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1. The whole-genome landscape of medulloblastoma subtypes

Author

Northcott, Paul A, Buchhalter, Ivo, Morrissy, A Sorana, Hovestadt, Volker, Weischenfeldt, Joachim, Ehrenberger, Tobias, Gröbner, Susanne, Segura-Wang, Maia, Zichner, Thomas, Rudneva, Vasilisa A, Warnatz, Hans-Jörg, Sidiropoulos, Nikos, Phillips, Aaron H, Schumacher, Steven, Kleinheinz, Kortine, Waszak, Sebastian M, Erkek, Serap, Jones, David TW, Worst, Barbara C, Kool, Marcel, Zapatka, Marc, Jäger, Natalie, Chavez, Lukas, Hutter, Barbara, Bieg, Matthias, Paramasivam, Nagarajan, Heinold, Michael, Gu, Zuguang, Ishaque, Naveed, Jäger-Schmidt, Christina, Imbusch, Charles D, Jugold, Alke, Hübschmann, Daniel, Risch, Thomas, Amstislavskiy, Vyacheslav, Gonzalez, Francisco German Rodriguez, Weber, Ursula D, Wolf, Stephan, Robinson, Giles W, Zhou, Xin, Wu, Gang, Finkelstein, David, Liu, Yanling, Cavalli, Florence MG, Luu, Betty, Ramaswamy, Vijay, Wu, Xiaochong, Koster, Jan, Ryzhova, Marina, Cho, Yoon-Jae, Pomeroy, Scott L, Herold-Mende, Christel, Schuhmann, Martin, Ebinger, Martin, Liau, Linda M, Mora, Jaume, McLendon, Roger E, Jabado, Nada, Kumabe, Toshihiro, Chuah, Eric, Ma, Yussanne, Moore, Richard A, Mungall, Andrew J, Mungall, Karen L, Thiessen, Nina, Tse, Kane, Wong, Tina, Jones, Steven JM, Witt, Olaf, Milde, Till, Von Deimling, Andreas, Capper, David, Korshunov, Andrey, Yaspo, Marie-Laure, Kriwacki, Richard, Gajjar, Amar, Zhang, Jinghui, Beroukhim, Rameen, Fraenkel, Ernest, Korbel, Jan O, Brors, Benedikt, Schlesner, Matthias, Eils, Roland, Marra, Marco A, Pfister, Stefan M, Taylor, Michael D, and Lichter, Peter

Subjects
Cancer, Human Genome, Brain Disorders, Pediatric Cancer, Brain Cancer, Genetics, Biotechnology, Rare Diseases, Neurosciences, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Good Health and Well Being, Carcinogenesis, Carrier Proteins, Cohort Studies, DNA Methylation, DNA Mutational Analysis, Datasets as Topic, Epistasis, Genetic, Genome, Human, Genomics, Humans, Medulloblastoma, Molecular Targeted Therapy, Muscle Proteins, Mutation, Oncogenes, Transcription Factors, Whole Genome Sequencing, Wnt Proteins, General Science & Technology
Abstract

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.

Published
2017

2. Cell competition is a tumour suppressor mechanism in the thymus

Author

Martins, Vera C., Busch, Katrin, Juraeva, Dilafruz, Blum, Carmen, Ludwig, Carolin, Rasche, Volker, Lasitschka, Felix, Mastitsky, Sergey E., Brors, Benedikt, Hielscher, Thomas, Fehling, Hans Joerg, and Rodewald, Hans-Reimer

Subjects
Tumors -- Development and progression, T cells -- Physiological aspects, Thymus -- Physiological aspects, Cell interaction -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Cell competition is an emerging principle underlying selection for cellular fitness during development and disease. Competition may be relevant for cancer, but an experimental link between defects in competition and tumorigenesis is elusive. In the thymus, T lymphocytes develop from precursors that are constantly replaced by bone-marrow-derived progenitors. Here we show that in mice this turnover is regulated by natural cell competition between 'young' bone-marrow-derived and 'old' thymus-resident progenitors that, although genetically identical, execute differential gene expression programs. Disruption of cell competition leads to progenitor self-renewal, upregulation of Hmga1, transformation, and T-cell acute lymphoblastic leukaemia (T-ALL) resembling the human disease in pathology, genomic lesions, leukaemia-associated transcripts, and activating mutations in Notch1. Hence, cell competition is a tumour suppressor mechanism in the thymus. Failure to select fit progenitors through cell competition may explain leukaemia in X-linked severe combined immune deficiency patients who showed thymus-autonomous T-cell development after therapy with gene-corrected autologous progenitors. T cells develop from thymic precursor cells that are constantly replaced with newly arriving bone marrow progenitor cells, and the 'old' and 'new' cells are shown here to compete; in the absence of cell competition, when the influx of new bone marrow progenitor cells is blocked, the old cells acquire the ability to self-renew and eventually become transformed, leading to the development of a form of leukaemia. New T cells for old in the thymus In the thymus, T cells develop from precursor cells that are constantly replaced by newly arriving bone marrow progenitor cells. Hans-Reimer Rodewald and colleagues show that this is the result of competition between the 'old' and 'new' cells. In the absence of cell competition, when the influx of new bone marrow progenitor cells is blocked in mice, old cells reacquire the ability to self-renew and eventually become transformed, leading to the development of T-cell acute lymphoblastic leukaemia (T-ALL) resembling the human disease. At the same time there are changes in gene expression and the appearance of genetic mutations often also found in human T-ALL. Thus cell competition can act as a tumour-suppressor mechanism. This work may also help to explain the widely discussed T-cell leukaemia seen in X-linked severe combined immune deficiency patients after therapy with gene-corrected autologous progenitors., Author(s): Vera C. Martins [sup.1] [sup.2] , Katrin Busch [sup.1] , Dilafruz Juraeva [sup.3] , Carmen Blum [sup.2] , Carolin Ludwig [sup.2] , Volker Rasche [sup.4] , Felix Lasitschka [sup.5] [...]

Published
2014
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3. The landscape of genomic alterations across childhood cancers

Author

Grbner, Susanne N., Worst, Barbara C., Weischenfeldt, Joachim, Buchhalter, Ivo, Kleinheinz, Kortine, Rudneva, Vasilisa A., Johann, Pascal D., Balasubramanian, Gnana Prakash, Segura-Wang, Maia, Brabetz, Sebastian, Bender, Sebastian, Hutter, Barbara, Sturm, Dominik, Pfaff, Elke, Hbschmann, Daniel, Zipprich, Gideon, Heinold, Michael, Eils, Jrgen, Lawerenz, Christian, Erkek, Serap, Lambo, Sander, Waszak, Sebastian, Blattmann, Claudia, Borkhardt, Arndt, Kuhlen, Michaela, Eggert, Angelika, Fulda, Simone, Gessler, Manfred, Wegert, Jenny, Kappler, Roland, Baumhoer, Daniel, Burdach, Stefan, Kirschner-Schwabe, Renate, Kontny, Udo, Kulozik, Andreas E., Lohmann, Dietmar, Hettmer, Simone, Eckert, Cornelia, Bielack, Stefan, Nathrath, Michaela, Niemeyer, Charlotte, Richter, Gnther H., Schulte, Johannes, Siebert, Reiner, Westermann, Frank, Molenaar, Jan J., Vassal, Gilles, Witt, Hendrik, Lichter, Peter, Weber, Ursula, Eils, Roland, Korshunov, Andrey, Witt, Olaf, Pfister, Stefan, Reifenberger, Guido, Felsberg, Jrg, von Kalle, Christof, Schmidt, Manfred, Bartholom, Cynthia, Taylor, Michael, Jones, David, Jger, Natalie, Korbel, Jan, Sttz, Adrian, Rausch, Tobias, Radlwimmer, Bernhard, Yaspo, Marie-Laure, Lehrach, Hans, Warnatz, Hans-Jrg, Landgraf, Pablo, Brors, Benedikt, Zapatka, Marc, Wagner, Susanne, Haake, Andrea, Richter, Julia, Richter, Gesine, Lawerenz, Chris, Kerssemakers, Jules, Jaeger-Schmidt, Christina, Scholz, Ingrid, Bergmann, Anke K., Borst, Christoph, Burkhardt, Birgit, Claviez, Alexander, Dreyling, Martin, Eberth, Sonja, Einsele, Hermann, Frickhofen, Norbert, Haas, Siegfried, Hansmann, Martin-Leo, Karsch, Dennis, Kneba, Michael, Lisfeld, Jasmin, Mantovani-Lffler, Luisa, Rohde, Marius, Ott, German, Stadler, Christina, Staib, Peter, Stilgenbauer, Stephan, Trmper, Lorenz, Zenz, Thorsten, Kube, Dieter, Kppers, Ralf, Weniger, Marc, Hummel, Michael, Klapper, Wolfram, Kostezka, Ulrike, Lenze, Dido, Mller, Peter, Rosenwald, Andreas, Szczepanowski, Monika, Ammerpohl, Ole, Aukema, Sietse M., Binder, Vera, Hoell, Jessica I., Leich, Ellen, Lpez, Cristina, Nagel, Inga, Pischimariov, Jordan, Rosenstiel, Philip, Schilhabel, Markus, Schreiber, Stefan, Vater, Inga, Wagener, Rabea, Bernhart, Stephan H., Binder, Hans, Doose, Gero, Hoffmann, Steve, Hopp, Lydia, Kretzmer, Helene, Kreuz, Markus, Langenberger, David, Loeffler, Markus, Rosolowski, Maciej, Schlesner, Matthias, Stadler, Peter F., Sungalee, Stephanie, Kratz, Christian P., van Tilburg, Cornelis M., Kramm, Christof M., Fleischhack, Gudrun, Dirksen, Uta, Rutkowski, Stefan, Frhwald, Michael, von Hoff, Katja, Wolf, Stephan, Klingebiel, Thomas, Koscielniak, Ewa, Koster, Jan, Resnick, Adam C., Zhang, Jinghui, Liu, Yanling, Zhou, Xin, Waanders, Angela J., Zwijnenburg, Danny A., Raman, Pichai, Weber, Ursula D., Northcott, Paul A., Pajtler, Kristian W., Kool, Marcel, Piro, Rosario M., Korbel, Jan O., Jones, David T. W., Chavez, Lukas, and Pfister, Stefan M.

Subjects
Childhood cancer -- Genetic aspects, Cancer research, Gene mutation -- Health aspects, Genomics -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 78% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials., Author(s): Susanne N. Grbner [1, 2, 3]; Barbara C. Worst [1, 2, 3, 4]; Joachim Weischenfeldt [5, 6]; Ivo Buchhalter [7]; Kortine Kleinheinz [7]; Vasilisa A. Rudneva [5, 8]; Pascal [...]

Published
2018
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4. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

Author

Northcott, Paul A., Lee, Catherine, Zichner, Thomas, Stütz, Adrian M., Erkek, Serap, Kawauchi, Daisuke, Shih, David J. H., Hovestadt, Volker, Zapatka, Marc, Sturm, Dominik, Jones, David T. W., Kool, Marcel, Remke, Marc, Cavalli, Florence M. G., Zuyderduyn, Scott, Bader, Gary D., VandenBerg, Scott, Esparza, Lourdes Adriana, Ryzhova, Marina, Wang, Wei, Wittmann, Andrea, Stark, Sebastian, Sieber, Laura, Seker-Cin, Huriye, Linke, Linda, Kratochwil, Fabian, Jäger, Natalie, Buchhalter, Ivo, Imbusch, Charles D., Zipprich, Gideon, Raeder, Benjamin, Schmidt, Sabine, Diessl, Nicolle, Wolf, Stephan, Wiemann, Stefan, Brors, Benedikt, Lawerenz, Chris, Eils, Jürgen, Warnatz, Hans-Jörg, Risch, Thomas, Yaspo, Marie-Laure, Weber, Ursula D., Bartholomae, Cynthia C., von Kalle, Christof, Turányi, Eszter, Hauser, Peter, Sanden, Emma, Darabi, Anna, Siesjö, Peter, Sterba, Jaroslav, Zitterbart, Karel, Sumerauer, David, van Sluis, Peter, Versteeg, Rogier, Volckmann, Richard, Koster, Jan, Schuhmann, Martin U., Ebinger, Martin, Grimes, Leighton H., Robinson, Giles W., Gajjar, Amar, Mynarek, Martin, von Hoff, Katja, Rutkowski, Stefan, Pietsch, Torsten, Scheurlen, Wolfram, Felsberg, Jörg, Reifenberger, Guido, Kulozik, Andreas E., von Deimling, Andreas, Witt, Olaf, Eils, Roland, Gilbertson, Richard J., Korshunov, Andrey, Taylor, Michael D., Lichter, Peter, Korbel, Jan O., Wechsler-Reya, Robert J., and Pfister, Stefan M.

Published
2014
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5. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing

Author

Hovestadt, Volker, Jones, David T. W., Picelli, Simone, Wang, Wei, Kool, Marcel, Northcott, Paul A., Sultan, Marc, Stachurski, Katharina, Ryzhova, Marina, Warnatz, Hans-Jörg, Ralser, Meryem, Brun, Sonja, Bunt, Jens, Jäger, Natalie, Kleinheinz, Kortine, Erkek, Serap, Weber, Ursula D., Bartholomae, Cynthia C., von Kalle, Christof, Lawerenz, Chris, Eils, Jürgen, Koster, Jan, Versteeg, Rogier, Milde, Till, Witt, Olaf, Schmidt, Sabine, Wolf, Stephan, Pietsch, Torsten, Rutkowski, Stefan, Scheurlen, Wolfram, Taylor, Michael D., Brors, Benedikt, Felsberg, Jörg, Reifenberger, Guido, Borkhardt, Arndt, Lehrach, Hans, Wechsler-Reya, Robert J., Eils, Roland, Yaspo, Marie-Laure, Landgraf, Pablo, Korshunov, Andrey, Zapatka, Marc, Radlwimmer, Bernhard, Pfister, Stefan M., and Lichter, Peter

Published
2014
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6. Dissecting the genomic complexity underlying medulloblastoma

Author

Jones, David T. W., Jäger, Natalie, Kool, Marcel, Zichner, Thomas, Hutter, Barbara, Sultan, Marc, Cho, Yoon-Jae, Pugh, Trevor J., Hovestadt, Volker, Stütz, Adrian M., Rausch, Tobias, Warnatz, Hans-Jörg, Ryzhova, Marina, Bender, Sebastian, Sturm, Dominik, Pleier, Sabrina, Cin, Huriye, Pfaff, Elke, Sieber, Laura, Wittmann, Andrea, Remke, Marc, Witt, Hendrik, Hutter, Sonja, Tzaridis, Theophilos, Weischenfeldt, Joachim, Raeder, Benjamin, Avci, Meryem, Amstislavskiy, Vyacheslav, Zapatka, Marc, Weber, Ursula D., Wang, Qi, Lasitschka, Bärbel, Bartholomae, Cynthia C., Schmidt, Manfred, von Kalle, Christof, Ast, Volker, Lawerenz, Chris, Eils, Jürgen, Kabbe, Rolf, Benes, Vladimir, van Sluis, Peter, Koster, Jan, Volckmann, Richard, Shih, David, Betts, Matthew J., Russell, Robert B., Coco, Simona, Tonini, Gian Paolo, Schüller, Ulrich, Hans, Volkmar, Graf, Norbert, Kim, Yoo-Jin, Monoranu, Camelia, Roggendorf, Wolfgang, Unterberg, Andreas, Herold-Mende, Christel, Milde, Till, Kulozik, Andreas E., von Deimling, Andreas, Witt, Olaf, Maass, Eberhard, Rössler, Jochen, Ebinger, Martin, Schuhmann, Martin U., Frühwald, Michael C., Hasselblatt, Martin, Jabado, Nada, Rutkowski, Stefan, von Bueren, André O., Williamson, Dan, Clifford, Steven C., McCabe, Martin G., Collins, Peter V., Wolf, Stephan, Wiemann, Stefan, Lehrach, Hans, Brors, Benedikt, Scheurlen, Wolfram, Felsberg, Jörg, Reifenberger, Guido, Northcott, Paul A., Taylor, Michael D., Meyerson, Matthew, Pomeroy, Scott L., Yaspo, Marie-Laure, Korbel, Jan O., Korshunov, Andrey, Eils, Roland, Pfister, Stefan M., and Lichter, Peter

Published
2012
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7. International network of cancer genome projects

Author

Hudson, Thomas J., Anderson, Warwick, Aretz, Axel, Bell, Cindy, Bernabé, Rosa R., Bhan, M. K., Calvo, Fabien, Eerola, Iiro, Gerhard, Daniela S., Guttmacher, Alan, Guyer, Mark, Hemsley, Fiona M., Jennings, Jennifer L., Kerr, David, Klatt, Peter, Kolar, Patrik, Lane, David P., Laplace, Frank, Nettekoven, Gerd, Ozenberger, Brad, Peterson, Jane, Rao, T. S., Remacle, Jacques, Schafer, Alan J., Shibata, Tatsuhiro, Stratton, Michael R., Watanabe, Koichi, Yuen, Matthew M. F., Cambon-Thomsen, Anne, Dressler, Lynn G., Joly, Yann, Kennedy, Karen L., Parker, Michael J., Romeo-Casabona, Carlos M., Wallace, Susan, Wiesner, Georgia L., Zeps, Nikolajs, Biankin, Andrew V., Chabannon, Christian, de Alava, Enrique, Ferguson, Martin L., Geary, Peter, Hayes, Neil D., Johns, Amber L., Kasprzyk, Arek, Nakagawa, Hidewaki, Piris, Miguel A., van de Vijver, Marc, Aburatani, Hiroyuki, Bayés, Mónica, Bowtell, David D.L., Campbell, Peter J., Hirst, Martin, López-Otín, Carlos, Marra, Marco, Ning, Zemin, Puente, Xose S., Ruan, Yijun, Stunnenberg, Hendrik G., Swerdlow, Harold, Velculescu, Victor E., Xue, Hong H., Yang, Liu, Spellman, Paul T., Bader, Gary D., Boutros, Paul C., Flicek, Paul, Getz, Gad, Guigó, Roderic, Guo, Guangwu, Haussler, David, Hubbard, Tim J., Jiang, Tao, Jones, Steven M., Li, Qibin, López-Bigas, Nuria, Luo, Ruibang, Muthuswamy, Lakshmi, Ouellette, Francis B. F., Pearson, John V., Quesada, Victor, Raphael, Benjamin J., Sander, Chris, Stein, Lincoln D., Stuart, Joshua M., Teague, Jon W., Totoki, Yasushi, Tsunoda, Tatsuhiko, Valencia, Alfonso, Wheeler, David A., Wu, Honglong, Zhao, Shancen, Zhou, Guangyu, Lathrop, Mark, Axton, Myles, Dyke, Stephanie O. M., Gunter, Chris, McPherson, John D., Miller, Linda J., Zhang, Junjun, Haider, Syed A., Wang, Jianxin, Yung, Christina K., Cross, Anthony, Liang, Yong, Gnaneshan, Saravanamuttu, Guberman, Jonathan, Hsu, Jack, Bobrow, Martin, Chalmers, Don R. C., Hasel, Karl W., Kaan, Terry S. H., Knoppers, Bartha M., Lowrance, William W., Masui, Tohru, Nicolás, Pilar, Rial-Sebbag, Emmanuelle, Rodriguez, Laura Lyman, Vergely, Catherine, Grimmond, Sean M., Bowtell, David D. L., Cloonan, Nicole, deFazio, Anna, Eshleman, James R., Etemadmoghadam, Dariush, Gardiner, Brooke A., Kench, James G., Scarpa, Aldo, Sutherland, Robert L., Tempero, Margaret A., Waddell, Nicola J., Wilson, Peter J., Gallinger, Steve, Tsao, Ming-Sound, Shaw, Patricia A., Petersen, Gloria M., Mukhopadhyay, Debabrata, Chin, Lynda, DePinho, Ronald A., Thayer, Sarah, Shazand, Kamran, Beck, Timothy, Sam, Michelle, Timms, Lee, Ballin, Vanessa, Ji, Jiafu, Zhang, Xiuqing, Chen, Feng, Hu, Xueda, Yang, Qi, Tian, Geng, Zhang, Lianhai, Xing, Xiaofang, Li, Xianghong, Zhu, Zhenggang, Yu, Yingyan, Yu, Jun, Yang, Huanming, Tost, Jörg, Brennan, Paul, Holcatova, Ivana, Zaridze, David, Brazma, Alvis, Egevad, Lars, Prokhortchouk, Egor, Banks, Rosamonde Elizabeth, Uhlén, Mathias, Viksna, Juris, Ponten, Fredrik, Skryabin, Konstantin, Futreal, Andrew P., Birney, Ewan, Caldas, Carlos, Reis-Filho, Jorge S., Richardson, Andrea L., Sotiriou, Christos, Birnbaum, Daniel, Blanche, Hélène, Boucher, Pascal, Boyault, Sandrine, Masson-Jacquemier, Jocelyne D., Pauporté, Iris, Pivot, Xavier, Vincent-Salomon, Anne, Tabone, Eric, Theillet, Charles, Treilleux, Isabelle, Bioulac-Sage, Paulette, Clément, Bruno, Decaens, Thomas, Degos, Françoise, Franco, Dominique, Gut, Ivo, Gut, Marta, Heath, Simon, Samuel, Didier, Thomas, Gilles, Zucman-Rossi, Jessica, Eils, Roland, Brors, Benedikt, Korbel, Jan O., Korshunov, Andrey, Landgraf, Pablo, Lehrach, Hans, Pfister, Stefan, Radlwimmer, Bernhard, Reifenberger, Guido, Taylor, Michael D., von Kalle, Christof, Majumder, Partha P., Sarin, Rajiv, Pederzoli, Paolo, Lawlor, Rita T., Delledonne, Massimo, Bardelli, Alberto, Gress, Thomas, Klimstra, David, Zamboni, Giuseppe, Nakamura, Yusuke, Kusuda, Jun, Miyano, Satoru, Kato, Kazuto, Fujimoto, Akihiro, Yoshida, Teruhiko, Campo, Elias, Estivill, Xavier, de Sanjosé, Silvia, Montserrat, Emili, González-Díaz, Marcos, Jares, Pedro, Himmelbaue, Heinz, Bea, Silvia, Aparicio, Samuel, Borg, Ake, Børresen-Dale, Anne-Lise, Foekens, John A., vanʼt Veer, Laura, Easton, Douglas F., Martin, Sancha, Compton, Carolyn C., Lander, Eric S., Penny, Robert, Shaw, Kenna M., Speed, Terence P., Vockley, Joseph G., Lichter, Peter, Barker, Anna D., Burke, Wylie, Collins, Francis S., Green, Anthony R., Hamilton, Stanley R., Kallioniemi, Olli P., Ley, Timothy J., Liu, Edison T., Lu, Youyong, Majumder, Partha, Wainwright, Brandon J., and Wilson, Richard K.

Published
2010
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8. The whole-genome landscape of medulloblastoma subtypes

Author

Daniel Hübschmann, Olaf Witt, Eric Chuah, Michael Heinold, Andrey Korshunov, Zuguang Gu, Vyacheslav Amstislavskiy, Aaron H. Phillips, Matthias Bieg, David Finkelstein, Thomas Risch, Nikos Sidiropoulos, Peter Lichter, Tina Wong, Yanling Liu, Roland Eils, Barbara Hutter, Marc Zapatka, Sebastian M. Waszak, Charles D. Imbusch, Roger E. McLendon, Marie-Laure Yaspo, Susanne Gröbner, Volker Hovestadt, Ernest Fraenkel, Martin Ebinger, Florence M.G. Cavalli, Steven E. Schumacher, Hans-Jörg Warnatz, Amar Gajjar, Tobias Ehrenberger, Michael D. Taylor, Ivo Buchhalter, Kane Tse, Betty Luu, Ursula D. Weber, Christel Herold-Mende, Benedikt Brors, Vasilisa A. Rudneva, Barbara C. Worst, Scott L. Pomeroy, Jinghui Zhang, Martin U. Schuhmann, Marina Ryzhova, Stephan Wolf, Andrew J. Mungall, Xin Zhou, Matthias Schlesner, A. Sorana Morrissy, Nagarajan Paramasivam, Maia Segura-Wang, Jan Koster, Stefan M. Pfister, Joachim Weischenfeldt, Marcel Kool, Yoon Jae Cho, Kortine Kleinheinz, Natalie Jäger, Richard A. Moore, Toshihiro Kumabe, Rameen Beroukhim, David Capper, Vijay Ramaswamy, Gang Wu, Linda M. Liau, Francisco German Rodriguez Gonzalez, Xiaochong Wu, Karen Mungall, Jan O. Korbel, Christina Jäger-Schmidt, Alke Jugold, Serap Erkek, Andreas von Deimling, Richard W. Kriwacki, Steven J.M. Jones, Thomas Zichner, Paul A. Northcott, David T.W. Jones, Lukas Chavez, Till Milde, Jaume Mora, Marco A. Marra, Yussanne Ma, Naveed Ishaque, Nina Thiessen, Nada Jabado, Giles W. Robinson, Other departments, CCA - Cancer biology and immunology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, Oncogenomics, Massachusetts Institute of Technology. Department of Biological Engineering, Ehrenberger, Tobias, and Fraenkel, Ernest

Subjects
0301 basic medicine, Carcinogenesis, DNA Mutational Analysis, Datasets as Topic, Muscle Proteins, medicine.disease_cause, Bioinformatics, Genome, Cohort Studies, 2.1 Biological and endogenous factors, Molecular Targeted Therapy, Aetiology, Cancer, Pediatric, Multidisciplinary, Genomics, 5.1 Pharmaceuticals, DNA methylation, Development of treatments and therapeutic interventions, Human, Biotechnology, Pediatric Cancer, General Science & Technology, Biology, Article, 03 medical and health sciences, Rare Diseases, Genetic, medicine, Genetics, Humans, ddc:610, Gene, Medulloblastoma, Whole Genome Sequencing, Genome, Human, Human Genome, Neurosciences, Epistasis, Genetic, Oncogenes, DNA Methylation, medicine.disease, Human genetics, Brain Disorders, Brain Cancer, Wnt Proteins, 030104 developmental biology, Good Health and Well Being, Mutation, Epistasis, Human genome, Carrier Proteins, Transcription Factors
Abstract

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.

Published
2017
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9. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing

Author

Stephan Wolf, David T.W. Jones, Jürgen Eils, Andrey Korshunov, Sonja N. Brun, Peter Lichter, Benedikt Brors, Natalie Jäger, Till Milde, Olaf Witt, Marc Zapatka, Simone Picelli, Serap Erkek, Marina Ryzhova, Chris Lawerenz, Katharina Stachurski, Torsten Pietsch, Ursula D. Weber, Christof von Kalle, Marie-Laure Yaspo, Jan Koster, Roland Eils, Sabine Schmidt, Marcel Kool, Meryem Ralser, Robert J. Wechsler-Reya, Guido Reifenberger, Volker Hovestadt, Wolfram Scheurlen, Michael D. Taylor, Pablo Landgraf, Wei Wang, Hans-Jörg Warnatz, Hans Lehrach, Arndt Borkhardt, Kortine Kleinheinz, Jens Bunt, Cynthia C. Bartholomae, Stefan Rutkowski, Paul A. Northcott, Marc Sultan, Stefan M. Pfister, Rogier Versteeg, Jörg Felsberg, Bernhard Radlwimmer, Other departments, Oncogenomics, and CCA -Cancer Center Amsterdam

Subjects
Chromatin Immunoprecipitation, Transcription, Genetic, Biology, DNA sequencing, Histones, Mice, Epigenetics of physical exercise, Cell Line, Tumor, Histone methylation, Epigenome editing, Animals, Humans, Gene Silencing, Epigenetics, Promoter Regions, Genetic, RNA-Directed DNA Methylation, Epigenomics, Genetics, Binding Sites, Genome, Multidisciplinary, RNA-Binding Proteins, Sequence Analysis, DNA, DNA Methylation, Chromatin, Gene Expression Regulation, Neoplastic, DNA methylation, Female, Medulloblastoma, Transcription Factors
Abstract

Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context.

Published
2014
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10. Patterns of somatic structural variation in human cancer genomes.

Author

Li, Yilong, Roberts, Nicola D., Wala, Jeremiah A., Shapira, Ofer, Schumacher, Steven E., Kumar, Kiran, Khurana, Ekta, Waszak, Sebastian, Korbel, Jan O., Haber, James E., Imielinski, Marcin, PCAWG Structural Variation Working Group, Akdemir, Kadir C., Alvarez, Eva G., Baez-Ortega, Adrian, Beroukhim, Rameen, Boutros, Paul C., Bowtell, David D. L., Brors, Benedikt, and Burns, Kathleen H.

Abstract

A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes1–7. Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types8. Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions—as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2–7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and—in liver cancer—frequently activate the telomerase gene TERT. A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act. Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer. [ABSTRACT FROM AUTHOR]

Published
2020
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11. Cell competition is a tumour suppressor mechanism in the thymus

Author

Benedikt Brors, Thomas Hielscher, Carmen Blum, Volker Rasche, Felix Lasitschka, Vera C. Martins, Hans Joerg Fehling, Carolin Ludwig, Dilafruz Juraeva, Hans Reimer Rodewald, Sergey E. Mastitsky, and Katrin Busch

Subjects
Male, Cell division, media_common.quotation_subject, T-Lymphocytes, Cell, Thymus Gland, Biology, medicine.disease_cause, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Competition (biology), Mice, Downregulation and upregulation, Cell Movement, medicine, Cytotoxic T cell, Animals, Humans, Progenitor cell, Receptor, Notch1, Letter to the Editor, media_common, HMGA Proteins, Multidisciplinary, Hematopoietic Stem Cells, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, medicine.anatomical_structure, Cell Transformation, Neoplastic, Immunology, Myeloid-derived Suppressor Cell, Cancer research, Disease Progression, Female, Carcinogenesis, Transcriptome, Cell Division
Abstract

Cell competition is an emerging principle underlying selection for cellular fitness during development and disease. Competition may be relevant for cancer, but an experimental link between defects in competition and tumorigenesis is elusive. In the thymus, T lymphocytes develop from precursors that are constantly replaced by bone-marrow-derived progenitors. Here we show that in mice this turnover is regulated by natural cell competition between 'young' bone-marrow-derived and 'old' thymus-resident progenitors that, although genetically identical, execute differential gene expression programs. Disruption of cell competition leads to progenitor self-renewal, upregulation of Hmga1, transformation, and T-cell acute lymphoblastic leukaemia (T-ALL) resembling the human disease in pathology, genomic lesions, leukaemia-associated transcripts, and activating mutations in Notch1. Hence, cell competition is a tumour suppressor mechanism in the thymus. Failure to select fit progenitors through cell competition may explain leukaemia in X-linked severe combined immune deficiency patients who showed thymus-autonomous T-cell development after therapy with gene-corrected autologous progenitors.

Published
2013

12. The landscape of genomic alterations across childhood cancers

Author

Gröbner, Susanne N., Worst, Barbara C., Weischenfeldt, Joachim, Buchhalter, Ivo, Kleinheinz, Kortine, Rudneva, Vasilisa A., Johann, Pascal D., Balasubramanian, Gnana Prakash, Segura-Wang, Maia, Brabetz, Sebastian, Bender, Sebastian, Hutter, Barbara, Sturm, Dominik, Pfaff, Elke, Hübschmann, Daniel, Zipprich, Gideon, Heinold, Michael, Eils, Jürgen, Lawerenz, Christian, Erkek, Serap, Lambo, Sander, Waszak, Sebastian, Blattmann, Claudia, Borkhardt, Arndt, Kuhlen, Michaela, Eggert, Angelika, Fulda, Simone, Gessler, Manfred, Wegert, Jenny, Kappler, Roland, Baumhoer, Daniel, Burdach, Stefan, Kirschner-Schwabe, Renate, Kontny, Udo, Kulozik, Andreas E., Lohmann, Dietmar, Hettmer, Simone, Eckert, Cornelia, Bielack, Stefan, Nathrath, Michaela, Niemeyer, Charlotte, Richter, Günther H., Schulte, Johannes, Siebert, Reiner, Westermann, Frank, Molenaar, Jan J., Vassal, Gilles, Witt, Hendrik, Burkhardt, Birgit, Kratz, Christian P., Witt, Olaf, van Tilburg, Cornelis M., Kramm, Christof M., Fleischhack, Gudrun, Dirksen, Uta, Rutkowski, Stefan, Frühwald, Michael, von Hoff, Katja, Wolf, Stephan, Klingebiel, Thomas, Koscielniak, Ewa, Landgraf, Pablo, Koster, Jan, Resnick, Adam C., Zhang, Jinghui, Liu, Yanling, Zhou, Xin, Waanders, Angela J., Zwijnenburg, Danny A., Raman, Pichai, Brors, Benedikt, Weber, Ursula D., Northcott, Paul A., Pajtler, Kristian W., Kool, Marcel, Piro, Rosario M., Korbel, Jan O., Schlesner, Matthias, Eils, Roland, Jones, David T. W., Lichter, Peter, Chavez, Lukas, Zapatka, Marc, and Pfister, Stefan M.

Abstract

Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7–8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.

Published
2018
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13. Author Correction: The landscape of genomic alterations across childhood cancers

Author

Gröbner, Susanne, Worst, Barbara, Weischenfeldt, Joachim, Buchhalter, Ivo, Kleinheinz, Kortine, Rudneva, Vasilisa, Johann, Pascal, Balasubramanian, Gnana, Segura-Wang, Maia, Brabetz, Sebastian, Bender, Sebastian, Hutter, Barbara, Sturm, Dominik, Pfaff, Elke, Hübschmann, Daniel, Zipprich, Gideon, Heinold, Michael, Eils, Jürgen, Lawerenz, Christian, Erkek, Serap, Lambo, Sander, Waszak, Sebastian, Blattmann, Claudia, Borkhardt, Arndt, Kuhlen, Michaela, Eggert, Angelika, Fulda, Simone, Gessler, Manfred, Wegert, Jenny, Kappler, Roland, Baumhoer, Daniel, Burdach, Stefan, Kirschner-Schwabe, Renate, Kontny, Udo, Kulozik, Andreas, Lohmann, Dietmar, Hettmer, Simone, Eckert, Cornelia, Bielack, Stefan, Nathrath, Michaela, Niemeyer, Charlotte, Richter, Günther, Schulte, Johannes, Siebert, Reiner, Westermann, Frank, Molenaar, Jan, Vassal, Gilles, Witt, Hendrik, Burkhardt, Birgit, Kratz, Christian, Witt, Olaf, Tilburg, Cornelis, Kramm, Christof, Fleischhack, Gudrun, Dirksen, Uta, Rutkowski, Stefan, Frühwald, Michael, Hoff, Katja, Wolf, Stephan, Klingebiel, Thomas, Koscielniak, Ewa, Landgraf, Pablo, Koster, Jan, Resnick, Adam, Zhang, Jinghui, Liu, Yanling, Zhou, Xin, Waanders, Angela, Zwijnenburg, Danny, Raman, Pichai, Brors, Benedikt, Weber, Ursula, Northcott, Paul, Pajtler, Kristian, Kool, Marcel, Piro, Rosario, Korbel, Jan, Schlesner, Matthias, Eils, Roland, Jones, David, Lichter, Peter, Chavez, Lukas, Zapatka, Marc, and Pfister, Stefan

Abstract

In this Article, author Benedikt Brors was erroneously associated with affiliation number ‘8’ (Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA); the author’s two other affiliations (affiliations ‘3’ and ‘7’, both at the German Cancer Research Center (DKFZ)) were correct. This has been corrected online.

Published
2018
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