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201. Drug-perturbation-based stratification of blood cancer

Author

Dietrich, Sascha, Oles, Malgorzata, Lu, Junyan, Sellner, Leopold, Anders, Simon, Velten, Britta, Wu, Bian, Huellein, Jennifer, Liberio, Michelle da Silva, Walther, Tatjana, Wagner, Lena, Rabe, Sophie, Ghidelli-Disse, Sonja, Bantscheff, Marcus, Oles, Andrzej K., Slabicki, Mikolaj, Mock, Andreas, Oakes, Christopher C., Wang, Shihui, Oppermann, Sina, Lukas, Marina, Kim, Vladislav, Sill, Martin, Benner, Axel, Jauch, Anna, Sutton, Lesley Ann, Young, Emma, Rosenquist, Richard, Liu, Xiyang, Jethwa, Alexander, Lee, Kwang Seok, Lewis, Joe, Putzker, Kerstin, Lutz, Christoph, Rossi, Davide, Mokhir, Andriy, Oellerich, Thomas, Zirlik, Katja, Herling, Marco, Nguyen-Khac, Florence, Plass, Christoph, Andersson, Emma, Mustjoki, Satu, von Kalle, Christof, Ho, Anthony D., Hensel, Manfred, Duerig, Jan, Ringshausen, Ingo, Zapatka, Marc, Huber, Wolfgang, Zenz, Thorsten, Dietrich, Sascha, Oles, Malgorzata, Lu, Junyan, Sellner, Leopold, Anders, Simon, Velten, Britta, Wu, Bian, Huellein, Jennifer, Liberio, Michelle da Silva, Walther, Tatjana, Wagner, Lena, Rabe, Sophie, Ghidelli-Disse, Sonja, Bantscheff, Marcus, Oles, Andrzej K., Slabicki, Mikolaj, Mock, Andreas, Oakes, Christopher C., Wang, Shihui, Oppermann, Sina, Lukas, Marina, Kim, Vladislav, Sill, Martin, Benner, Axel, Jauch, Anna, Sutton, Lesley Ann, Young, Emma, Rosenquist, Richard, Liu, Xiyang, Jethwa, Alexander, Lee, Kwang Seok, Lewis, Joe, Putzker, Kerstin, Lutz, Christoph, Rossi, Davide, Mokhir, Andriy, Oellerich, Thomas, Zirlik, Katja, Herling, Marco, Nguyen-Khac, Florence, Plass, Christoph, Andersson, Emma, Mustjoki, Satu, von Kalle, Christof, Ho, Anthony D., Hensel, Manfred, Duerig, Jan, Ringshausen, Ingo, Zapatka, Marc, Huber, Wolfgang, and Zenz, Thorsten

Abstract

As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non-BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.

Published
2018

202. Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations

Author

Reinhardt, Annekathrin, Stichel, Damian, Schrimpf, Daniel, Sahm, Felix, Korshunov, Andrey, Reuss, David E., Koelsche, Christian, Huang, Kristin, Wefers, Annika K., Hovestadt, Volker, Sill, Martin, Gramatzki, Dorothee, Felsberg, Joerg, Reifenberger, Guido, Koch, Arend, Thomale, Ulrich-W., Becker, Albert, Hans, Volkmar H., Prinz, Marco, Staszewski, Ori, Acker, Till, Dohmen, Hildegard, Hartmann, Christian, Mueller, Wolf, Tuffaha, Muin S. A., Paulus, Werner, Hess, Katharina, Brokinkel, Benjamin, Schittenhelm, Jens, Monoranu, Camelia-Maria, Kessler, Almuth Friederike, Loehr, Mario, Buslei, Rolf, Deckert, Martina, Mawrin, Christian, Kohlhof, Patricia, Hewer, Ekkehard, Olar, Adriana, Rodriguez, Fausto J., Giannini, Caterina, NageswaraRao, Amulya A., Tabori, Uri, Nunes, Nuno Miguel, Weller, Michael, Pohl, Ute, Jaunmuktane, Zane, Brandner, Sebastian, Unterberg, Andreas, Haenggi, Daniel, Platten, Michael, Pfister, Stefan M., Wick, Wolfgang, Herold-Mende, Christel, Jones, David T. W., von Deimling, Andreas, Capper, David, Reinhardt, Annekathrin, Stichel, Damian, Schrimpf, Daniel, Sahm, Felix, Korshunov, Andrey, Reuss, David E., Koelsche, Christian, Huang, Kristin, Wefers, Annika K., Hovestadt, Volker, Sill, Martin, Gramatzki, Dorothee, Felsberg, Joerg, Reifenberger, Guido, Koch, Arend, Thomale, Ulrich-W., Becker, Albert, Hans, Volkmar H., Prinz, Marco, Staszewski, Ori, Acker, Till, Dohmen, Hildegard, Hartmann, Christian, Mueller, Wolf, Tuffaha, Muin S. A., Paulus, Werner, Hess, Katharina, Brokinkel, Benjamin, Schittenhelm, Jens, Monoranu, Camelia-Maria, Kessler, Almuth Friederike, Loehr, Mario, Buslei, Rolf, Deckert, Martina, Mawrin, Christian, Kohlhof, Patricia, Hewer, Ekkehard, Olar, Adriana, Rodriguez, Fausto J., Giannini, Caterina, NageswaraRao, Amulya A., Tabori, Uri, Nunes, Nuno Miguel, Weller, Michael, Pohl, Ute, Jaunmuktane, Zane, Brandner, Sebastian, Unterberg, Andreas, Haenggi, Daniel, Platten, Michael, Pfister, Stefan M., Wick, Wolfgang, Herold-Mende, Christel, Jones, David T. W., von Deimling, Andreas, and Capper, David

Abstract

Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical ou

Published
2018

203. Heterogeneity within the PF-EPN-B ependymoma subgroup.

Author

Cavalli, Florence MG, Cavalli, Florence MG, Hübner, Jens-Martin, Sharma, Tanvi, Luu, Betty, Sill, Martin, Zapotocky, Michal, Mack, Stephen C, Witt, Hendrik, Lin, Tong, Shih, David JH, Ho, Ben, Santi, Mariarita, Emery, Lyndsey, Hukin, Juliette, Dunham, Christopher, McLendon, Roger E, Lipp, Eric S, Gururangan, Sridharan, Grossbach, Andrew, French, Pim, Kros, Johan M, van Veelen, Marie-Lise C, Rao, Amulya A Nageswara, Giannini, Caterina, Leary, Sarah, Jung, Shin, Faria, Claudia C, Mora, Jaume, Schüller, Ulrich, Alonso, Marta M, Chan, Jennifer A, Klekner, Almos, Chambless, Lola B, Hwang, Eugene I, Massimino, Maura, Eberhart, Charles G, Karajannis, Matthias A, Lu, Benjamin, Liau, Linda M, Zollo, Massimo, Ferrucci, Veronica, Carlotti, Carlos, Tirapelli, Daniela PC, Tabori, Uri, Bouffet, Eric, Ryzhova, Marina, Ellison, David W, Merchant, Thomas E, Gilbert, Mark R, Armstrong, Terri S, Korshunov, Andrey, Pfister, Stefan M, Taylor, Michael D, Aldape, Kenneth, Pajtler, Kristian W, Kool, Marcel, Ramaswamy, Vijay, Cavalli, Florence MG, Cavalli, Florence MG, Hübner, Jens-Martin, Sharma, Tanvi, Luu, Betty, Sill, Martin, Zapotocky, Michal, Mack, Stephen C, Witt, Hendrik, Lin, Tong, Shih, David JH, Ho, Ben, Santi, Mariarita, Emery, Lyndsey, Hukin, Juliette, Dunham, Christopher, McLendon, Roger E, Lipp, Eric S, Gururangan, Sridharan, Grossbach, Andrew, French, Pim, Kros, Johan M, van Veelen, Marie-Lise C, Rao, Amulya A Nageswara, Giannini, Caterina, Leary, Sarah, Jung, Shin, Faria, Claudia C, Mora, Jaume, Schüller, Ulrich, Alonso, Marta M, Chan, Jennifer A, Klekner, Almos, Chambless, Lola B, Hwang, Eugene I, Massimino, Maura, Eberhart, Charles G, Karajannis, Matthias A, Lu, Benjamin, Liau, Linda M, Zollo, Massimo, Ferrucci, Veronica, Carlotti, Carlos, Tirapelli, Daniela PC, Tabori, Uri, Bouffet, Eric, Ryzhova, Marina, Ellison, David W, Merchant, Thomas E, Gilbert, Mark R, Armstrong, Terri S, Korshunov, Andrey, Pfister, Stefan M, Taylor, Michael D, Aldape, Kenneth, Pajtler, Kristian W, Kool, Marcel, and Ramaswamy, Vijay

Abstract

Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalize

Published
2018

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

Author

Pathologie Pathologen staf, Capper, David, Jones, David T.W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, 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, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Blümcke, Ingmar, Bendszus, Martin, Debus, Jürgen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schüller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, Von Deimling, Andreas, Pfister, Stefan M., Pathologie Pathologen staf, Capper, David, Jones, David T.W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, 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, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Blümcke, Ingmar, Bendszus, Martin, Debus, Jürgen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schüller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, Von Deimling, Andreas, and Pfister, Stefan M.

Published
2018

205. 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, and Brandner, Sebastian

Subjects
*DNA methylation, *EPIGENOMICS, *CELL analysis, *YOUNG adults, *MENINGIOMA, *CELL populations
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. [ABSTRACT FROM AUTHOR]

Published
2021
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206. 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., and Reinhardt, Annekathrin

Subjects
DNA methylation, DNA fingerprinting, SARCOMA, DNA, MACHINE learning, IFOSFAMIDE
Abstract

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

Published
2021
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207. 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, and Korshunov, Andrey

Published
2021
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208. 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, et al, and University of Zurich

Subjects
610 Medicine & health, 2730 Oncology, 10040 Clinic for Neurology
Published
2017
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209. MOESM1 of Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases

Author

Koelsche, Christian, Schrimpf, Daniel, Tharun, Lars, Roth, Eva, Sturm, Dominik, Jones, David, Eva-Kristin Renker, Sill, Martin, Baude, Annika, Sahm, Felix, Capper, David, Bewerunge-Hudler, Melanie, Hartmann, Wolfgang, Kulozik, Andreas, Petersen, Iver, Flucke, Uta, Schreuder, Hendrik, BĂźttner, Reinhard, Marc-AndrĂŠ Weber, Schirmacher, Peter, Plass, Christoph, Pfister, Stefan, Deimling, Andreas, and Mechtersheimer, Gunhild

Abstract

Additional file 1: Table S1. Clinical information of the entire study cohort.

Published
2017
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211. Molecular subgrouping of primary pineal parenchymal tumors reveals distinct subtypes correlated with clinical parameters and genetic alterations.

Author

Pfaff, Elke, Aichmüller, Christian, Sill, Martin, Stichel, Damian, Snuderl, Matija, Karajannis, Matthias A., Schuhmann, Martin U., Schittenhelm, Jens, Hasselblatt, Martin, Thomas, Christian, Korshunov, Andrey, Rhizova, Marina, Wittmann, Andrea, Kaufhold, Anna, Iskar, Murat, Ketteler, Petra, Lohmann, Dietmar, Orr, Brent A., Ellison, David W., and von Hoff, Katja

Subjects
DNA methylation, DNA fingerprinting, EPIGENOMICS, PINEAL gland, TUMORS, DNA analysis, PANEL analysis, MICRORNA
Abstract

Tumors of the pineal region comprise several different entities with distinct clinical and histopathological features. Whereas some entities predominantly affect adults, pineoblastoma (PB) constitutes a highly aggressive malignancy of childhood with a poor outcome. PBs mainly arise sporadically, but may also occur in the context of cancer predisposition syndromes including DICER1 and RB1 germline mutation. With this study, we investigate clinico-pathological subgroups of pineal tumors and further characterize their biological features. We performed genome-wide DNA methylation analysis in 195 tumors of the pineal region and 20 normal pineal gland controls. Copy-number profiles were obtained from DNA methylation data; gene panel sequencing was added for 93 tumors and analysis was further complemented by miRNA sequencing for 22 tumor samples. Unsupervised clustering based on DNA methylation profiling separated known subgroups, like pineocytoma, pineal parenchymal tumor of intermediate differentiation, papillary tumor of the pineal region and PB, and further distinct subtypes within these groups, including three subtypes within the core PB subgroup. The novel molecular subgroup Pin-RB includes cases of trilateral retinoblastoma as well as sporadic pineal tumors with RB1 alterations, and displays similarities with retinoblastoma. Distinct clinical associations discriminate the second novel molecular subgroup PB-MYC from other PB cases. Alterations within the miRNA processing pathway (affecting DROSHA, DGCR8 or DICER1) are found in about two thirds of cases in the three core PB subtypes. Methylation profiling revealed biologically distinct groups of pineal tumors with specific clinical and molecular features. Our findings provide a foundation for further clinical as well as molecular and functional characterization of PB and other pineal tumors, including the role of miRNA processing defects in oncogenesis. [ABSTRACT FROM AUTHOR]

Published
2020
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212. 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, and Jabado, Nada

Subjects
FLUORESCENCE in situ hybridization
Abstract

1 a Unsupervised hierarchical clustering of DNA methylation profiles in nine YAP1-fused meningiomas (MNG YAP1) alongside 128 well-characterized CNS neoplasms and control tissue shown in a two-dimensional representation of pairwise sample correlations using the 15,000 most variant probes by t-distributed stochastic neighbor embedding (t-SNE) dimensionality reduction. Histological meningioma subtypes meningiomas and WHO grade are provided in Supplementary Table 2 I MNG i meningioma, I PXA i pleomorphic xanthoastrocytoma, I pHGG i pediatric high grade glioma, I F i female, I M i male Seven tumors harbored a rearrangement of I YAP1-MAML2 i involving exons 1-5 ( I n i = 5) or only in exon 1 ( I n i = 2) of I YAP1 i (NM 001130145) and exon 2-5 of I MAML2 i (NM 032427) I . In line, I YAP1 i fusion positive meningiomas clustered closer to I NF2 i mutant cases than other pediatric meningiomas (Online Resource Supplementary Fig. [Extracted from the article]

Published
2020
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216. Modulation of B Cells and Homing Marker on NK Cells Through Extracorporeal Photopheresis in Patients With Steroid-Refractory/Resistant Graft-Vs.-Host Disease Without Hampering Anti-viral/Anti-leukemic Effects

Author

Wang, Lei, primary, Ni, Ming, additional, Hückelhoven-Krauss, Angela, additional, Sellner, Leopold, additional, Hoffmann, Jean-Marc, additional, Neuber, Brigitte, additional, Luft, Thomas, additional, Hegenbart, Ute, additional, Schönland, Stefan, additional, Kleist, Christian, additional, Sill, Martin, additional, Chen, Bao-an, additional, Wuchter, Patrick, additional, Eckstein, Volker, additional, Krüger, William, additional, Hilgendorf, Inken, additional, Yerushalmi, Ronit, additional, Nagler, Arnon, additional, Müller-Tidow, Carsten, additional, Ho, Anthony D., additional, Dreger, Peter, additional, Schmitt, Michael, additional, and Schmitt, Anita, additional

Published
2018
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217. Voxel-wise radiogenomic mapping of tumor location with key molecular alterations in patients with glioma

Author

Tejada Neyra, Miguel Angel, primary, Neuberger, Ulf, additional, Reinhardt, Annekathrin, additional, Brugnara, Gianluca, additional, Bonekamp, David, additional, Sill, Martin, additional, Wick, Antje, additional, Jones, David T W, additional, Radbruch, Alexander, additional, Unterberg, Andreas, additional, Debus, Jürgen, additional, Heiland, Sabine, additional, Schlemmer, Heinz-Peter, additional, Herold-Mende, Christel, additional, Pfister, Stefan, additional, von Deimling, Andreas, additional, Wick, Wolfgang, additional, Capper, David, additional, Bendszus, Martin, additional, and Kickingereder, Philipp, additional

Published
2018
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218. Heterogeneity within the PF-EPN-B ependymoma subgroup

Author

Cavalli, Florence M. G., primary, Hübner, Jens-Martin, additional, Sharma, Tanvi, additional, Luu, Betty, additional, Sill, Martin, additional, Zapotocky, Michal, additional, Mack, Stephen C., additional, Witt, Hendrik, additional, Lin, Tong, additional, Shih, David J. H., additional, Ho, Ben, additional, Santi, Mariarita, additional, Emery, Lyndsey, additional, Hukin, Juliette, additional, Dunham, Christopher, additional, McLendon, Roger E., additional, Lipp, Eric S., additional, Gururangan, Sridharan, additional, Grossbach, Andrew, additional, French, Pim, additional, Kros, Johan M., additional, van Veelen, Marie-Lise C., additional, Rao, Amulya A. Nageswara, additional, Giannini, Caterina, additional, Leary, Sarah, additional, Jung, Shin, additional, Faria, Claudia C., additional, Mora, Jaume, additional, Schüller, Ulrich, additional, Alonso, Marta M., additional, Chan, Jennifer A., additional, Klekner, Almos, additional, Chambless, Lola B., additional, Hwang, Eugene I., additional, Massimino, Maura, additional, Eberhart, Charles G., additional, Karajannis, Matthias A., additional, Lu, Benjamin, additional, Liau, Linda M., additional, Zollo, Massimo, additional, Ferrucci, Veronica, additional, Carlotti, Carlos, additional, Tirapelli, Daniela P. C., additional, Tabori, Uri, additional, Bouffet, Eric, additional, Ryzhova, Marina, additional, Ellison, David W., additional, Merchant, Thomas E., additional, Gilbert, Mark R., additional, Armstrong, Terri S., additional, Korshunov, Andrey, additional, Pfister, Stefan M., additional, Taylor, Michael D., additional, Aldape, Kenneth, additional, Pajtler, Kristian W., additional, Kool, Marcel, additional, and Ramaswamy, Vijay, additional

Published
2018
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219. Myxoid glioneuronal tumor of the septum pellucidum and lateral ventricle is defined by a recurrent PDGFRA p.K385 mutation and DNT-like methylation profile

Author

Solomon, David A., primary, Korshunov, Andrey, additional, Sill, Martin, additional, Jones, David T. W., additional, Kool, Marcel, additional, Pfister, Stefan M., additional, Fan, Xuemo, additional, Bannykh, Serguei, additional, Hu, Jethro, additional, Danielpour, Moise, additional, Li, Rong, additional, Johnston, James, additional, Cham, Elaine, additional, Cooney, Tabitha, additional, Sun, Peter P., additional, Oberheim Bush, Nancy Ann, additional, McDermott, Michael, additional, Van Ziffle, Jessica, additional, Onodera, Courtney, additional, Grenert, James P., additional, Bastian, Boris C., additional, Villanueva-Meyer, Javier E., additional, Pekmezci, Melike, additional, Bollen, Andrew W., additional, and Perry, Arie, additional

Published
2018
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220. Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience

Author

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

Published
2018
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221. Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas

Author

Pajtler, Kristian W., primary, Wen, Ji, additional, Sill, Martin, additional, Lin, Tong, additional, Orisme, Wilda, additional, Tang, Bo, additional, Hübner, Jens-Martin, additional, Ramaswamy, Vijay, additional, Jia, Sujuan, additional, Dalton, James D., additional, Haupfear, Kelly, additional, Rogers, Hazel A., additional, Punchihewa, Chandanamali, additional, Lee, Ryan, additional, Easton, John, additional, Wu, Gang, additional, Ritzmann, Timothy A., additional, Chapman, Rebecca, additional, Chavez, Lukas, additional, Boop, Fredrick A., additional, Klimo, Paul, additional, Sabin, Noah D., additional, Ogg, Robert, additional, Mack, Stephen C., additional, Freibaum, Brian D., additional, Kim, Hong Joo, additional, Witt, Hendrik, additional, Jones, David T. W., additional, Vo, Baohan, additional, Gajjar, Amar, additional, Pounds, Stan, additional, Onar-Thomas, Arzu, additional, Roussel, Martine F., additional, Zhang, Jinghui, additional, Taylor, J. Paul, additional, Merchant, Thomas E., additional, Grundy, Richard, additional, Tatevossian, Ruth G., additional, Taylor, Michael D., additional, Pfister, Stefan M., additional, Korshunov, Andrey, additional, Kool, Marcel, additional, and Ellison, David W., additional

Published
2018
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224. EPEN-28. HETEROGENEITY WITHIN THE PFB EPENDYMOMA SUBGROUP

Author

Cavalli, Florence, primary, Hübner, Jens-Martin, additional, Sharma, Tanvi, additional, Sill, Martin, additional, Luu, Betty, additional, Zapotocky, Michal, additional, Korshunov, Andrey, additional, Pfister, Stefan, additional, Pajtler, Kristian, additional, Taylor, Michael, additional, Aldape, Kenneth, additional, Kool, Marcel, additional, and Ramaswamy, Vijay, additional

Published
2018
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225. EPEN-23. MOLECULAR HETEROGENEITY AMONG PEDIATRIC POSTERIOR FOSSA EPENDYMOMA

Author

Pajtler, Kristian W, primary, Wen, Ji, additional, Sill, Martin, additional, Lin, Tong, additional, Hübner, Jens M, additional, Ramaswamy, Vijay, additional, Punchihewa, Chandanamali, additional, Jones, David T W, additional, Witt, Hendrik, additional, Chavez, Lukas, additional, Tatevossian, Ruth G, additional, Grundy, Richard, additional, Merchant, Thomas E, additional, Onar-Thomas, Arzu, additional, Taylor, Michael D, additional, Pfister, Stefan M, additional, Korshunov, Andrey, additional, Kool, Marcel, additional, and Ellison, David W, additional

Published
2018
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226. LGG-20. MOLECULARLY-DEFINED DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT) COMPRISES TWO SUBGROUPS WITH DISTINCT CLINICAL AND GENETIC FEATURES

Author

Deng, Maximilian Y, primary, Sahm, Felix, additional, Sill, Martin, additional, Chiang, Jason, additional, Capper, David, additional, Milde, Till, additional, Ebinger, Martin, additional, Schuhmann, Martin, additional, Schittenhelm, Jens, additional, Monoranu, Camelia-Maria, additional, Korshunov, Andrey, additional, Ellison, David, additional, von Deimling, Andreas, additional, Pfister, Stefan M, additional, and Jones, David, additional

Published
2018
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227. Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features

Author

Deng, Maximilian Y., primary, Sill, Martin, additional, Chiang, Jason, additional, Schittenhelm, Jens, additional, Ebinger, Martin, additional, Schuhmann, Martin U., additional, Monoranu, Camelia-Maria, additional, Milde, Till, additional, Wittmann, Andrea, additional, Hartmann, Christian, additional, Sommer, Clemens, additional, Paulus, Werner, additional, Gärtner, Jutta, additional, Brück, Wolfgang, additional, Rüdiger, Thomas, additional, Leipold, Alfred, additional, Jaunmuktane, Zane, additional, Brandner, Sebastian, additional, Giangaspero, Felice, additional, Nozza, Paolo, additional, Mora, Jaume, additional, Morales la Madrid, Andres, additional, Cruz Martinez, Ofelia, additional, Hansford, Jordan R., additional, Pietsch, Torsten, additional, Tietze, Anna, additional, Hernáiz-Driever, Pablo, additional, Stoler, Iris, additional, Capper, David, additional, Korshunov, Andrey, additional, Ellison, David W., additional, von Deimling, Andreas, additional, Pfister, Stefan M., additional, Sahm, Felix, additional, and Jones, David T. W., additional

Published
2018
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228. DNA methylation-based reclassification of olfactory neuroblastoma

Author

Capper, David, primary, Engel, Nils W., additional, Stichel, Damian, additional, Lechner, Matt, additional, Glöss, Stefanie, additional, Schmid, Simone, additional, Koelsche, Christian, additional, Schrimpf, Daniel, additional, Niesen, Judith, additional, Wefers, Annika K., additional, Jones, David T. W., additional, Sill, Martin, additional, Weigert, Oliver, additional, Ligon, Keith L., additional, Olar, Adriana, additional, Koch, Arend, additional, Forster, Martin, additional, Moran, Sebastian, additional, Tirado, Oscar M., additional, Sáinz-Jaspeado, Miguel, additional, Mora, Jaume, additional, Esteller, Manel, additional, Alonso, Javier, additional, del Muro, Xavier Garcia, additional, Paulus, Werner, additional, Felsberg, Jörg, additional, Reifenberger, Guido, additional, Glatzel, Markus, additional, Frank, Stephan, additional, Monoranu, Camelia M., additional, Lund, Valerie J., additional, von Deimling, Andreas, additional, Pfister, Stefan, additional, Buslei, Rolf, additional, Ribbat-Idel, Julika, additional, Perner, Sven, additional, Gudziol, Volker, additional, Meinhardt, Matthias, additional, and Schüller, Ulrich, additional

Published
2018
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230. Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations

Author

Reinhardt, Annekathrin, primary, Stichel, Damian, additional, Schrimpf, Daniel, additional, Sahm, Felix, additional, Korshunov, Andrey, additional, Reuss, David E., additional, Koelsche, Christian, additional, Huang, Kristin, additional, Wefers, Annika K., additional, Hovestadt, Volker, additional, Sill, Martin, additional, Gramatzki, Dorothee, additional, Felsberg, Joerg, additional, Reifenberger, Guido, additional, Koch, Arend, additional, Thomale, Ulrich-W., additional, Becker, Albert, additional, Hans, Volkmar H., additional, Prinz, Marco, additional, Staszewski, Ori, additional, Acker, Till, additional, Dohmen, Hildegard, additional, Hartmann, Christian, additional, Mueller, Wolf, additional, Tuffaha, Muin S. A., additional, Paulus, Werner, additional, Heß, Katharina, additional, Brokinkel, Benjamin, additional, Schittenhelm, Jens, additional, Monoranu, Camelia-Maria, additional, Kessler, Almuth Friederike, additional, Loehr, Mario, additional, Buslei, Rolf, additional, Deckert, Martina, additional, Mawrin, Christian, additional, Kohlhof, Patricia, additional, Hewer, Ekkehard, additional, Olar, Adriana, additional, Rodriguez, Fausto J., additional, Giannini, Caterina, additional, NageswaraRao, Amulya A., additional, Tabori, Uri, additional, Nunes, Nuno Miguel, additional, Weller, Michael, additional, Pohl, Ute, additional, Jaunmuktane, Zane, additional, Brandner, Sebastian, additional, Unterberg, Andreas, additional, Hänggi, Daniel, additional, Platten, Michael, additional, Pfister, Stefan M., additional, Wick, Wolfgang, additional, Herold-Mende, Christel, additional, Jones, David T. W., additional, von Deimling, Andreas, additional, and Capper, David, additional

Published
2018
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231. DNA methylation-based classification of central nervous system tumours

Author

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

Published
2018
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232. Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases

Author

Koelsche, Christian, Schrimpf, Daniel, Tharun, Lars, Roth, Eva, Sturm, Dominik, Jones, David T. W., Renker, Eva-Kristin, Sill, Martin, Baude, Annika, Sahm, Felix, Capper, David, Bewerunge-Hudler, Melanie, Hartmann, Wolfgang, Kulozik, Andreas E., Petersen, Iver, Flucke, Uta, Schreuder, Hendrik W. B., Buettner, Reinhard, Weber, Marc-Andre, Schirmacher, Peter, Plass, Christoph, Pfister, Stefan M., von Deimling, Andreas, Mechtersheimer, Gunhild, Koelsche, Christian, Schrimpf, Daniel, Tharun, Lars, Roth, Eva, Sturm, Dominik, Jones, David T. W., Renker, Eva-Kristin, Sill, Martin, Baude, Annika, Sahm, Felix, Capper, David, Bewerunge-Hudler, Melanie, Hartmann, Wolfgang, Kulozik, Andreas E., Petersen, Iver, Flucke, Uta, Schreuder, Hendrik W. B., Buettner, Reinhard, Weber, Marc-Andre, Schirmacher, Peter, Plass, Christoph, Pfister, Stefan M., von Deimling, Andreas, and Mechtersheimer, Gunhild

Abstract

Background: Histone 3.3 (H3.3) hotspot mutations in bone tumors occur in the vast majority of giant cell tumors of bone (GCTBs; 96%), chondroblastomas (95%) and in a few cases of osteosarcomas. However, clinical presentation, histopathological features, and additional molecular characteristics of H3.3 mutant osteosarcomas are largely unknown. Methods: In this multicentre, retrospective study, a total of 106 conventional high-grade osteosarcomas, across all age groups were re-examined for hotspot mutations in the H3.3 coding genes H3F3A and H3F3B. H3.3 mutant osteosarcomas were re-evaluated in a multidisciplinary manner and analyzed for genome-wide DNA-methylation patterns and DNA copy number aberrations alongside H3.3 wild-type osteosarcomas and H3F3A G34W/L mutant GCTBs. Results: Six osteosarcomas (6/106) carried H3F3A hotspot mutations. No mutations were found in H3F3B. All patients with H3F3A mutant osteosarcoma were older than 30 years with a median age of 65 years. Copy number aberrations that are commonly encountered in high-grade osteosarcomas also occurred in H3F3A mutant osteosarcomas. Unlike a single osteosarcoma with a H3F3A K27M mutation, the DNA methylation profiles of H3F3A G34W/R mutant osteosarcomas were clearly different from H3.3 wild-type osteosarcomas, but more closely related to GCTBs. The most differentially methylated promoters between H3F3A G34W/R mutant and H3.3 wild-type osteosarcomas were in KLLN/PTEN (p < 0.00005) and HIST1H2BB (p < 0.0005). Conclusions: H3.3 mutations in osteosarcomas may occur in H3F3A at mutational hotspots. They are overall rare, but become more frequent in osteosarcoma patients older than 30 years. Osteosarcomas carrying H3F3A G34W/R mutations are associated with epigenetic dysregulation of KLLN/PTEN and HIST1H2BB.

Published
2017

233. Drug-perturbation-based stratification of blood cancer

Author

Daum, Steffen, Šíša, Miroslav, Dietrich, Sascha, Oleś, Małgorzata, Lu, Junyan, Sellner, Leopold, Anders, Simon, Velten, Britta, Wu, Bian, Hüllein, Jennifer, Silva Liberio, Michelle da, Walther, Tatjana, Wagner, Lena, Rabe, Sophie, Ghidelli-Disse, Sonja, Bantscheff, Marcus, Oleś, Andrzej K., Słabicki, Mikołaj, Mock, Andreas, Oakes, Christopher C., Wang, Shihui, Oppermann, Sina, Lukas, Marina, Kim, Vladislav, Sill, Martin, Benner, Axel, Jauch, Anna, Sutton, Lesley-Ann, Young, Emma, Rosenquist, Richard, Liu, Xiyang, Jethwa, Alexander, Lee, Kwang Seok, Lewis, Joe, Putzker, Kerstin, Lutz, Christoph, Rossi, Davide, Mokhir, Andriy, Oellerich, Thomas, Zirlik, Katja, Herling, Marco, Nguyen-Khac, Florence, Plass, Christoph, Andersson, Emma, Mustjoki, Satu, Kalle, Christof von, Ho, Anthony Dick, Hensel, Manfred, Dürig, Jan, Ringshausen, Ingo, Zapatka, Marc, Huber, Wolfgang, Zenz, Thorsten, Daum, Steffen, Šíša, Miroslav, Dietrich, Sascha, Oleś, Małgorzata, Lu, Junyan, Sellner, Leopold, Anders, Simon, Velten, Britta, Wu, Bian, Hüllein, Jennifer, Silva Liberio, Michelle da, Walther, Tatjana, Wagner, Lena, Rabe, Sophie, Ghidelli-Disse, Sonja, Bantscheff, Marcus, Oleś, Andrzej K., Słabicki, Mikołaj, Mock, Andreas, Oakes, Christopher C., Wang, Shihui, Oppermann, Sina, Lukas, Marina, Kim, Vladislav, Sill, Martin, Benner, Axel, Jauch, Anna, Sutton, Lesley-Ann, Young, Emma, Rosenquist, Richard, Liu, Xiyang, Jethwa, Alexander, Lee, Kwang Seok, Lewis, Joe, Putzker, Kerstin, Lutz, Christoph, Rossi, Davide, Mokhir, Andriy, Oellerich, Thomas, Zirlik, Katja, Herling, Marco, Nguyen-Khac, Florence, Plass, Christoph, Andersson, Emma, Mustjoki, Satu, Kalle, Christof von, Ho, Anthony Dick, Hensel, Manfred, Dürig, Jan, Ringshausen, Ingo, Zapatka, Marc, Huber, Wolfgang, and Zenz, Thorsten

Abstract

As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non–BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.

Published
2017

234. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs

Author

Sturm, Dominik, Orr, Brent A, Toprak, Umut H, Hovestadt, Volker, Jones, David T W, Capper, David, Sill, Martin, Buchhalter, Ivo, Northcott, Paul A, Leis, Irina, Ryzhova, Marina, Koelsche, Christian, Pfaff, Elke, Allen, Sariah J, Balasubramanian, Gnanaprakash, Worst, Barbara C, Pajtler, Kristian W, Brabetz, Sebastian, Johann, Pascal D, Sahm, Felix, Reimand, Jüri, Mackay, Alan, Carvalho, Diana M, Remke, Marc, Phillips, Joanna J, Perry, Arie, Cowdrey, Cynthia, Drissi, Rachid, Fouladi, Maryam, Giangaspero, Felice, et al, and University of Zurich

Subjects
10036 Medical Clinic, 1300 General Biochemistry, Genetics and Molecular Biology, 610 Medicine & health
Published
2016

235. Additional file 2: Table S1. of Adamantinomatous and papillary craniopharyngiomas are characterized by distinct epigenomic as well as mutational and transcriptomic profiles

Author

Hölsken, Annett, Sill, Martin, Merkle, Jessica, Leonille Schweizer, Buchfelder, Michael, Flitsch, Jörg, Fahlbusch, Rudolf, Metzler, Markus, Kool, Marcel, Pfister, Stefan, Deimling, Andreas Von, Capper, David, Jones, David, and Buslei, Rolf

Abstract

Single Affymetrix U133 Plus2.0 expression array data of all adaCP and papCP analysed, given in log2 expression units. (DOC 22.6 kb)

Published
2016
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236. The age of adult pilocytic astrocytoma cells

Author

Voronina, Natalia, Aichmüller, Christian, Kolb, Thorsten, Korshunov, Andrey, Ryzhova, Marina, Barnholtz-Sloan, Jill, Cioffi, Gino, Sill, Martin, von Deimling, Andreas, Pfister, Stefan M., Gronych, Jan, Jones, David T. W., Frisén, Jonas, Zapatka, Marc, and Ernst, Aurélie

Abstract

Adult pilocytic astrocytomas (PAs) have been regarded as indistinguishable from pediatric PAs in terms of genome-wide expression and methylation patterns. It has been unclear whether adult PAs arise early in life and remain asymptomatic until adulthood, or whether they develop during adulthood. We sought to determine the age and origin of adult human PAs using two types of “marks” in the genomic DNA. First, we analyzed the DNA methylation patterns of adult and pediatric PAs to distinguish between PAs of different anatomic locations (n= 257 PA and control brain tissues). Second, we measured the concentration of nuclear bomb test-derived 14C in genomic DNA (n= 14 cases), which indicates the time point of the formation of human cell populations. Our data suggest that adult and pediatric PAs developing in the infratentorial brain are closely related and potentially develop from precursor cells early in life, whereas supratentorial PAs might show age and location-specific differences.

Published
2021
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237. Drug-perturbation-based stratification of blood cancer

Author

Dietrich, Sascha, primary, Oleś, Małgorzata, additional, Lu, Junyan, additional, Sellner, Leopold, additional, Anders, Simon, additional, Velten, Britta, additional, Wu, Bian, additional, Hüllein, Jennifer, additional, da Silva Liberio, Michelle, additional, Walther, Tatjana, additional, Wagner, Lena, additional, Rabe, Sophie, additional, Ghidelli-Disse, Sonja, additional, Bantscheff, Marcus, additional, Oleś, Andrzej K., additional, Słabicki, Mikołaj, additional, Mock, Andreas, additional, Oakes, Christopher C., additional, Wang, Shihui, additional, Oppermann, Sina, additional, Lukas, Marina, additional, Kim, Vladislav, additional, Sill, Martin, additional, Benner, Axel, additional, Jauch, Anna, additional, Sutton, Lesley Ann, additional, Young, Emma, additional, Rosenquist, Richard, additional, Liu, Xiyang, additional, Jethwa, Alexander, additional, Lee, Kwang Seok, additional, Lewis, Joe, additional, Putzker, Kerstin, additional, Lutz, Christoph, additional, Rossi, Davide, additional, Mokhir, Andriy, additional, Oellerich, Thomas, additional, Zirlik, Katja, additional, Herling, Marco, additional, Nguyen-Khac, Florence, additional, Plass, Christoph, additional, Andersson, Emma, additional, Mustjoki, Satu, additional, von Kalle, Christof, additional, Ho, Anthony D., additional, Hensel, Manfred, additional, Dürig, Jan, additional, Ringshausen, Ingo, additional, Zapatka, Marc, additional, Huber, Wolfgang, additional, and Zenz, Thorsten, additional

Published
2017
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238. PATH-32. MOLECULAR HETEROGENEITY AMONG PEDIATRIC POSTERIOR FOSSA EPENDYMOMA

Author

Pajtler, Kristian W, primary, Wen, Ji, additional, Sill, Martin, additional, Lin, Tong, additional, Hübner, Jens, additional, Ramaswamy, Vijay, additional, Jones, David, additional, Witt, Hendrik, additional, Chavez, Lukas, additional, Tatevossian, Ruth, additional, Grundy, Richard, additional, Merchant, Thomas, additional, Onar-Thomas, Arzu, additional, Taylor, Michael, additional, Pfister, Stefan M, additional, Korshunov, Andrey, additional, Kool, Marcel, additional, and Ellison, David W, additional

Published
2017
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239. Radiomic subtyping improves disease stratification beyond key molecular, clinical, and standard imaging characteristics in patients with glioblastoma

Author

Kickingereder, Philipp, primary, Neuberger, Ulf, additional, Bonekamp, David, additional, Piechotta, Paula L, additional, Götz, Michael, additional, Wick, Antje, additional, Sill, Martin, additional, Kratz, Annekathrin, additional, Shinohara, Russell T, additional, Jones, David T W, additional, Radbruch, Alexander, additional, Muschelli, John, additional, Unterberg, Andreas, additional, Debus, Jürgen, additional, Schlemmer, Heinz-Peter, additional, Herold-Mende, Christel, additional, Pfister, Stefan, additional, von Deimling, Andreas, additional, Wick, Wolfgang, additional, Capper, David, additional, Maier-Hein, Klaus H, additional, and Bendszus, Martin, additional

Published
2017
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240. Three-dimensional tumor cell growth stimulates autophagic flux and recapitulates chemotherapy resistance

Author

Bingel, Corinna, primary, Koeneke, Emily, additional, Ridinger, Johannes, additional, Bittmann, Annika, additional, Sill, Martin, additional, Peterziel, Heike, additional, Wrobel, Jagoda K, additional, Rettig, Inga, additional, Milde, Till, additional, Fernekorn, Uta, additional, Weise, Frank, additional, Schober, Andreas, additional, Witt, Olaf, additional, and Oehme, Ina, additional

Published
2017
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241. EPND-07. MOLECULAR HETEROGENEITY AMONG PEDIATRIC POSTERIOR FOSSA EPENDYMOMA

Author

Pajtler, Kristian, primary, Wen, Ji, additional, Sill, Martin, additional, Lin, Tong, additional, Hübner, Jens, additional, Ramaswamy, Vijay, additional, Punchihewa, Chandanamali, additional, Jones, David, additional, Witt, Hendrik, additional, Chavez, Lukas, additional, Tatevossian, Ruth, additional, Grundy, Richard, additional, Merchant, Thomas, additional, Taylor, Michael, additional, Pfister, Stefan, additional, Korshunov, Andrey, additional, Kool, Marcel, additional, and Ellison, David, additional

Published
2017
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242. Meningiomas induced by low-dose radiation carry structural variants of NF2 and a distinct mutational signature

Author

Sahm, Felix, primary, Toprak, Umut H., additional, Hübschmann, Daniel, additional, Kleinheinz, Kortine, additional, Buchhalter, Ivo, additional, Sill, Martin, additional, Stichel, Damian, additional, Schick, Matthias, additional, Bewerunge-Hudler, Melanie, additional, Schrimpf, Daniel, additional, Zadeh, Gelareh, additional, Aldape, Ken, additional, Herold-Mende, Christel, additional, Beck, Katja, additional, Staszewski, Ori, additional, Prinz, Marco, additional, Harosh, Carmit Ben, additional, Eils, Roland, additional, Sturm, Dominik, additional, Jones, David T. W., additional, Pfister, Stefan M., additional, Paulus, Werner, additional, Ram, Zvi, additional, Schlesner, Matthias, additional, Grossman, Rachel, additional, and von Deimling, Andreas, additional

Published
2017
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243. Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases

Author

Koelsche, Christian, primary, Schrimpf, Daniel, additional, Tharun, Lars, additional, Roth, Eva, additional, Sturm, Dominik, additional, Jones, David T. W., additional, Renker, Eva-Kristin, additional, Sill, Martin, additional, Baude, Annika, additional, Sahm, Felix, additional, Capper, David, additional, Bewerunge-Hudler, Melanie, additional, Hartmann, Wolfgang, additional, Kulozik, Andreas E., additional, Petersen, Iver, additional, Flucke, Uta, additional, Schreuder, Hendrik W. B., additional, Büttner, Reinhard, additional, Weber, Marc-André, additional, Schirmacher, Peter, additional, Plass, Christoph, additional, Pfister, Stefan M., additional, von Deimling, Andreas, additional, and Mechtersheimer, Gunhild, additional

Published
2017
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244. DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis

Author

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

Published
2017
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245. The molecular landscape of ETMR at diagnosis and relapse.

Author

Lambo, Sander, Gröbner, Susanne N., Rausch, Tobias, Waszak, Sebastian M., Schmidt, Christin, Gorthi, Aparna, Romero, July Carolina, Mauermann, Monika, Brabetz, Sebastian, Krausert, Sonja, Buchhalter, Ivo, Koster, Jan, Zwijnenburg, Danny A., Sill, Martin, Hübner, Jens-Martin, Mack, Norman, Schwalm, Benjamin, Ryzhova, Marina, Hovestadt, Volker, and Papillon-Cavanagh, Simon

Abstract

Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis1. Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC2–4 was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease. Analyses of primary and relapse samples of embryonal tumours with multilayered rosettes provide insights into the molecular mechanisms that underlie the development and opportunities for the treatment of this deadly disease. [ABSTRACT FROM AUTHOR]

Published
2019
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246. 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., and Witt, Hendrik

Subjects
*AGGRESSIVE driving, *FLUORESCENCE in situ hybridization, *CERVICAL cord, *PROGRESSION-free survival, *CELL junctions, *CYTOPLASMIC filaments
Abstract

Spinal ependymal tumors form a histologically and molecularly heterogeneous group of tumors with generally good prognosis. However, their treatment can be challenging if infiltration of the spinal cord or dissemination throughout the central nervous system (CNS) occurs and, in these cases, clinical outcome remains poor. Here, we describe a new and relatively rare subgroup of spinal ependymal tumors identified using DNA methylation profiling that is distinct from other molecular subgroups of ependymoma. Copy number variation plots derived from DNA methylation arrays showed MYCN amplification as a characteristic genetic alteration in all cases of our cohort (n = 13), which was subsequently validated using fluorescence in situ hybridization. The histological diagnosis was anaplastic ependymoma (WHO Grade III) in ten cases and classic ependymoma (WHO Grade II) in three cases. Histological re-evaluation in five primary tumors and seven relapses showed characteristic histological features of ependymoma, namely pseudorosettes, GFAP- and EMA positivity. Electron microscopy revealed cilia, complex intercellular junctions and intermediate filaments in a representative sample. Taking these findings into account, we suggest to designate this molecular subgroup spinal ependymoma with MYCN amplification, SP-EPN-MYCN. SP-EPN-MYCN tumors showed distinct growth patterns with intradural, extramedullary localization mostly within the thoracic and cervical spine, diffuse leptomeningeal spread throughout the whole CNS and infiltrative invasion of the spinal cord. Dissemination was observed in 100% of cases. Despite high-intensity treatment, SP-EPN-MYCN showed significantly worse median progression free survival (PFS) (17 months) and median overall survival (OS) (87 months) than all other previously described molecular spinal ependymoma subgroups. OS and PFS were similar to supratentorial ependymoma with RELA-fusion (ST-EPN-RELA) and posterior fossa ependymoma A (PF-EPN-A), further highlighting the aggressiveness of this distinct new subgroup. We, therefore, propose to establish SP-EPN-MYCN as a new molecular subgroup in ependymoma and advocate for testing newly diagnosed spinal ependymal tumors for MYCN amplification. [ABSTRACT FROM AUTHOR]

Published
2019
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247. Global DNA methylation reflects spatial heterogeneity and molecular evolution of lung adenocarcinomas.

Author

Dietz, Steffen, Lifshitz, Aviezer, Kazdal, Daniel, Harms, Alexander, Endris, Volker, Winter, Hauke, Stenzinger, Albrecht, Warth, Arne, Sill, Martin, Tanay, Amos, and Sültmann, Holger

Abstract

Lung adenocarcinoma (ADC) is the most prevalent subtype of lung cancer and characterized by considerable morphological and mutational heterogeneity. However, little is known about the epigenomic intratumor variability between spatially separated histological growth patterns of ADC. In order to reconstruct the clonal evolution of histomorphological patterns, we performed global DNA methylation profiling of 27 primary tumor regions, seven matched normal tissues and six lymph node metastases from seven ADC cases. Additionally, we investigated the methylation data from 369 samples of the TCGA ADC cohort. All regions showed varying degrees of methylation changes between segments of different, but also of the same growth patterns. Similarly, copy number variations were seen between spatially distinct segments of each patient. Hierarchical clustering of promoter methylation revealed extensive heterogeneity within and between the cases. Intratumor DNA methylation heterogeneity demonstrated a branched clonal evolution of ADC regions driven by genomic instability with subclonal copy number changes. Notably, methylation profiles within tumors were not more similar to each other than to those from other individuals. In two cases, different tumor regions of the same individuals were represented in distant clusters of the TCGA cohort, illustrating the extensive epigenomic intratumor heterogeneity of ADCs. We found no evidence for the lymph node metastases to be derived from a common growth pattern. Instead, they had evolved early and separately from a particular pattern in each primary tumor. Our results suggest that extensive variation of epigenomic features contributes to the molecular and phenotypic heterogeneity of primary ADCs and lymph node metastases. What's new? Non‐small cell lung cancer is a tumor with extensive histological heterogeneity caused by spatial and temporal genomic changes, posing major challenges for the treatment and prognosis of patients with lung adenocarcinoma. To date, however, little is known about epigenomic intratumor variability. In our study, the authors investigate the spatial variations of somatic DNA methylation and copy number aberrations in comparison with histological growth patterns of seven resected lung adenocarcinomas and six corresponding lymph node metastases. The results suggest that epigenomic variation contributes considerably to the molecular and phenotypic heterogeneity and evolution of lung adenocarcinomas and lymph node metastases. [ABSTRACT FROM AUTHOR]

Published
2019
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248. 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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249. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs

Author

Pathologie patiënten zorg, Pathologie, Cancer, Sturm, Dominik, Orr, Brent A., Toprak, Umut H., Hovestadt, Volker, Jones, David T W, Capper, David, Sill, Martin, Buchhalter, Ivo, Northcott, Paul A., Leis, Irina, Ryzhova, Marina, Koelsche, Christian, Pfaff, Elke, Allen, Sariah J., Balasubramanian, Gnanaprakash, Worst, Barbara C., Pajtler, Kristian W., Brabetz, Sebastian, Johann, Pascal D., Sahm, Felix, Reimand, Jüri, Mackay, Alan, Carvalho, Diana M., Remke, Marc, Phillips, Joanna J., Perry, Arie, Cowdrey, Cynthia, Drissi, Rachid, Fouladi, Maryam, Giangaspero, Felice, Łastowska, Maria, Grajkowska, Wiesława, Scheurlen, Wolfram, Pietsch, Torsten, Hagel, Christian, Gojo, Johannes, Lötsch, Daniela, Berger, Walter, Slavc, Irene, Haberler, Christine, Jouvet, Anne, Holm, Stefan, Hofer, Silvia, Prinz, Marco, Keohane, Catherine, Fried, Iris, Mawrin, Christian, Scheie, David, Mobley, Bret C., Schniederjan, Matthew J., Santi, Mariarita, Buccoliero, Anna M., Dahiya, Sonika, Kramm, Christof M., Von Bueren, André O., Von Hoff, Katja, Rutkowski, Stefan, Herold-Mende, Christel, Frühwald, Michael C., Milde, Till, Hasselblatt, Martin, Wesseling, Pieter, Rößler, Jochen, Schüller, Ulrich, Ebinger, Martin, Schittenhelm, Jens, Frank, Stephan, Grobholz, Rainer, Vajtai, Istvan, Hans, Volkmar, Schneppenheim, Reinhard, Zitterbart, Karel, Collins, V. Peter, Aronica, Eleonora, Varlet, Pascale, Puget, Stephanie, Dufour, Christelle, Grill, Jacques, Figarella-Branger, Dominique, Wolter, Marietta, Schuhmann, Martin U., Shalaby, Tarek, Grotzer, Michael, Van Meter, Timothy, Monoranu, Camelia Maria, Felsberg, Jörg, Reifenberger, Guido, Snuderl, Matija, Forrester, Lynn Ann, Koster, Jan, Versteeg, Rogier, Volckmann, Richard, Van Sluis, Peter, Wolf, Stephan, Mikkelsen, Tom, Gajjar, Amar, Aldape, Kenneth, Moore, Andrew S., Taylor, Michael D., Jones, Chris, Jabado, Nada, Karajannis, Matthias A., Eils, Roland, Schlesner, Matthias, Lichter, Peter, Von Deimling, Andreas, Pfister, Stefan M., Ellison, David W., Korshunov, Andrey, Kool, Marcel, Pathologie patiënten zorg, Pathologie, Cancer, Sturm, Dominik, Orr, Brent A., Toprak, Umut H., Hovestadt, Volker, Jones, David T W, Capper, David, Sill, Martin, Buchhalter, Ivo, Northcott, Paul A., Leis, Irina, Ryzhova, Marina, Koelsche, Christian, Pfaff, Elke, Allen, Sariah J., Balasubramanian, Gnanaprakash, Worst, Barbara C., Pajtler, Kristian W., Brabetz, Sebastian, Johann, Pascal D., Sahm, Felix, Reimand, Jüri, Mackay, Alan, Carvalho, Diana M., Remke, Marc, Phillips, Joanna J., Perry, Arie, Cowdrey, Cynthia, Drissi, Rachid, Fouladi, Maryam, Giangaspero, Felice, Łastowska, Maria, Grajkowska, Wiesława, Scheurlen, Wolfram, Pietsch, Torsten, Hagel, Christian, Gojo, Johannes, Lötsch, Daniela, Berger, Walter, Slavc, Irene, Haberler, Christine, Jouvet, Anne, Holm, Stefan, Hofer, Silvia, Prinz, Marco, Keohane, Catherine, Fried, Iris, Mawrin, Christian, Scheie, David, Mobley, Bret C., Schniederjan, Matthew J., Santi, Mariarita, Buccoliero, Anna M., Dahiya, Sonika, Kramm, Christof M., Von Bueren, André O., Von Hoff, Katja, Rutkowski, Stefan, Herold-Mende, Christel, Frühwald, Michael C., Milde, Till, Hasselblatt, Martin, Wesseling, Pieter, Rößler, Jochen, Schüller, Ulrich, Ebinger, Martin, Schittenhelm, Jens, Frank, Stephan, Grobholz, Rainer, Vajtai, Istvan, Hans, Volkmar, Schneppenheim, Reinhard, Zitterbart, Karel, Collins, V. Peter, Aronica, Eleonora, Varlet, Pascale, Puget, Stephanie, Dufour, Christelle, Grill, Jacques, Figarella-Branger, Dominique, Wolter, Marietta, Schuhmann, Martin U., Shalaby, Tarek, Grotzer, Michael, Van Meter, Timothy, Monoranu, Camelia Maria, Felsberg, Jörg, Reifenberger, Guido, Snuderl, Matija, Forrester, Lynn Ann, Koster, Jan, Versteeg, Rogier, Volckmann, Richard, Van Sluis, Peter, Wolf, Stephan, Mikkelsen, Tom, Gajjar, Amar, Aldape, Kenneth, Moore, Andrew S., Taylor, Michael D., Jones, Chris, Jabado, Nada, Karajannis, Matthias A., Eils, Roland, Schlesner, Matthias, Lichter, Peter, Von Deimling, Andreas, Pfister, Stefan M., Ellison, David W., Korshunov, Andrey, and Kool, Marcel

Published
2016

250. Malignant transformation of a polymorphous low grade neuroepithelial tumor of the young (PLNTY).

Author

Bale, Tejus A., Sait, Sameer F., Benhamida, Jamal, Ptashkin, Ryan, Haque, Sofia, Villafania, Liliana, Sill, Martin, Sadowska, Justyna, Akhtar, Razia B., Liechty, Benjamin, Juthani, Rupa, Ladanyi, Marc, Fowkes, Mary, Karajannis, Matthias A., and Rosenblum, Marc K.

Subjects
TUMOR grading, TUMORS in children, MITOGEN-activated protein kinases
Abstract

PLNTY comprise an indolent group of tumors in children and young adults harboring MAPK pathway alterations [[2], [5]] including I FGFR3-TACC3 i fusions, which also characterize a subset of glioblastomas [[1]]. T-SNE dimensionality reduction was performed on the primary (inverted filled triangle) and recurrent (filled triangle) tumors and a subset of CNS tumors from the DKFZ reference set (color coded according to methylation cluster assignation) with the Rtsne package version 0.15. Molecular characterization by a 468-gene tumor sequencing assay (MSK-IMPACT™) [[4]] re-demonstrated the I FGFR3-TACC3 i fusion, plus additional somatic alterations in I TP53, ATRX, PTEN, TEK i and I RB1 i typically seen in high-grade glioma. [Extracted from the article]

Published
2021
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