogeneity of DNA methylation profiles and copy number alterations in 10782 adult-type glioblastomas, IDH-wildtype

Author

David E. Reuss, Daniel Schrimpf, Asan Cherkezov, Abigail K. Suwala, Tereza Lausová, Matija Snuderl, David Capper, Martin Sill, David T. W. Jones, Stefan M. Pfister, Felix Sahm, and Andreas von Deimling

Subjects
Glioblastoma, Copy Number Variations, CNV, Methylation, Classification, 7/10 signature, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

The morphological patterns leading to the diagnosis of glioblastoma may also commonly be observed in several other distinct tumor entities, which can result in a mixed bag of tumors subsumed under this diagnosis. The 2021 WHO Classification of CNS Tumors has separated several of these entities from the diagnosis of glioblastoma, IDH-wildtype. This study determines the DNA methylation classes most likely receiving the diagnosis glioblastoma, IDH wildtype according to the definition by the WHO 2021 Classification and provides comparative copy number analyses. We identified 10782 methylome datasets uploaded to the web page www.molecularneuropathology.org with a calibrated score of ≥0.9 by the Heidelberg Brain Tumor Classifier version v12.8. These methylation classes were characterized by the diagnosis glioblastoma being the most frequent classification encountered in each of the classes according to the WHO 2021 definition. Further, methylation classes selected for this study predominantly contained adult patients. Unsupervised clustering confirmed the presence of nine methylation classes containing tumors most likely receiving the diagnosis glioblastoma, IDH-wildtype according to the WHO 2021 definition. Copy number analysis and a focus on genes with typical numerical alterations in glioblastoma revealed clear differences between the nine methylation classes. Although great progress in diagnostic precision has been achieved over the last decade, our data clearly demonstrate that glioblastoma, IDH-wildtype still is a heterogeneous group in need of further stratification.

Published
2024
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24. IDH-mutant astrocytomas with primitive neuronal component have a distinct methylation profile and a higher risk of leptomeningeal spread

Author

Hinz, Felix, Friedel, Dennis, Korshunov, Andrey, Ippen, Franziska M., Bogumil, Henri, Banan, Rouzbeh, Brandner, Sebastian, Hasselblatt, Martin, Boldt, Henning B., Dirse, Vaidas, Dohmen, Hildegard, Aronica, Eleonora, Brodhun, Michael, Broekman, Marike L. D., Capper, David, Cherkezov, Asan, Deng, Maximilian Y., van Dis, Vera, Felsberg, Jörg, Frank, Stephan, French, Pim J., Gerlach, Rüdiger, Göbel, Kirsten, Goold, Eric, Hench, Jürgen, Kantelhardt, Sven, Kohlhof-Meinecke, Patricia, Krieg, Sandro, Mawrin, Christian, Morrison, Gillian, Mühlebner, Angelika, Ozduman, Koray, Pfister, Stefan M., Poliani, Pietro Luigi, Prinz, Marco, Reifenberger, Guido, Riemenschneider, Markus J., Sankowski, Roman, Schrimpf, Daniel, Sill, Martin, Snuderl, Matija, Verdijk, Robert M., Voisin, Mathew R., Wesseling, Pieter, Wick, Wolfgang, Reuss, David E., von Deimling, Andreas, Sahm, Felix, Maas, Sybren L. N., and Suwala, Abigail K.

Published
2025
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27. Efficacy and safety of aldosterone synthase inhibition with and without empagliflozin for chronic kidney disease: a randomised, controlled, phase 2 trial

Author

Tuttle, Katherine R, Hauske, Sibylle J, Canziani, Maria Eugenia, Caramori, Maria Luiza, Cherney, David, Cronin, Lisa, Heerspink, Hiddo J L, Hugo, Christian, Nangaku, Masaomi, Rotter, Ricardo Correa, Silva, Arnold, Shah, Shimoli V, Sun, Zhichao, Urbach, Dorothea, de Zeeuw, Dick, Rossing, Peter, SZETO, Cheuk Chun, Echeverri, Diego, Martin, Edouard, Yee, Ming Li, Wah, William, Wang, Ray, Chacko, Bobby, Swaminathan, Shriram, MacIsaac, Richard, Hashimura, Hikaru, Ward, Glenn, De Vusser, Katrien, Claes, Kathleen, Kuypers, Dirk, Meijers, Björn, Van Craenenbroeck, Amaryllis, Hilbrands, Robert, Debroye, Corinne, Wissing, Karl Martin, Jadoul, Michel, Demoulin, Nathalie, Treille De Grandsaigne, Serge, Beklevic, Ishak, Marcoux, Diane, Liénart, Fabienne, Daper, Claude, De Brouckere, Véronique, Heureux, Mercédès, Felicio, Joao, Felicio, Karem Mileo, Leite, Daniella, Melo, Franciane, Queiroz, Natercia, Souza, Ana Carolina, Vieira, Jocyelle, Franco, Roberto, Mendes, Adriana, Picolli, Giovana, Canani, Luis Henrique, Sartori, Carla, Valenti, Adriana, Eliaschewitz, Freddy, Bona, Renata, Franco, Denise, Ludovico Costa de Castro, Denise, Magalhaes, Vanessa, Oliveira, Marcelo, Sampaio, Célia Regina, Visconti, Guilherme, Halpern, Bruno, Nihei, Camila, Pessoa, Bruna, Seraphim, Carlos, Santos, Daniel, Brito, Claudia, Douverny, Joao, Colella, Marina, Gazeta, Cristina, Vercia, Monique, Watanabe, Renato, Temelkova, Theodora, Kjurkchiev, Dimo, Statkova, Silviya, Popov, Iliya, Radeva, Radosveta, Arabadzhiev, Lachezar, Binova, Mariya, Bosilkov, Aleksandar, Koleva-Stoicheva, Neli, Ivanov, Ivaylo, Ivanova, Zornitsa, Kotseva, Viktoria, Spasov, Petar, Tsvetkov, Ivaylo, Jolly, Shivinder, Bailey, Gordon, Ye, Zhiming, Niu, Jianying, Li, Hongmei, Wu, Qing, Liao, Bing, Hao, Chuanming, Lai, Lingyun, Xu, Yunyu, Zhang, Min, Li, Yiwen, Liu, Bo, Shao, Lina, Chen, Wei, Wu, Haishan, Pirchala, Marian, Skarpova, Iva, Hraskova, Marketa, Soukupova, Simoneta, Veberova, Lucie, Drasnar, Tomas, Falc, Matej, Racz, Blazej, Votocek, Stepan, Weissova, Danica, Syc-Krivanova, Lenka, Slezak, Dagmar, Kantola, Ilkka, Nieminen, Sakari, Anttonen, Milla, Taurio, Jyrki, Lahtela, Jorma, Tsimihodimos, Vasileios, Balafa, Olga, Dounousi, Evangelia, Sakkou, Sissy, Tentolouris, Nikolaos, Siafarikas, Christos, Siami, Evangelia, Doupis, Ioannis, Angelopoulos, Theodoros, Georgoulias, Christodoulos, Pall, Denes, Esze, Regina, Kobling, Tamas, Varadi, Zita, Zsiros, Noemi, Vass, Viktor, Balo, Timea, Csanyi, Erika, Ory, Ivan, Pall, Istvan, Patai, Valentina, Zeak, Zsuzsanna, Takacs, Istvan, Petho, Akos, Szili, Balazs, Koranyi, Laszlo, Bezzegh, Katalin, Pauer, Jozsef, Peterfai, Eva, Konyves, Laszlo, Szoke, Brigitta, Hajdu, Csaba, Kalman, Krisztina, Yadav, Raj, Saxena, Navneet, Bhattacharya, Meenakshi, Sharma, Bal, Thomas, Nihal, K, Felix Jebasingh, Kapoor, Nitin, Kurian, Mathews E., Paul, Jinson, Ramesh, Priyadharshini, Varghese, Sheeba, Shibusawa, Nobuyuki, Nishi, Hiroshi, Noritake, Nobuyasu, Oda, Takashi, Okamoto, Hideki, Kasuga, Hirotake, Hori, Hiroshi, Ito, Yukiko, Mizukoshi, Toshihiro, Ishii, Hideto, Han, Seung Hyeok, Kim, Hyung Woo, Oh, Kook-Hwan, Han, Seung Seok, Han, Sang Youb, Cha, Dae Ryong, Cha, Jin Joo, Kwon, Soon-Kil, Cho, Hyunjeong, Kim, Hye-Young, Kim, Sun Moon, Lee, Jung Pyo, Lee, Jeonghwan, Lee, Li Yuan, Chang, Meng Lee, Laang, Shian Tuck, Tan, Zhao Zhi, Ahmad Rosdi, Hajar, Mohammad Ismail, Siti Hafizah, Simatherai, Devamalar, Tay, Ju Fan, Wong, Eddie, Fook Sem, Yakob, Suryati, Abdul Sukur, Noorhafini, Anuar, Amalina, Md. Rasid, Syaliza, Mushaddik, Irma Liyana, Mustafar, Ruslinda, Abu Shamsi, Muhammad Yusuf, Fong, Voon Ken, Kamaruzaman, Lydia, Mohd, Rozita, Wan Daud, Wan Rohaslizan, Wan Hassan, Wan Hasnul Halimi, Ab Hamid, Suhaidarwani, Abdullah, Muhammad Nabil, Yusoff, Mohd Yusran, Ramanathan, G R Letchuman, Lee, Kim Yen, Wan Ismail, Wan Fadhilah, Morales Villegas, Enrique, Ramirez Baez, Rubria, Vital Lopez, Jorge, Arias Delgadillo, Cristhian, Herrera Marmolejo, Marisol, Parra Perez, Rosa, Alpizar Salazar, Melchor, Flores Montealegre, Ana, Galvan Magaña, Jose, Gutierrez Tlapale, Minerva, Reyes Munguia, Daniela, Witczak, Bartlomiej, Gøransson, Lasse, Strand Thorsen, Inga, Caringal, Clodoaido, Villardo, Mario, Toledo, Ronaldo, Dijamco, Emerlinda Fausto, De Asis, Norman Cornelio, Kuizon, Angelica, Catindig, Elizabeth Ann, Perez, Ronald, Aquitania, Grace, Pableo, Jimrie David, Sanchez, Jay Karlou, Czernecka, Ewa, Cegiel, Aleksandra, Knychas, Dorota, Ochnio, Malgorzata, Kuligowska-Jakubowska, Monika, Cesarz, Marek, Kowalewska-Celejewska, Milena, Masajtis-Zagajewska, Anna, Jankowski, Lukasz, Ojrzanowski, Marcin, Olszewska-Jander, Magdalena, Skokowska, Ewa, Giermakowska-Samek, Malgorzata, Luchowska, Elzbieta, Patkowska, Renata, Sekulska, Marzenna, Marczuk-Krynicka, Dorota, Marciniak, Andrzej, Barwijuk, Michal, Myslicki, Marcin, Siek, Michal, Wronska, Danuta, Tomsia-Goncerz, Jadwiga, Wronski, Krzysztof, Junik, Roman, Dzialak, Szymon, Kurlapska, Ewelina, Malecha, Wieslaw, Suwala, Szymon, Branco, Patrícia, Birne, Rita, Raposo, João, Ferreira, Marta, Alexandrino, Henrique, Alves, Helena, Correia, Sara, Oliveira, Maria João, Ramalho, Diogo, Tavares, Patricia, Coetzee, Kathleen, Blignaut, Sue, Viljoen, Winifred, Potgieter, Elsje, Malherbe, Elmien, Ortiz Arduán, Alberto, Goma Garcés, Elena, Pérez, María, Santamaría, Rafael, López López, Isabel, Pendón de Mier, Victoria, Rodelo Haad, Cristian, Marques, María, Domènech, Esther, Portoles, Josep Maria, Soler, María José, Agraz, Irene, Azancot, María Antonieta, Bermejo, Sheila, Bolufer, Mónica, López, Marina, Ramos, Natalia, Toapanta, Néstor, Cigarrán Guldris, Secundino, Primo, Juan Carlos, Pérez, Luis Enrique, Rebollido Fernández, María, Holmer, Helene, Bruchfeld, Annette, Rofors, Justus, Tengmark, Bengt-Olov, Wuerzner, Gregoire, Leanizbarrutia, Garazi, Ozturk, Savas, Guler, Nurana, Safak, Seda, Lee, Keung, Campbell, Stephen, Siddiqui, Imran, Abbasi, Nadia, Tahir, Faiza, Azizad, Masoud, Jackson, Timothy, Everhart, Brian, Oliver, Michael, Rust, William, Sniezek, Matthew, Arif, Ahmed, Syed, Mohammed, Bhasin, Nitin, Bien, Michael, Gallego, Claudio, Jamal, Aamir, Moghadam, Mojtaba, Rizvi, Abid, Rizvi, Amna, Rizvi, Syed, Wong, Christopher, Lucas, Kathryn, Buery, Andrea, Chang, Ku-Lang, Presswood, Claire, Smith, Justin, Doshi, Ankur, Parikh, Manish, Wallace, Jeannine, Krishna, Arvind, Daugherty, Heidi, Fearday, Aaron, Keller, Christopher, Meng, Jerry, Nielsen, Alexandra, Rovner, Sergio, Almeida, Javier, Marranzini, Benito, Selby, Lisa, Yablon, Zachary, Jean-Louis, Daphne, Kotzker, Wayne, Perez, Chabely, Richards, Marc, Rosario, Reinaldo, Marcus, Roy, Okechukwu, Chike, Ross, Dennis, Gromala, Rachel, Reed, Matthew, Weber, Lisa, Nazeer, Imran, Kumar, Prashant, Mir, Muhammad, Shea, Heidi, Hart, Amanda, Wiebel, Jaime, Kooienga, Laura, Newsome, Britt, Suyumova, Irina, Alvarez, German, Bireddy, Venkata, Lansang, Maria, Mandry, Jose, Freire, Maria, Herrera Albornoz, Oscarina, Desai, Anant, Gandhi, Dayan, Rajan, Sibu, Raymond, Louis, Posada, Jorge, Garcia-Mayol, Luis, Gutierrez-Alsina, Rodolfo, Fernandez, Juan, Bruce, Kendaling, Cuellar, Juan, Ranz y Alvarez, Maria, Bartolacci, Ines, Pautasso, Mauro, Stoppa, Daniela, Riella, Miguel, Barbosa, Maria, Harcsa, Eleonora, Gulati, Yuvraj, Savalia, Denish, Khetan, Prakash, Sinha, Dhananjay, R, Niranjan, K, Srinivas, Pazos, Fabiola, Gacutan-Liwag, Aretha, Duszynska, Malgorzata, Antkowiak-Piatyszek, Karolina, Konieczny, Grzegorz, Sidorowicz-Bialynicka, Anna, Ciesiolkiewicz-Wojcik, Agnieszka, Dwojak, Marek, Szymkowiak, Katarzyna, Gorczyca-Siudak, Daria, Janik-Palazzolo, Marzena, Siudak, Lukasz, Opiela, Jaroslaw, Iwanow, Dariusz, Solkiewicz, Monika, Sipinska-Surzynska, Malgorzata, Olszanecka - Glinianowicz, Magdalena, Rozmilowska, Izabela, Trokis, Julian, Prozesky, Hans, Burgess, Lesley, Cyster, Henry, Jordaan, Jurie, Mohamed, Hawa, Naude, Christina, Sitsila, Thembie, Mehta, Arvind, Mocherla, Bharat, Lee, Sungchun, Boren, Kenneth, Rudolph, Lance, Benjamin, Sabrina, Sugimoto, Danny, Hammoud, Jamal, Bakleh, Muhammad, Hashish, Yaseen, Da Costa, Jonathan, Gold, Marina, Majul, Claudio, Buscema, Juan, Gatto, Maria, Lombardi, Facundo, Paez, Olga, Puleio, Pablo, Alvarisqueta, Andrés, Pajon, Vanessa, Suarez, Gabriel, Hernandez Gauna, Adrian, Pereyra, Alejandro, Reig, Moira, Gelersztein, Elizabeth, Campestri, Gina, Gonzalez Santos, Maria, Sambresqui, Julieta, Catalano, Gustavo, Igarzabal, Cecilia, Vallejos, Augusto, Escobari, Claudio, Marchetto, Rocio, Chahin, Mariano, Aguilera, Andrea, Comes, Ana, Rodriguez Segade, Silvia, Baccaro, Claudia, Larrieu Lacoste, María Verónica, Saurral, Ruben, Cristino, Alberto, Dran, Dario, Koretzky, Martin, Ponti, Juan, Porto, Alejandro, Tenaglia, Yasmin, Maldonado, Natacha, Bertollo, Natalia, Van Perdeck, Verónica, Lopau, Kai, Wanner, Christoph, Berfelo, Florieke, Contzen, Christel, Arbi, Abdulwahab, Lee-Barkey, Young Hee, Maciejewska, Aleksandra, Arelin, Katrin, Haller, Hermann, Kaufeld, Jessica, Schmidt-Ott, Kai, Heinrichs, Sven, Krüger, Thilo, Gebauer, Chris, Paliege, Alexander, Henkel, Elena, Axthelm, Christoph, Derwahl, Karl-Michael, Trevisan, Roberto, Bellante, Rosalia, Borrella, Nicolò, Corsi, Anna, Gesualdo, Loreto, Ardillo, Teodora, Ficarella, Maria, Fikry, Sameh, Mazza, Giuseppe, Poirier, Lysane, Bajaj, Harpreet, Hatziagelaki, Erifili, Katopodis, Sokratis, Katsoudas, Spiros, Yamaura, Shuichi, Shikano, Tsutomu, Tosaki, Takahiro, Miho, Otoya, Tachibana, Naoki, Yumita, Wataru, Kado, Hiroshi, Villarreal Martinez, Jesus, Soto Miranda, Ernesto, Gonzalez Rodriguez, David, Panelo, Araceli, Santos, Telma, Martins, Ana, Mateus, Catarina, Teixeira e Costa, Fernando, Barreto, Sara, Silva Costa, Joana, Ferrer, Francisco, Silva, Joana, Awad, Ahmed, Khaleel, Shatha, Lustig, Ryan, Maharjan, Gajendra, Moya, Jaynier, Johnsingh, Amit, Acosta, Idalia, Newman, George, Buckle, Anita, and Hendon, Kendra

Published
2024
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28. 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

29. Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology

Author

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
2023
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30. Overexpression of Cystine/Glutamate Antiporter xCT Correlates with Nutrient Flexibility and ZEB1 Expression in Highly Clonogenic Glioblastoma Stem-like Cells (GSCs)

Author

Koch, Katharina, Hartmann, Rudolf, Suwala, Abigail Kora, Rios, Dayana Herrera, Kamp, Marcel Alexander, Sabel, Michael, Steiger, Hans-Jakob, Willbold, Dieter, Sharma, Amit, Kahlert, Ulf Dietrich, and Maciaczyk, Jarek

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Brain Disorders, Rare Diseases, Brain Cancer, Cancer, Stem Cell Research, Stem Cell Research - Nonembryonic - Human, Biotechnology, glioblastoma, cancer stem cells, NMR spectroscopy, glutamine, metabolism, xCT, ZEB1, oncometabolites, Oncology and carcinogenesis
Abstract

Cancer stem-like cells mediate tumor initiation, progression, and therapy resistance; however, their identification and selective eradication remain challenging. Herein, we analyze the metabolic dependencies of glioblastoma stem-like cells (GSCs) with high-resolution proton nuclear magnetic resonance (1H-NMR) spectroscopy. We stratify our in vitro GSC models into two subtypes primarily based on their relative amount of glutamine in relationship to glutamate (Gln/Glu). Gln/GluHigh GSCs were found to be resistant to glutamine deprivation, whereas Gln/GluLow GSCs respond with significantly decreased in vitro clonogenicity and impaired cell growth. The starvation resistance appeared to be mediated by an increased expression of the glutamate/cystine antiporter SLC7A11/xCT and efficient cellular clearance of reactive oxygen species (ROS). Moreover, we were able to directly correlate xCT-dependent starvation resistance and high Gln/Glu ratios with in vitro clonogenicity, since targeted differentiation of GSCs with bone morphogenic protein 4 (BMP4) impaired xCT expression, decreased the Gln/Glu ratio, and restored the sensitivity to glutamine starvation. Moreover, significantly reduced levels of the oncometabolites lactate (Lac), phosphocholine (PC), total choline (tCho), myo-inositol (Myo-I), and glycine (Gly) were observed in differentiated GSCs. Furthermore, we found a strong association between high Gln/Glu ratios and increased expression of Zinc finger E-box-binding homeobox 1 (ZEB1) and xCT in primary GBM tumor tissues. Our analyses suggest that the inhibition of xCT represents a potential therapeutic target in glioblastoma; thus, we could further extend its importance in GSC biology and stress responses. We also propose that monitoring of the intracellular Gln/Glu ratio can be used to predict nutrient stress resistance.

Published
2021

31. Ausgangslage und Zielsetzung

Author

König, Jonas, Willwacher, Hanna, Ziemer, Torge, Feller, Zarina, Piesker, Axel, Delargy, Colin, Ziekow, Jan, Suwala, Lech, Albers, Hans-Hermann, Merkel, Janet, Porth, Jan, König, Jonas, Willwacher, Hanna, Ziemer, Torge, Feller, Zarina, Piesker, Axel, Delargy, Colin, Ziekow, Jan, Suwala, Lech, Albers, Hans-Hermann, Merkel, Janet, and Porth, Jan

Published
2023
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32. Author Correction: Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology

Author

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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33. Gleichwertige Lebensverhältnisse

Author

König, Jonas, primary, Willwacher, Hanna, additional, Ziemer, Torge, additional, Feller, Zarina, additional, Piesker, Axel, additional, Delargy, Colin, additional, Ziekow, Jan, additional, Suwala, Lech, additional, Albers, Hans-Hermann, additional, Merkel, Janet, additional, and Porth, Jan, additional

Published
2023
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34. Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer

Author

Carter J. Barger, Abigail K. Suwala, Katarzyna M. Soczek, Albert S. Wang, Min Y. Kim, Chibo Hong, Jennifer A. Doudna, Susan M. Chang, Joanna J. Phillips, David A. Solomon, and Joseph F. Costello

Subjects
Science
Abstract

TERT promoter mutations are the most common noncoding alterations in cancers, although some remain to be characterised. Here, the authors identify TERT promoter duplications across seven cancer types that are functionally equivalent to well-known hotspot TERT mutations and are clonal in a multifocal glioblastoma patient.

Published
2022
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35. Allergic march: a comprehensive approach to diagnosing, treating and preventing atopic diseases

Author

Zuzanna Suwala, Urszula Marchewka, Borys Bieńkowski, Krzysztof Feja, Ewa Łuczak, Krzysztof Jachowicz, Piotr Petryla, Kamil Ostafin, Natalia Rektor, and Mikołaj Minkner

Subjects
allergic march, sublingual immunotherapy, atopic dermatitis, asthma, Education, Sports, GV557-1198.995, Medicine
Abstract

The article discusses the phenomenon of allergic march, which is a progressive process of atopic disease development in allergic patients. The inflammatory process changes localization, causing various symptoms such as atopic dermatitis, food allergy, asthma, allergic rhinitis and eosinophilic esophagitis. Allergic march has a major impact on the development of asthma and allergic rhinitis. The diversity of allergic march trajectories is due to the interaction of genetic, environmental and psychosocial factors. Understanding these mechanisms is crucial to prevent effectively the progression of allergic diseases. The article also discusses the advantages of sublingual immunotherapy (SILT) in the treatment of allergic diseases. SILT shows safety profile and may be more acceptable treatment option for the patients comparing to the traditional subcutaneous immunotherapy (SCIT). There are evidence of the beneficial effects of SILT in reducing allergy symptoms and improving quality of life in allergic patients.

Published
2023
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36. TERTP Mutant Meningiomas in the Absence of Concurrent Aggressive Features Exhibit Better Outcomes than TERTP Wild-Type Who Grade 3 Meningiomas.

Author

Groff, Karenna J., Patel, Ruchit V., Chen, William C., Youngblood, Mark W., Ghosh, Hia S., Kresbach, Catena, Mount, Christopher, Nitturi, Vijay, Rosenblum, Marc, Save, Akshay, Suwala, Abigail K., Bale, Tejus A., Cai, Chunyu, Patel, Akash J., Richardson, Timothy E., Santagata, Sandro, Sahm, Felix, Schüller, Ulrich, Sen, Chandra, and Magill, Stephen T.

Subjects
TUMOR classification, TUMOR grading, OVERALL survival, DNA methylation, MULTIVARIATE analysis
Abstract

The article explores the impact of TERT-promoter (TERTp) mutation on meningiomas, indicating that TERTp-mutant meningiomas are associated with aggressive characteristics and worse outcomes. However, TERTp-mutant meningiomas without additional aggressive molecular markers exhibit a more indolent behavior. The study suggests that TERTp mutation in meningiomas is context-dependent and highlights the importance of considering other molecular markers in assessing prognosis. [Extracted from the article]

Published
2025
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37. Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen.

Author

Chih, Yu-Chan, Dietsch, Amelie C., Koopmann, Philipp, Ma, Xiujian, Agardy, Dennis A., Zhao, Binghao, De Roia, Alice, Kourtesakis, Alexandros, Kilian, Michael, Krämer, Christopher, Suwala, Abigail K., Stenzinger, Miriam, Boenig, Halvard, Blum, Agnieszka, Pienkowski, Victor Murcia, Aman, Kuralay, Becker, Jonas P., Feldmann, Henrike, Bunse, Theresa, and Harbottle, Richard

Subjects
MEDICAL sciences, BRAIN tumors, T cells, CANCER cells, CELL receptors
Abstract

T cell receptor-engineered T cells (TCR-T) could be advantageous in glioblastoma by allowing safe and ubiquitous targeting of the glioblastoma-derived peptidome. Protein tyrosine phosphatase receptor type Z1 (PTPRZ1), is a clinically targetable glioblastoma antigen associated with glioblastoma cell stemness. Here, we identify a therapeutic HLA-A*02-restricted PTPRZ1-reactive TCR retrieved from a vaccinated glioblastoma patient. Single-cell sequencing of primary brain tumors shows PTPRZ1 overexpression in malignant cells, especially in glioblastoma stem cells (GSCs) and astrocyte-like cells. The validated vaccine-induced TCR recognizes the endogenously processed antigen without off-target cross-reactivity. PTPRZ1-specific TCR-T (PTPRZ1-TCR-T) kill target cells antigen-specifically, and in murine experimental brain tumors, their combined intravenous and intracerebroventricular administration is efficacious. PTPRZ1-TCR-T maintain stem cell memory phenotype in vitro and in vivo and lyse all examined HLA-A*02+ primary glioblastoma cell lines with a preference for GSCs and astrocyte-like cells. In summary, we demonstrate the proof of principle to employ TCR-T to treat glioblastoma. Vaccination in glioblastomas does lead to the emergence of tumour-antigen-specific T cells but T cell dysfunction, poor tumour infiltration and persistence hinder efficient tumour killing. Here authors identify a T cell receptor in a vaccinated glioblastoma patient that specifically recognizes the glioblastoma stem cell antigen PTPRZ1 and utilise it in T cell receptor-engineered T (TCR-T) cell therapy, resulting in efficient tumour cell killing in vitro and in a mouse model. [ABSTRACT FROM AUTHOR]

Published
2025
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39. 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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44. N2M2/NOA-20: Phase I/IIa umbrella trial of molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation.

Author

Wick, Wolfgang, primary, Lanz, Lisa-Marie, additional, Wick, Antje, additional, Harting, Inga, additional, Dettmer, Susan, additional, Suwala, Abigail k, additional, Ketter, Ralf, additional, Tabatabai, Ghazaleh, additional, Seliger-Behme, Corinna, additional, Glas, Martin, additional, Burger, Michael C, additional, Timmer, Marco, additional, Ringel, Florian A, additional, Mildenberger, Iris, additional, Schulz-Schaeffer, Walter J, additional, Renovanz, Mirjam, additional, Bendszus, Martin, additional, Sahm, Felix, additional, Platten, Michael, additional, and Kessler, Tobias, additional

Published
2024
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45. Vascular density and macular sensitivity in eyes after scleral buckling surgery for macula-on rhegmatogenous retinal detachment

Author

Przemyslaw Zabel, Katarzyna Zabel, Karolina Kazmierczak, Martyna Stankiewicz, Damian Jaworski, Karolina Suwala, Katarzyna Buszko, Joanna Stafiej, Grazyna Malukiewicz, and Jakub J. Kaluzny

Subjects
Medicine, Science
Abstract

Purpose To investigate the structure and function of the retina after scleral buckling (SB) surgery due to macula-on rhegmatogenous retinal detachment (RRD). Methods Twenty eyes with repaired macula-on RRD and 20 fellow eyes were included. All patients within 6–12 months of the procedure, were examined to evaluate retinal structure using spectral domain optical coherence tomography (SD-OCT) and vessel density (VD) by OCT angiography (OCTA). Best corrected visual acuity (BCVA) and microperimetry (MP) tests were used to assess retinal function. Results Analysis of the microvascular network using OCTA between the operated and healthy fellow eyes showed a significant reduction on VD in superficial vascular plexus (SVP), deep vascular plexus (DVP) and radial peripapillary capillaries (RPC) (p< 0.001, p = 0.019 and p = 0.008, respectively). Comparison of retinal structure in SD-OCT showed no significant differences on thickness in ganglion cell complex (GCC) and peripaillary retinal nerve fiber layer (pRNFL) (p> 0.05) between examined eyes. Retinal function analysis by MP examination showed a decrease of retinal sensitivity (p = 0.0013) whereas postoperative BCVA showed no differences (p = 0.62) in the operated eyes. Significant Pearson’s correlations were observed between retinal sensitivity and VD in SVP, RPC (p< 0.05). Conclusion In the eyes after SB surgery due to macula-on RRD, changes in retinal sensitivity were accompanied by impairment of the microvascular network assessed by the OCTA.

Published
2023

47. Comparison of Vessel Density and Retinal Sensitivity After Scleral Buckling and Phacovitrectomy in the Management of Macula-on Primary Rhegmatogenous Retinal Detachment.

Author

Zabel, Przemyslaw, Charytoniuk, Tomasz, Zabel, Katarzyna, Kazmierczak, Karolina, Suwala, Karolina, Buszko, Katarzyna, and Kaluzny, Jakub J

Subjects
OPTICAL coherence tomography, RETINAL detachment, OPHTHALMIC surgery, VISUAL acuity, RETINAL blood vessels, RETINAL surgery
Abstract

Purpose: The choice of surgical method for rhegmatogenous retinal detachment (RRD) may have a significant impact on the retina. In this study, we aimed to compare retinal function and structure after scleral buckling (SB) and phacovitrectomy (phaco-PPV) for macula-on RRD. Patients and Methods: This cross-sectional study included patients who underwent anatomically successful repair of macula-on RRD managed with SB (n=35) and phaco-PPV (n=35) between 2019– 2023. All participants were examined within 6– 20 months of surgery to evaluate the retinal structure using spectral domain optical coherence tomography (SD-OCT) and vessel density (VD) by OCT angiography (OCTA). Best-corrected visual acuity (BCVA) and microperimetry (MP) tests were used to assess the retinal function. Results: Analysis of the microvascular network with OCTA between eyes after surgery and healthy eyes showed a decrease in VD. Significant changes in the superficial vascular plexus (SVP) and deep vascular plexus (DVP) were observed only in eyes after SB surgery (p < 0.001 and p=0.02, respectively). Analysis of retinal function assessed by MP showed a significant decrease (p< 0.05) in retinal sensitivity after phaco-PPV (24.81± 2.25 dB) and SB (24.18± 2.14 dB) operations compared to the healthy control group (25.97 ± 1.51 dB), whereas postoperative BCVA showed no differences (p> 0.05). Conclusion: Changes in retinal sensitivity were accompanied by impairment of the microvascular network in the eyes after SB and phaco-PPV surgeries due to macula-on RRD. Disorders were more pronounced in eyes following SB surgery, possibly secondary to mechanical stress. [ABSTRACT FROM AUTHOR]

Published
2024
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49. Molecular analysis of pediatric CNS-PNET revealed nosologic heterogeneity and potent diagnostic markers for CNS neuroblastoma with FOXR2-activation

Author

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

Subjects
CNS-PNET, Neuroblastoma, FOXR2-activation, SOX10, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly malignant neoplasms posing diagnostic challenge due to a lack of defining molecular markers. CNS neuroblastoma with forkhead box R2 (FOXR2) activation (CNS_NBL) emerged as a distinct pediatric brain tumor entity from a pool previously diagnosed as primitive neuroectodermal tumors of the central nervous system (CNS-PNETs). Current standard of identifying CNS_NBL relies on molecular analysis. We set out to establish immunohistochemical markers allowing safely distinguishing CNS_NBL from morphological mimics. To this aim we analyzed a series of 84 brain tumors institutionally diagnosed as CNS-PNET. As expected, epigenetic analysis revealed different methylation groups corresponding to the (1) CNS-NBL (24%), (2) glioblastoma IDH wild-type subclass H3.3 G34 (26%), (3) glioblastoma IDH wild-type subclass MYCN (21%) and (4) ependymoma with RELA_C11orf95 fusion (29%) entities. Transcriptome analysis of this series revealed a set of differentially expressed genes distinguishing CNS_NBL from its mimics. Based on RNA-sequencing data we established SOX10 and ANKRD55 expression as genes discriminating CNS_NBL from other tumors exhibiting CNS-PNET. Immunohistochemical detection of combined expression of SOX10 and ANKRD55 clearly identifies CNS_NBL discriminating them to other hemispheric CNS neoplasms harboring “PNET-like” microscopic appearance. Owing the rarity of CNS_NBL, a confirmation of the elaborated diagnostic IHC algorithm will be necessary in prospective patient series.

Published
2021
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50. Sarcoma classification by DNA methylation profiling

Author

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

Subjects
Science
Abstract

Sarcomas are morphologically heterogeneous tumours rendering their classification challenging. Here the authors developed a classifier using DNA methylation data from several soft tissue and bone sarcoma subtypes, which has the potential to improve classification for research and clinical purposes.

Published
2021
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