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

Author

Sturm, Dominik, Orr, Brent A, Toprak, Umut H, Hovestadt, Volker, Jones, David TW, 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, and Jones, Chris

Subjects
Humans, Neuroectodermal Tumors, Central Nervous System Neoplasms, Trans-Activators, Proto-Oncogene Proteins, Tumor Suppressor Proteins, Repressor Proteins, Gene Expression Profiling, Signal Transduction, DNA Methylation, Gene Expression Regulation, Neoplastic, Amino Acid Sequence, Molecular Sequence Data, Child, Forkhead Transcription Factors, Neuroblastoma, Cancer, Pediatric, Neurosciences, Brain Disorders, Rare Diseases, Orphan Drug, Brain Cancer, Pediatric Research Initiative, Pediatric Cancer, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.

Published
2016

2. Divergent clonal selection dominates medulloblastoma at recurrence

Author

Morrissy, A Sorana, Garzia, Livia, Shih, David JH, Zuyderduyn, Scott, Huang, Xi, Skowron, Patryk, Remke, Marc, Cavalli, Florence MG, Ramaswamy, Vijay, Lindsay, Patricia E, Jelveh, Salomeh, Donovan, Laura K, Wang, Xin, Luu, Betty, Zayne, Kory, Li, Yisu, Mayoh, Chelsea, Thiessen, Nina, Mercier, Eloi, Mungall, Karen L, Ma, Yusanne, Tse, Kane, Zeng, Thomas, Shumansky, Karey, Roth, Andrew JL, Shah, Sohrab, Farooq, Hamza, Kijima, Noriyuki, Holgado, Borja L, Lee, John JY, Matan-Lithwick, Stuart, Liu, Jessica, Mack, Stephen C, Manno, Alex, Michealraj, KA, Nor, Carolina, Peacock, John, Qin, Lei, Reimand, Juri, Rolider, Adi, Thompson, Yuan Y, Wu, Xiaochong, Pugh, Trevor, Ally, Adrian, Bilenky, Mikhail, Butterfield, Yaron SN, Carlsen, Rebecca, Cheng, Young, Chuah, Eric, Corbett, Richard D, Dhalla, Noreen, He, An, Lee, Darlene, Li, Haiyan I, Long, William, Mayo, Michael, Plettner, Patrick, Qian, Jenny Q, Schein, Jacqueline E, Tam, Angela, Wong, Tina, Birol, Inanc, Zhao, Yongjun, Faria, Claudia C, Pimentel, José, Nunes, Sofia, Shalaby, Tarek, Grotzer, Michael, Pollack, Ian F, Hamilton, Ronald L, Li, Xiao-Nan, Bendel, Anne E, Fults, Daniel W, Walter, Andrew W, Kumabe, Toshihiro, Tominaga, Teiji, Collins, V Peter, Cho, Yoon-Jae, Hoffman, Caitlin, Lyden, David, Wisoff, Jeffrey H, Garvin, James H, Stearns, Duncan S, Massimi, Luca, Schüller, Ulrich, Sterba, Jaroslav, Zitterbart, Karel, Puget, Stephanie, Ayrault, Olivier, Dunn, Sandra E, Tirapelli, Daniela PC, Carlotti, Carlos G, Wheeler, Helen, Hallahan, Andrew R, Ingram, Wendy, MacDonald, Tobey J, Olson, Jeffrey J, Van Meir, Erwin G, Lee, Ji-Yeoun, and Wang, Kyu-Chang

Subjects
Pediatric, Biotechnology, Genetics, Brain Disorders, Human Genome, Brain Cancer, Rare Diseases, Cancer, Animals, Cerebellar Neoplasms, Clone Cells, Craniospinal Irradiation, DNA Mutational Analysis, Disease Models, Animal, Drosophila melanogaster, Female, Genome, Human, Humans, Male, Medulloblastoma, Mice, Molecular Targeted Therapy, Neoplasm Recurrence, Local, Radiotherapy, Image-Guided, Selection, Genetic, Signal Transduction, Xenograft Model Antitumor Assays, General Science & Technology
Abstract

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (

Published
2016

3. Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups

Author

Pajtler, Kristian W, Witt, Hendrik, Sill, Martin, Jones, David TW, Hovestadt, Volker, Kratochwil, Fabian, Wani, Khalida, Tatevossian, Ruth, Punchihewa, Chandanamali, Johann, Pascal, Reimand, Jüri, Warnatz, Hans-Jörg, Ryzhova, Marina, Mack, Steve, Ramaswamy, Vijay, Capper, David, Schweizer, Leonille, Sieber, Laura, Wittmann, Andrea, Huang, Zhiqin, van Sluis, Peter, Volckmann, Richard, Koster, Jan, Versteeg, Rogier, Fults, Daniel, Toledano, Helen, Avigad, Smadar, Hoffman, Lindsey M, Donson, Andrew M, Foreman, Nicholas, Hewer, Ekkehard, Zitterbart, Karel, Gilbert, Mark, Armstrong, Terri S, Gupta, Nalin, Allen, Jeffrey C, Karajannis, Matthias A, Zagzag, David, Hasselblatt, Martin, Kulozik, Andreas E, Witt, Olaf, Collins, V Peter, von Hoff, Katja, Rutkowski, Stefan, Pietsch, Torsten, Bader, Gary, Yaspo, Marie-Laure, von Deimling, Andreas, Lichter, Peter, Taylor, Michael D, Gilbertson, Richard, Ellison, David W, Aldape, Kenneth, Korshunov, Andrey, Kool, Marcel, and Pfister, Stefan M

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Cancer, Adaptor Proteins, Signal Transducing, Adolescent, Adult, Age Factors, Aged, Central Nervous System Neoplasms, Child, Child, Preschool, DNA Methylation, Ependymoma, Female, Gene Dosage, Gene Expression Profiling, Gene Fusion, Humans, Infant, Male, Middle Aged, Phosphoproteins, Transcription Factors, Transcription, Genetic, YAP-Signaling Proteins, Young Adult, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based on its lack of reproducibility in predicting patients' outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.

Published
2015

5. International Society Of Neuropathology--Haarlem consensus guidelines for nervous system tumor classification and grading.

Author

Louis, David N, Perry, Arie, Burger, Peter, Ellison, David W, Reifenberger, Guido, von Deimling, Andreas, Aldape, Kenneth, Brat, Daniel, Collins, V Peter, Eberhart, Charles, Figarella-Branger, Dominique, Fuller, Gregory N, Giangaspero, Felice, Giannini, Caterina, Hawkins, Cynthia, Kleihues, Paul, Korshunov, Andrey, Kros, Johan M, Beatriz Lopes, M, Ng, Ho-Keung, Ohgaki, Hiroko, Paulus, Werner, Pietsch, Torsten, Rosenblum, Marc, Rushing, Elisabeth, Soylemezoglu, Figen, Wiestler, Otmar, Wesseling, Pieter, and International Society Of Neuropathology--Haarlem

Subjects
International Society Of Neuropathology--Haarlem, Humans, Nervous System Neoplasms, Molecular Diagnostic Techniques, Severity of Illness Index, Astrocytoma, World Health Organization, atypical teratoid rhabdoid tumor, brain tumors, classification, glioblastoma, glioma, grading, medulloblastoma, oligodendroglioma, Neurology & Neurosurgery, Clinical Sciences, Neurosciences
Abstract

Major discoveries in the biology of nervous system tumors have raised the question of how non-histological data such as molecular information can be incorporated into the next World Health Organization (WHO) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, the Netherlands, under the sponsorship of the International Society of Neuropathology (ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro-oncological specialties. The present "white paper" catalogs the recommendations of the meeting, at which a consensus was reached that incorporation of molecular information into the next WHO classification should follow a set of provided "ISN-Haarlem" guidelines. Salient recommendations include that (i) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility, clinicopathological predictions and therapeutic planning; (ii) diagnoses should be "layered" with histologic classification, WHO grade and molecular information listed below an "integrated diagnosis"; (iii) determinations should be made for each tumor entity as to whether molecular information is required, suggested or not needed for its definition; (iv) some pediatric entities should be separated from their adult counterparts; (v) input for guiding decisions regarding tumor classification should be solicited from experts in complementary disciplines of neuro-oncology; and (iv) entity-specific molecular testing and reporting formats should be followed in diagnostic reports. It is hoped that these guidelines will facilitate the forthcoming update of the fourth edition of the WHO classification of central nervous system tumors.

Published
2014

6. ISN‐Haarlem Brain Tumor Classification Guidelines

Author

Louis, David N, Perry, Arie, Burger, Peter, Ellison, David W, Reifenberger, Guido, von Deimling, Andreas, Aldape, Kenneth, Brat, Daniel, Collins, V Peter, Eberhart, Charles, Figarella‐Branger, Dominique, Fuller, Gregory N, Giangaspero, Felice, Giannini, Caterina, Hawkins, Cynthia, Kleihues, Paul, Korshunov, Andrey, Kros, Johan M, Lopes, M Beatriz, Ng, Ho‐Keung, Ohgaki, Hiroko, Paulus, Werner, Pietsch, Torsten, Rosenblum, Marc, Rushing, Elisabeth, Soylemezoglu, Figen, Wiestler, Otmar, and Wesseling, Pieter

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Brain Disorders, Rare Diseases, Brain Cancer, Neurosciences, Cancer, Humans, Molecular Diagnostic Techniques, Nervous System Neoplasms, Severity of Illness Index, Astrocytoma, atypical teratoid rhabdoid tumor, brain tumors, classification, glioblastoma, glioma, grading, medulloblastoma, oligodendroglioma, World Health Organization, International Society Of Neuropathology--Haarlem, Neurology & Neurosurgery, Clinical sciences
Abstract

Major discoveries in the biology of nervous system tumors have raised the question of how non-histological data such as molecular information can be incorporated into the next World Health Organization (WHO) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, the Netherlands, under the sponsorship of the International Society of Neuropathology (ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro-oncological specialties. The present "white paper" catalogs the recommendations of the meeting, at which a consensus was reached that incorporation of molecular information into the next WHO classification should follow a set of provided "ISN-Haarlem" guidelines. Salient recommendations include that (i) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility, clinicopathological predictions and therapeutic planning; (ii) diagnoses should be "layered" with histologic classification, WHO grade and molecular information listed below an "integrated diagnosis"; (iii) determinations should be made for each tumor entity as to whether molecular information is required, suggested or not needed for its definition; (iv) some pediatric entities should be separated from their adult counterparts; (v) input for guiding decisions regarding tumor classification should be solicited from experts in complementary disciplines of neuro-oncology; and (iv) entity-specific molecular testing and reporting formats should be followed in diagnostic reports. It is hoped that these guidelines will facilitate the forthcoming update of the fourth edition of the WHO classification of central nervous system tumors.

Published
2014

7. Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition

Author

Kool, Marcel, Jones, David TW, Jäger, Natalie, Northcott, Paul A, Pugh, Trevor J, Hovestadt, Volker, Piro, Rosario M, Esparza, L Adriana, Markant, Shirley L, Remke, Marc, Milde, Till, Bourdeaut, Franck, Ryzhova, Marina, Sturm, Dominik, Pfaff, Elke, Stark, Sebastian, Hutter, Sonja, Şeker-Cin, Huriye, Johann, Pascal, Bender, Sebastian, Schmidt, Christin, Rausch, Tobias, Shih, David, Reimand, Jüri, Sieber, Laura, Wittmann, Andrea, Linke, Linda, Witt, Hendrik, Weber, Ursula D, Zapatka, Marc, König, Rainer, Beroukhim, Rameen, Bergthold, Guillaume, van Sluis, Peter, Volckmann, Richard, Koster, Jan, Versteeg, Rogier, Schmidt, Sabine, Wolf, Stephan, Lawerenz, Chris, Bartholomae, Cynthia C, von Kalle, Christof, Unterberg, Andreas, Herold-Mende, Christel, Hofer, Silvia, Kulozik, Andreas E, von Deimling, Andreas, Scheurlen, Wolfram, Felsberg, Jörg, Reifenberger, Guido, Hasselblatt, Martin, Crawford, John R, Grant, Gerald A, Jabado, Nada, Perry, Arie, Cowdrey, Cynthia, Croul, Sydney, Zadeh, Gelareh, Korbel, Jan O, Doz, Francois, Delattre, Olivier, Bader, Gary D, McCabe, Martin G, Collins, V Peter, Kieran, Mark W, Cho, Yoon-Jae, Pomeroy, Scott L, Witt, Olaf, Brors, Benedikt, Taylor, Michael D, Schüller, Ulrich, Korshunov, Andrey, Eils, Roland, Wechsler-Reya, Robert J, Lichter, Peter, Pfister, Stefan M, and Project, on behalf of the ICGC PedBrain Tumor

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Neurosciences, Pediatric Research Initiative, Genetics, Rare Diseases, Cancer, Pediatric, Brain Cancer, Pediatric Cancer, Brain Disorders, Adolescent, Adult, Animals, Base Sequence, Biphenyl Compounds, Cerebellar Neoplasms, Child, Child, Preschool, DEAD-box RNA Helicases, DNA Copy Number Variations, Drug Resistance, Neoplasm, Female, Gene Expression Profiling, Hedgehog Proteins, High-Throughput Nucleotide Sequencing, Humans, Infant, Kruppel-Like Transcription Factors, Male, Medulloblastoma, Mice, Mice, Inbred NOD, Mice, SCID, Molecular Sequence Data, N-Myc Proto-Oncogene Protein, Neoplasm Transplantation, Nuclear Proteins, Oncogene Proteins, Patched Receptors, Patched-1 Receptor, Phosphatidylinositol 3-Kinases, Promoter Regions, Genetic, Proto-Oncogene Proteins c-akt, Pyridines, Receptors, Cell Surface, Receptors, G-Protein-Coupled, Repressor Proteins, Signal Transduction, Smoothened Receptor, Telomerase, Tumor Suppressor Protein p53, Young Adult, Zinc Finger Protein Gli2, ICGC PedBrain Tumor Project, Oncology and Carcinogenesis, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant.

Published
2014

8. Clonal selection drives genetic divergence of metastatic medulloblastoma.

Author

Wu, Xiaochong, Northcott, Paul A, Dubuc, Adrian, Dupuy, Adam J, Shih, David JH, Witt, Hendrik, Croul, Sidney, Bouffet, Eric, Fults, Daniel W, Eberhart, Charles G, Garzia, Livia, Van Meter, Timothy, Zagzag, David, Jabado, Nada, Schwartzentruber, Jeremy, Majewski, Jacek, Scheetz, Todd E, Pfister, Stefan M, Korshunov, Andrey, Li, Xiao-Nan, Scherer, Stephen W, Cho, Yoon-Jae, Akagi, Keiko, MacDonald, Tobey J, Koster, Jan, McCabe, Martin G, Sarver, Aaron L, Collins, V Peter, Weiss, William A, Largaespada, David A, Collier, Lara S, and Taylor, Michael D

Subjects
Animals, Humans, Mice, Medulloblastoma, Neoplasm Metastasis, Li-Fraumeni Syndrome, Disease Models, Animal, DNA Transposable Elements, Survival Rate, Mutagenesis, Insertional, DNA Methylation, CpG Islands, Germ-Line Mutation, Genes, p53, Clonal Evolution, Disease Models, Animal, Genes, p53, Mutagenesis, Insertional, General Science & Technology
Abstract

Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.

Published
2012

10. An integrated genomic analysis of anaplastic meningioma identifies prognostic molecular signatures

Author

Collord, Grace, Tarpey, Patrick, Kurbatova, Natalja, Martincorena, Inigo, Moran, Sebastian, Castro, Manuel, Nagy, Tibor, Bignell, Graham, Maura, Francesco, Young, Matthew D., Berna, Jorge, Tubio, Jose M. C., McMurran, Chris E., Young, Adam M. H., Sanders, Mathijs, Noorani, Imran, Price, Stephen J., Watts, Colin, Leipnitz, Elke, Kirsch, Matthias, Schackert, Gabriele, Pearson, Danita, Devadass, Abel, Ram, Zvi, Collins, V. Peter, Allinson, Kieren, Jenkinson, Michael D., Zakaria, Rasheed, Syed, Khaja, Hanemann, C. Oliver, Dunn, Jemma, McDermott, Michael W., Kirollos, Ramez W., Vassiliou, George S., Esteller, Manel, Behjati, Sam, Brazma, Alvis, Santarius, Thomas, and McDermott, Ultan

Published
2018
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12. Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma

Author

Sturm, Dominik, Witt, Hendrik, Hovestadt, Volker, Khuong-Quang, Dong-Anh, Jones, David T.W., Konermann, Carolin, Pfaff, Elke, Tönjes, Martje, Sill, Martin, Bender, Sebastian, Kool, Marcel, Zapatka, Marc, Becker, Natalia, Zucknick, Manuela, Hielscher, Thomas, Liu, Xiao-Yang, Fontebasso, Adam M., Ryzhova, Marina, Albrecht, Steffen, Jacob, Karine, Wolter, Marietta, Ebinger, Martin, Schuhmann, Martin U., van Meter, Timothy, Frühwald, Michael C., Hauch, Holger, Pekrun, Arnulf, Radlwimmer, Bernhard, Niehues, Tim, von Komorowski, Gregor, Dürken, Matthias, Kulozik, Andreas E., Madden, Jenny, Donson, Andrew, Foreman, Nicholas K., Drissi, Rachid, Fouladi, Maryam, Scheurlen, Wolfram, von Deimling, Andreas, Monoranu, Camelia, Roggendorf, Wolfgang, Herold-Mende, Christel, Unterberg, Andreas, Kramm, Christof M., Felsberg, Jörg, Hartmann, Christian, Wiestler, Benedikt, Wick, Wolfgang, Milde, Till, Witt, Olaf, Lindroth, Anders M., Schwartzentruber, Jeremy, Faury, Damien, Fleming, Adam, Zakrzewska, Magdalena, Liberski, Pawel P., Zakrzewski, Krzysztof, Hauser, Peter, Garami, Miklos, Klekner, Almos, Bognar, Laszlo, Morrissy, Sorana, Cavalli, Florence, Taylor, Michael D., van Sluis, Peter, Koster, Jan, Versteeg, Rogier, Volckmann, Richard, Mikkelsen, Tom, Aldape, Kenneth, Reifenberger, Guido, Collins, V. Peter, Majewski, Jacek, Korshunov, Andrey, Lichter, Peter, Plass, Christoph, Jabado, Nada, and Pfister, Stefan M.

Published
2012
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13. Frequent Amplification of a chr19q13.41 MicroRNA Polycistron in Aggressive Primitive Neuroectodermal Brain Tumors

Author

Li, Meihua, Lee, Kyle F., Lu, Yuntao, Clarke, Ian, Shih, David, Eberhart, Charles, Collins, V. Peter, Van Meter, Tim, Picard, Daniel, Zhou, Limei, Boutros, Paul C., Modena, Piergiorgio, Liang, Muh-Lii, Scherer, Steve W., Bouffet, Eric, Rutka, James T., Pomeroy, Scott L., Lau, Ching C., Taylor, Michael D., Gajjar, Amar, Dirks, Peter B., Hawkins, Cynthia E., and Huang, Annie

Published
2009
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18. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma

Author

Schwartzentruber, Jeremy, Korshunov, Andrey, Liu, Xiao-Yang, Jones, David T.W., Pfaff, Elke, Jacob, Karine, Sturm, Dominik, Fontebasso, Adam M., Quang, Dong-Anh Khuong, Tonjes, Martje, Hovestadt, Volker, Albrecht, Steffen, Kool, Marcel, Nantel, Andre, Konermann, Carolin, Lindroth, Anders, Jager, Natalie, Rausch, Tobias, Ryzhova, Marina, Korbel, Jan O., Hielscher, Thomas, Hauser, Peter, Garami, Miklos, Klekner, Almos, Bognar, Laszlo, Ebinger, Martin, Schuhmann, Martin U., Scheurlen, Wolfram, Pekrun, Arnulf, Fruhwald, Michael C., Roggendorf, Wolfgang, Kramm, Christoph, Durken, Matthias, Atkinson, Jeffrey, Lepage, Pierre, Montpetit, Alexandre, Zakrzewska, Magdalena, Zakrzewski, Krzystof, Liberski, Pawel P., Dong, Zhifeng, Siegel, Peter, Kulozik, Andreas E., Zapatka, Marc, Guha, Abhijit, Malkin, David, Felsberg, Jorg, Reifenberger, Guido, von Deimling, Andreas, Ichimura, Koichi, Collins, V. Peter, Witt, Hendrik, Milde, Till, Witt, Olaf, Zhang, Cindy, Castelo-Branco, Pedro, Lichter, Peter, Faury, Damien, Tabori, Uri, Plass, Christoph, Majewski, Jacek, Pfister, Stefan M., and Jabado, Nada

Subjects
Gene mutations -- Research, DNA -- Physiological aspects -- Research, Tumor proteins -- Physiological aspects -- Research, Glioblastoma multiforme -- Genetic aspects -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases (1-4). To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX(α-thalassaemia/mental retardation syndrome X-linked) (5) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres (6,7), were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis., Brain tumours are currently the leading cause of cancer-related mortality and morbidity in children. Glioblastoma multiforme (GBM) is a highly aggressive brain tumour and the first cancer to be comprehensively [...]

Published
2012
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26. Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: toward a genetic model of meningioma progression

Author

Weber, Ruthild G., Bostrom, Jan, Wolter, Marietta, Baudis, Michael, Collins, V. Peter, Reifenberger, Guido, and Lichter, Peter

Subjects
Brain tumors -- Genetic aspects, Cancer invasiveness -- Genetic aspects, Chromosome abnormalities -- Analysis, Meningioma -- Genetic aspects, Metastasis -- Genetic aspects, Science and technology
Abstract

Nineteen benign [World Health Organization (WHO) grade I; MI], 21 atypical (WHO grade II; MII), and 19 anaplastic (WHO grade III; MIII) sporadic meningiomas were screened for chromosomal imbalances by comparative genomic hybridization (CGH). These data were supplemented by molecular genetic analyses of selected chromosomal regions and genes. With increasing malignancy grade, a marked accumulation of genomic aberrations was observed; i.e., the numbers (mean [+ or -] SEM) of total alterations detected per tumor were 2.9 [+ or -] 0.7 for MI, 9.2 [+ or -] 1.2 for MII, and 13.3 [+ or -] 1.9 for MIII. The most frequent alteration detected in MI was loss on 22q (58%). In MII aberrations most commonly identified were losses on 1p (76%), 22q (71%), 14q (43%), 18q (43%), 10 (38%), and 6q (33%), as well as gains on 20q (48%), 12q (43%), 15q (43%), 1q (33%), 9q (33%), and 17q (33%). In MIII, most of these alterations were found at similar frequencies. However, an increase in losses on 6q (53%), 10 (68%), and 14q (63%) was observed. In addition, 32% of MIII demonstrated loss on 9p. Homozygous deletions in the CDKN2A gene at 9p21 were found in 4 of 16 MIII (25%). Highly amplified DNA sequences were mapped to 12q13-q15 by CGH in 1 MII Southern blot analysis of this tumor revealed amplification of CDK4 and MDM2. By CGH, DNA sequences from 17q were found to be amplified in 1 MII and 8 MIII, involving 17q23 in all cases. Despite the high frequency of chromosomal aberrations in the MII and MIII investigated, none of these tumors showed mutations in exons 5-8 of the TP53 gene. On the basis of the most common aberrations identified in the various malignancy grades, a model for the genomic alterations associated with meningioma progression is proposed.

Published
1997

31. An integrated genomic analysis of anaplastic meningioma identifies prognostic molecular signatures

Author

Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Zooloxía, Xenética e Antropoloxía Física, Collord, Grace, Tarpey, Patrick, Kurbatova, Natalja, Martincorena, Inigo, Morán, Sebastián, Castro, Manuel, Nagy, Tibor, Bignell, Graham, Maura, Francesco, Young, Matthew D., Berna, Jorge, Castro Tubío, José Manuel, McMurran, Chris E., Young, Adam M.H., Sanders, Mathijs, Noorani, Imran, Price, Stephen J., Watts, Colin, Leipnitz, Elke, Kirsch, Matthias, Schackert, Gabriele, Pearson, Danita, Devadass, Abel, Ram, Zvi, Collins, V. Peter, Allinson, Kieren, Jenkinson, Michael D., Zakaria, Rasheed, Syed, Khaja, Hanemann, C. Oliver, Dunn, Jemma, McDermott, Michael W., Kirollos, Ramez W., Vassiliou, George S., Esteller, Manel, Behjati, Sam, Brazma, Alvis, Santarius, Thomas, McDermott, Ultan, Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Zooloxía, Xenética e Antropoloxía Física, Collord, Grace, Tarpey, Patrick, Kurbatova, Natalja, Martincorena, Inigo, Morán, Sebastián, Castro, Manuel, Nagy, Tibor, Bignell, Graham, Maura, Francesco, Young, Matthew D., Berna, Jorge, Castro Tubío, José Manuel, McMurran, Chris E., Young, Adam M.H., Sanders, Mathijs, Noorani, Imran, Price, Stephen J., Watts, Colin, Leipnitz, Elke, Kirsch, Matthias, Schackert, Gabriele, Pearson, Danita, Devadass, Abel, Ram, Zvi, Collins, V. Peter, Allinson, Kieren, Jenkinson, Michael D., Zakaria, Rasheed, Syed, Khaja, Hanemann, C. Oliver, Dunn, Jemma, McDermott, Michael W., Kirollos, Ramez W., Vassiliou, George S., Esteller, Manel, Behjati, Sam, Brazma, Alvis, Santarius, Thomas, and McDermott, Ultan

Abstract

Anaplastic meningioma is a rare and aggressive brain tumor characterised by intractable recurrences and dismal outcomes. Here, we present an integrated analysis of the whole genome, transcriptome and methylation profiles of primary and recurrent anaplastic meningioma. A key finding was the delineation of distinct molecular subgroups that were associated with diametrically opposed survival outcomes. Relative to lower grade meningiomas, anaplastic tumors harbored frequent driver mutations in SWI/SNF complex genes, which were confined to the poor prognosis subgroup. Aggressive disease was further characterised by transcriptional evidence of increased PRC2 activity, stemness and epithelial-to-mesenchymal transition. Our analyses discern biologically distinct variants of anaplastic meningioma with prognostic and therapeutic significance

Published
2018

32. Differential expression of selected histone modifier genes in human solid cancers

Author

Bowtell David, Collins V Peter, Arends Mark J, Subkhankulova Tanya, Burtt Glynn, Veerakumarasivam Abhi, Bobrow Linda, Blenkiron Cherie, Hyland Sarah J, Ahmed Ahmed, Teschendorff Andrew E, Özdağ Hilal, Kouzarides Tony, Brenton James D, and Caldas Carlos

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Post-translational modification of histones resulting in chromatin remodelling plays a key role in the regulation of gene expression. Here we report characteristic patterns of expression of 12 members of 3 classes of chromatin modifier genes in 6 different cancer types: histone acetyltransferases (HATs)- EP300, CREBBP, and PCAF; histone deacetylases (HDACs)- HDAC1, HDAC2, HDAC4, HDAC5, HDAC7A, and SIRT1; and histone methyltransferases (HMTs)- SUV39H1and SUV39H2. Expression of each gene in 225 samples (135 primary tumours, 47 cancer cell lines, and 43 normal tissues) was analysedby QRT-PCR, normalized with 8 housekeeping genes, and given as a ratio by comparison with a universal reference RNA. Results This involved a total of 13,000 PCR assays allowing for rigorous analysis by fitting a linear regression model to the data. Mutation analysis of HDAC1, HDAC2, SUV39H1, and SUV39H2 revealed only two out of 181 cancer samples (both cell lines) with significant coding-sequence alterations. Supervised analysis and Independent Component Analysis showed that expression of many of these genes was able to discriminate tumour samples from their normal counterparts. Clustering based on the normalized expression ratios of the 12 genes also showed that most samples were grouped according to tissue type. Using a linear discriminant classifier and internal cross-validation revealed that with as few as 5 of the 12 genes, SIRT1, CREBBP, HDAC7A, HDAC5 and PCAF, most samples were correctly assigned. Conclusion The expression patterns of HATs, HDACs, and HMTs suggest these genes are important in neoplastic transformation and have characteristic patterns of expression depending on tissue of origin, with implications for potential clinical application.

Published
2006
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34. 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

35. Divergent clonal selection dominates medulloblastoma at recurrence

Author

Morrissy, A. Sorana, Garzia, Livia, Shih, David J. H., Zuyderduyn, Scott, Huang, Xi, Skowron, Patryk, Remke, Marc, Cavalli, Florence M. G., Ramaswamy, Vijay, Lindsay, Patricia E., Jelveh, Salomeh, Donovan, Laura K., Wang, Xin, Luu, Betty, Zayne, Kory, Li, Yisu, Mayoh, Chelsea, Thiessen, Nina, Mercier, Eloi, Mungall, Karen L., Ma, Yusanne, Tse, Kane, Zeng, Thoma, Shumansky, Karey, Roth, Andrew J. L., Shah, Sohrab, Farooq, Hamza, Kijima, Noriyuki, Holgado, Borja L., Lee, John J. Y., Matan-Lithwick, Stuart, Liu, Jessica, Mack, Stephen C., Manno, Alex, Michealraj, K. A., Nor, Carolina, Peacock, John, Qin, Lei, Reimand, Juri, Rolider, Adi, Thompson, Yuan Y., Wu, Xiaochong, Pugh, Trevor, Ally, Adrian, Bilenky, Mikhail, Butterfield, Yaron S. N., Carlsen, Rebecca, Cheng, Young, Chuah, Eric, Corbett, Richard D., Dhalla, Noreen, He, An, Lee, Darlene, Li, Haiyan I., Long, William, Mayo, Michael, Plettner, Patrick, Qian, Jenny Q., Schein, Jacqueline E., Tam, Angela, Wong, Tina, Birol, Inanc, Zhao, Yongjun, Faria, Claudia C., Pimentel, José, Nunes, Sofia, Shalaby, Tarek, Grotzer, Michael, Pollack, Ian F., Hamilton, Ronald L., Li, Xiao-Nan, Bendel, Anne E., Fults, Daniel W., Walter, Andrew W., Kumabe, Toshihiro, Tominaga, Teiji, Collins, V. Peter, Cho, Yoon-Jae, Hoffman, Caitlin, Lyden, David, Wisoff, Jeffrey H., Garvin, James H., Stearns, Duncan S., Massimi, Luca, Schüller, Ulrich, Sterba, Jaroslav, Zitterbart, Karel, Puget, Stephanie, Ayrault, Olivier, Dunn, Sandra E., Tirapelli, Daniela P. C., Carlotti, Carlos G., Wheeler, Helen, Hallahan, Andrew R., Ingram, Wendy, Macdonald, Tobey J., Olson, Jeffrey J., Van Meir, Erwin G., Lee, Ji-Yeoun, Wang, Kyu-Chang, Kim, Seung-Ki, Cho, Byung-Kyu, Pietsch, Torsten, Fleischhack, Gudrun, Tippelt, Stephan, Ra, Young Shin, Bailey, Simon, Lindsey, Janet C., Clifford, Steven C., Eberhart, Charles G., Cooper, Michael K., Packer, Roger J., Massimino, Maura, Garre, Maria Luisa, Bartels, Ute, Tabori, Uri, Hawkins, Cynthia E., Dirks, Peter, Bouffet, Eric, Rutka, James T., Wechsler-Reya, Robert J., Weiss, William A., Collier, Lara S., Dupuy, Adam J., Korshunov, Andrey, Jones, David T. W., Kool, Marcel, Northcott, Paul A., Pfister, Stefan M., Largaespada, David A., Mungall, Andrew J., Moore, Richard A., Jabado, Nada, Bader, Gary D., Jones, Steven J. M., Malkin, David, Marra, Marco A., Taylor, Michael D., Morrissy, A. Sorana, Garzia, Livia, Shih, David J. H., Zuyderduyn, Scott, Huang, Xi, Skowron, Patryk, Remke, Marc, Cavalli, Florence M. G., Ramaswamy, Vijay, Lindsay, Patricia E., Jelveh, Salomeh, Donovan, Laura K., Wang, Xin, Luu, Betty, Zayne, Kory, Li, Yisu, Mayoh, Chelsea, Thiessen, Nina, Mercier, Eloi, Mungall, Karen L., Ma, Yusanne, Tse, Kane, Zeng, Thoma, Shumansky, Karey, Roth, Andrew J. L., Shah, Sohrab, Farooq, Hamza, Kijima, Noriyuki, Holgado, Borja L., Lee, John J. Y., Matan-Lithwick, Stuart, Liu, Jessica, Mack, Stephen C., Manno, Alex, Michealraj, K. A., Nor, Carolina, Peacock, John, Qin, Lei, Reimand, Juri, Rolider, Adi, Thompson, Yuan Y., Wu, Xiaochong, Pugh, Trevor, Ally, Adrian, Bilenky, Mikhail, Butterfield, Yaron S. N., Carlsen, Rebecca, Cheng, Young, Chuah, Eric, Corbett, Richard D., Dhalla, Noreen, He, An, Lee, Darlene, Li, Haiyan I., Long, William, Mayo, Michael, Plettner, Patrick, Qian, Jenny Q., Schein, Jacqueline E., Tam, Angela, Wong, Tina, Birol, Inanc, Zhao, Yongjun, Faria, Claudia C., Pimentel, José, Nunes, Sofia, Shalaby, Tarek, Grotzer, Michael, Pollack, Ian F., Hamilton, Ronald L., Li, Xiao-Nan, Bendel, Anne E., Fults, Daniel W., Walter, Andrew W., Kumabe, Toshihiro, Tominaga, Teiji, Collins, V. Peter, Cho, Yoon-Jae, Hoffman, Caitlin, Lyden, David, Wisoff, Jeffrey H., Garvin, James H., Stearns, Duncan S., Massimi, Luca, Schüller, Ulrich, Sterba, Jaroslav, Zitterbart, Karel, Puget, Stephanie, Ayrault, Olivier, Dunn, Sandra E., Tirapelli, Daniela P. C., Carlotti, Carlos G., Wheeler, Helen, Hallahan, Andrew R., Ingram, Wendy, Macdonald, Tobey J., Olson, Jeffrey J., Van Meir, Erwin G., Lee, Ji-Yeoun, Wang, Kyu-Chang, Kim, Seung-Ki, Cho, Byung-Kyu, Pietsch, Torsten, Fleischhack, Gudrun, Tippelt, Stephan, Ra, Young Shin, Bailey, Simon, Lindsey, Janet C., Clifford, Steven C., Eberhart, Charles G., Cooper, Michael K., Packer, Roger J., Massimino, Maura, Garre, Maria Luisa, Bartels, Ute, Tabori, Uri, Hawkins, Cynthia E., Dirks, Peter, Bouffet, Eric, Rutka, James T., Wechsler-Reya, Robert J., Weiss, William A., Collier, Lara S., Dupuy, Adam J., Korshunov, Andrey, Jones, David T. W., Kool, Marcel, Northcott, Paul A., Pfister, Stefan M., Largaespada, David A., Mungall, Andrew J., Moore, Richard A., Jabado, Nada, Bader, Gary D., Jones, Steven J. M., Malkin, David, Marra, Marco A., and Taylor, Michael D.

Abstract

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

Published
2016

36. Low-dose Actinomycin-D treatment re-establishes the tumoursuppressive function of P53 in RELA-positive ependymoma

Author

Tzaridis, Theophilos, primary, Milde, Till, additional, Pajtler, Kristian W., additional, Bender, Sebastian, additional, Jones, David T. W., additional, Müller, Simone, additional, Wittmann, Andrea, additional, Schlotter, Magdalena, additional, Kulozik, Andreas E., additional, Lichter, Peter, additional, Collins, V. Peter, additional, Witt, Olaf, additional, Kool, Marcel, additional, Korshunov, Andrey, additional, Pfister, Stefan M., additional, and Witt, Hendrik, additional

Published
2016
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37. Chromosome 17 alterations identify good-risk and poor-risk tumors independently of clinical factors in medulloblastoma

Author

Mccabe, Martin, McCabe, Martin G., Bäcklund, L. Magnus, Leong, Hui Sun, Ichimura, Koichi, and Collins, V. Peter

Subjects
Oncology, Cancer Research, Pathology, Lq gain, Survival, Isochromosome, Disease, Monosomy 6, risk stratification, Risk Factors, 17p loss, Young adult, Child, In Situ Hybridization, Fluorescence, Prognosis, Chromosome 17 (human), Survival Rate, Child, Preschool, Risk stratification, Basic and Translational Investigations, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, monosomy 6, isochromosome, Biology, survival, Young Adult, Internal medicine, medicine, Humans, Cytogenetic, Cerebellar Neoplasms, Survival rate, Anaplasia, Medulloblastoma, Chromosome Aberrations, 17 q gain, cytogenetic, Infant, Newborn, Infant, i(17q), medicine.disease, I(17q), 17q gain, Neurology (clinical), 1q gain, Chromosomes, Human, Pair 17
Abstract

Current risk stratification schemas for medulloblastoma, based on combinations of clinical variables and histotype, fail to accurately identify particularly good- and poor-risk tumors. Attempts have been made to improve discriminatory power by combining clinical variables with cytogenetic data. We report here a pooled analysis of all previous reports of chromosomal copy number related to survival data in medulloblastoma. We collated data from previous reports that explicitly quoted survival data and chromosomal copy number in medulloblastoma. We analyzed the relative prognostic significance of currently used clinical risk stratifiers and the chromosomal aberrations previously reported to correlate with survival. In the pooled dataset metastatic disease, incomplete tumor resection and severe anaplasia were associated with poor outcome, while young age at presentation was not prognostically significant. Of the chromosomal variables studied, isolated 17p loss and gain of 1q correlated with poor survival. Gain of 17q without associated loss of 17p showed a trend to improved outcome. The most commonly reported alteration, isodicentric chromosome 17, was not prognostically significant. Sequential multivariate models identified isolated 17p loss, isolated 17q gain, and 1q gain as independent prognostic factors. In a historical dataset, we have identified isolated 17p loss as a marker of poor outcome and 17q gain as a novel putative marker of good prognosis. Biological markers of poor-risk and good-risk tumors will be critical in stratifying treatment in future trials. Our findings should be prospectively validated independently in future clinical studies.

Published
2011

38. Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age

Author

Fontebasso, Adam M., primary, Shirinian, Margret, additional, Khuong-Quang, Dong-Anh, additional, Bechet, Denise, additional, Gayden, Tenzin, additional, Kool, Marcel, additional, De Jay, Nicolas, additional, Jacob, Karine, additional, Gerges, Noha, additional, Hutter, Barbara, additional, Şeker-Cin, Huriye, additional, Witt, Hendrik, additional, Montpetit, Alexandre, additional, Brunet, Sébastien, additional, Lepage, Pierre, additional, Bourret, Geneviève, additional, Klekner, Almos, additional, Bognár, László, additional, Hauser, Peter, additional, Garami, Miklós, additional, Farmer, Jean-Pierre, additional, Montes, Jose-Luis, additional, Atkinson, Jeffrey, additional, Lambert, Sally, additional, Kwan, Tony, additional, Korshunov, Andrey, additional, Tabori, Uri, additional, Collins, V. Peter, additional, Albrecht, Steffen, additional, Faury, Damien, additional, Pfister, Stefan M., additional, Paulus, Werner, additional, Hasselblatt, Martin, additional, Jones, David T.W., additional, and Jabado, Nada, additional

Published
2015
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39. Amplification of 2p as a Genomic Marker for Transformation in Lymphoma

Author

Kwiecinska, Anna, Ichimura, Koichi, Berglund, Mattias, Dinets, Andrii, Sulaiman, Luqman, Collins, V. Peter, Larsson, Catharina, Porwit, Anna, Lagercrantz, Svetlana Bajalica, Kwiecinska, Anna, Ichimura, Koichi, Berglund, Mattias, Dinets, Andrii, Sulaiman, Luqman, Collins, V. Peter, Larsson, Catharina, Porwit, Anna, and Lagercrantz, Svetlana Bajalica

Abstract

To outline further genetic mechanisms of transformation from follicular lymphoma (FL) to diffuse large B-cell lymphoma (DLBCL), we have performed whole genome array-CGH in 81 tumors from 60 patients [29 de novo DLBCL (dnDLBCL), 31 transformed DLBCL (tDLBCL), and 21 antecedent FL]. In 15 patients, paired tumor samples (primary FL and a subsequent tDLBCL) were available, among which three possessed more than two subsequent tumors, allowing us to follow specific genetic alterations acquired before, during, and after the transformation. Gain of 2p15-16.1 encompassing, among others, the REL, BCL11A, USP34, COMMD1, and OTX1 genes was found to be more common in the tDLBCL compared with dnDLBCL (P < 0.001). Furthermore, a high-level amplification of 2p15-16.1 was also detected in the FL stage prior to transformation, indicating its importance during the transformation event. Quantitative real-time PCR showed a higher level of amplification of REL, USP34, and COMMD1 (all involved in the NF kappa B-pathway) compared with BCL11A, which indicates that the altered genes disrupting the NF kappa B pathway may be the driver genes of transformation rather than the previously suggested BCL11A. Moreover, a 17q21.33 amplification was exclusively found in tDLBCL, never in FL (P < 0.04) or dnDLBCL, indicating an upregulation of genes of importance during the later phase of transformation. Taken together, our study demonstrates potential genomic markers for disease progression to clinically more aggressive forms. We also confirm the importance of the TP53-, CDKN2A-, and NF kappa B-pathways for the transformation from FL to DLBCL.

Published
2014
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40. Real-time quantitative PCR analysis with FRET probes reveals differential expression of the four ERBB4 juxtamembrane-region variants between medulloblastoma and pilocytic astrocytoma

Author

Zeng, Naiyan, Liu, Lu, McCabe, Martin G, Jones, David T W, Ichimura, Koichi, and Collins, V Peter

Subjects
Receptor, ErbB-4, Receptor, ErbB-3, Brain Neoplasms, Receptor, ErbB-2, Brain, Gene Expression, Genetic Variation, Astrocytoma, Polymerase Chain Reaction, Article, ErbB Receptors, Cerebellum, Fluorescence Resonance Energy Transfer, Humans, RNA, Messenger, Medulloblastoma, Peptide Hydrolases
Abstract

We report a comparative study on the mRNA expression of ErbB receptor tyrosine kinases, and in particular ERBB4 transcript variants, in two common paediatric brain tumours: medulloblastoma (MB) and pilocytic astrocytoma (PA).While the conventional real-time quantitative polymerase chain reaction was used to measure the expression of ERRBs and ErbB4-processing protease genes, the LightCycler fluorescence resonance energy transfer probes were specifically designed to investigate all of the known ERBB4 juxtamembrane (JM) and cytoplasmic transcript variants.The overall expression of ERBBs suggests that ErbB2/ErbB4 heterodimers and ErbB4 homodimers may be major functional units of the ErbBs in MB, while ErbB2/ErbB3 heterodimers may play a more prominent role in addition to ErbB4-containing dimers in PA. Different expression patterns of ERBB4 JM transcripts in MB, PA and normal brain were observed. The JM-d variant was only detected in MBs, while JM-c was present in MB and PA but was not identified in normal brain. The expression of cleavable ERBB4 transcript variants was elevated in PAs and MBs compared with normal brain, while mRNA levels of ErbB4-processing proteases were similar in both tumour types and normal brain. This suggests that proteolytic cleavage of ErbB4 may be more common in MB and PA, which leads to signalling events divergent from those in normal brain.Taken together, these results suggest that ErbB4 processing and function may be altered in brain tumours, such as MB and PA, via differential expression of JM transcript variants.

Published
2008

41. Abstract 3094: Epigenetic classification of ependymal brain tumors across age groups

Author

Witt, Hendrik, primary, Sill, Martin, additional, Wani, Khalida, additional, Mack, Steve, additional, Capper, David, additional, Heim, Stephanie, additional, Johann, Pascal, additional, Lambert, Sally, additional, Rhyzova, Marina, additional, Hovestadt, Volker, additional, Tzaridis, Theophilos, additional, Pajtler, Kristian, additional, Bender, Sebastian, additional, Milde, Till, additional, Northcott, Paul A., additional, Kulozik, Andreas E., additional, Witt, Olaf, additional, Lichter, Peter, additional, Collins, V Peter, additional, Deimling, Andreas von, additional, Kool, Marcel, additional, Taylor, Michael D., additional, Hasselblatt, Martin, additional, Jones, David T., additional, Korshunov, Andrey, additional, Aldape, Ken, additional, and Pfister, Stefan, additional

Published
2014
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42. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas

Author

Bender, Sebastian, Tang, Yujie, Lindroth, Anders M, Hovestadt, Volker, Jones, David T W, Kool, Marcel, Zapatka, Marc, Northcott, Paul A, Sturm, Dominik, Wang, Wei Guo, Radlwimmer, Bernhard, Højfeldt, Jonas W, Truffaux, Nathalène, Castel, David, Schubert, Simone, Ryzhova, Marina, Seker-Cin, Huriye, Gronych, Jan, Johann, Pascal David, Stark, Sebastian, Meyer, Jochen, Milde, Till, Schuhmann, Martin, Ebinger, Martin, Monoranu, Camelia-Maria, Ponnuswami, Anitha, Chen, Spenser, Jones, Chris, Witt, Olaf, Collins, V Peter, von Deimling, Andreas, Jabado, Nada, Puget, Stephanie, Grill, Jacques, Helin, Kristian, Korshunov, Andrey, Lichter, Peter, Monje, Michelle, Plass, Christoph, Cho, Yoon-Jae, Pfister, Stefan M, Bender, Sebastian, Tang, Yujie, Lindroth, Anders M, Hovestadt, Volker, Jones, David T W, Kool, Marcel, Zapatka, Marc, Northcott, Paul A, Sturm, Dominik, Wang, Wei Guo, Radlwimmer, Bernhard, Højfeldt, Jonas W, Truffaux, Nathalène, Castel, David, Schubert, Simone, Ryzhova, Marina, Seker-Cin, Huriye, Gronych, Jan, Johann, Pascal David, Stark, Sebastian, Meyer, Jochen, Milde, Till, Schuhmann, Martin, Ebinger, Martin, Monoranu, Camelia-Maria, Ponnuswami, Anitha, Chen, Spenser, Jones, Chris, Witt, Olaf, Collins, V Peter, von Deimling, Andreas, Jabado, Nada, Puget, Stephanie, Grill, Jacques, Helin, Kristian, Korshunov, Andrey, Lichter, Peter, Monje, Michelle, Plass, Christoph, Cho, Yoon-Jae, and Pfister, Stefan M

Abstract

Two recurrent mutations, K27M and G34R/V, within histone variant H3.3 were recently identified in ∼50% of pHGGs. Both mutations define clinically and biologically distinct subgroups of pHGGs. Here, we provide further insight about the dominant-negative effect of K27M mutant H3.3, leading to a global reduction of the repressive histone mark H3K27me3. We demonstrate that this is caused by aberrant recruitment of the PRC2 complex to K27M mutant H3.3 and enzymatic inhibition of the H3K27me3-establishing methyltransferase EZH2. By performing chromatin immunoprecipitation followed by next-generation sequencing and whole-genome bisulfite sequencing in primary pHGGs, we show that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs.

Published
2013

43. Alterations of the Tumor Suppressor Genes CDKN2A (p16INK4a), p14ARF, CDKN2B (p15INK4b), and CDKN2C (p18INK4c) in Atypical and Anaplastic Meningiomas

Author

Boström, Jan, Meyer-Puttlitz, Birgit, Wolter, Marietta, Blaschke, Britta, Weber, Ruthild G., Lichter, Peter, Ichimura, Koichi, Collins, V. Peter, and Reifenberger, Guido

Subjects
Adult, Cyclin-Dependent Kinase Inhibitor p21, Male, Molecular Sequence Data, Gene Dosage, Loss of Heterozygosity, Cell Cycle Proteins, Cyclins, Tumor Suppressor Protein p14ARF, otorhinolaryngologic diseases, Meningeal Neoplasms, Cyclin-Dependent Kinase Inhibitor p18, Humans, Genes, Tumor Suppressor, Enzyme Inhibitors, Child, neoplasms, Cyclin-Dependent Kinase Inhibitor p16, Aged, Cyclin-Dependent Kinase Inhibitor p15, Aged, 80 and over, Base Sequence, Tumor Suppressor Proteins, Chromosome Mapping, Proteins, Middle Aged, Cyclin-Dependent Kinases, nervous system diseases, Chromosomes, Human, Pair 1, Female, Carrier Proteins, Chromosomes, Human, Pair 9, Meningioma, Regular Articles, Microsatellite Repeats
Abstract

We investigated 67 meningothelial tumors (20 benign meningiomas, 34 atypical meningiomas, and 13 anaplastic meningiomas) for losses of genetic information from chromosome arms 1p and 9p, as well as for deletion, mutation, and expression of the tumor suppressor genes CDKN2A (p16(INKa)/MTS1), p14(ARF), CDKN2B (p15(INK4b)/MTS2) (all located at 9p21) and CDKN2C (1p32). Comparative genomic hybridization and microsatellite analysis showed losses on 1p in 11 anaplastic meningiomas (85%), 23 atypical meningiomas (68%), and 5 benign meningiomas (25%). One atypical meningioma with loss of heterozygosity on 1p carried a somatic CDKN2C mutation (c.202CT: R68X). Losses on 9p were found in five anaplastic meningiomas (38%), six atypical meningiomas (18%), and one benign meningioma (5%). Six anaplastic meningiomas (46%) and one atypical meningioma (3%) showed homozygous deletions of the CDKN2A, p14(ARF), and CDKN2B genes. Two anaplastic meningiomas carried somatic point mutations in CDKN2A (c.262GT: E88X and c.262GA: E88K) and p14(ARF) (c.305GT: G102V and c.305GA: G102E). One anaplastic meningioma, three atypical meningiomas, and one benign meningioma without a demonstrated homozygous deletion or mutation of CDKN2A, p14(ARF), or CDKN2B lacked detectable transcripts from at least one of these genes. Hypermethylation of CDKN2A, p14(ARF), and CDKN2B could be demonstrated in one of these cases. Taken together, our results indicate that CDKN2C is rarely altered in meningiomas. However, the majority of anaplastic meningiomas either show homozygous deletions of CDKN2A, p14(ARF), and CDKN2B, mutations in CDKN2A and p14(ARF), or lack of expression of one or more of these genes. Thus, inactivation of the G(1)/S-phase cell-cycle checkpoint is an important aberration in anaplastic meningiomas.

Published
2001

44. Characterization of 6q deletions in mature B cell lymphomas and childhood acute lymphoblastic leukemia

Author

Thelander, Emma Flordal, Ichimura, Koichi, Corcoran, Martin, Barbany, Gisela, Nordgren, Ann, Heyman, Mats, Berglund, Mattias, Mungall, Andy, Rosenquist, Richard, Collins, V Peter, Grandér, Dan, Larsson, Catharina, Lagercrantz, Svetlana, Thelander, Emma Flordal, Ichimura, Koichi, Corcoran, Martin, Barbany, Gisela, Nordgren, Ann, Heyman, Mats, Berglund, Mattias, Mungall, Andy, Rosenquist, Richard, Collins, V Peter, Grandér, Dan, Larsson, Catharina, and Lagercrantz, Svetlana

Abstract

The study was undertaken with the aim to outline deletion patterns involving the long arm of chromosome 6, a common abnormality in lymphoproliferative disorders. Using a chromosome 6 specific tile path array, 60 samples from in total 49 cases with mantle cell lymphoma (MCL), de novo diffuse large B-cell lymphoma (DLBCL), transformed DLBCL as well as preceding follicular lymphoma (FL), and childhood acute lymphoblastic leukemia (ALL), were characterized. Twenty-six of the studied cases, representing all diagnoses, showed a 6q deletion among which 85% involved a 3Mb region in 6q21. The minimal deleted interval in 6q21 encompasses the FOXO3A, PRDM1 and HACE1 candidate genes. The PRDM1 gene was found homozygously deleted in a case of DLBCL. Moreover, in two DLBCL cases, an overlapping homozygous deletion was identified in 6q23.3-24.1, encompassing the TNFAIP3 gene among others. Taken together, we refined the deletion pattern within the long arm of chromosome 6 in four different types of hematological malignances, suggesting the location of tumor suppressor genes involved in the tumor progression.

Published
2008
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45. Issues of diagnostic review in brain tumor studies : from the brain tumor epidemiology consortium

Author

Davis, Faith G, Malmer, Beatrice, Aldape, Ken, Barnholtz-Sloan, Jill S, Bondy, Melissa L, Brännström, Thomas, Bruner, Janet M, Burger, Peter C, Collins, V Peter, Inskip, Peter D, Kruchko, Carol, McCarthy, Bridget J, McLendon, Roger E, Sadetzki, Siegal, Tihan, Tarik, Wrensch, Margaret R, Buffler, Patricia A, Davis, Faith G, Malmer, Beatrice, Aldape, Ken, Barnholtz-Sloan, Jill S, Bondy, Melissa L, Brännström, Thomas, Bruner, Janet M, Burger, Peter C, Collins, V Peter, Inskip, Peter D, Kruchko, Carol, McCarthy, Bridget J, McLendon, Roger E, Sadetzki, Siegal, Tihan, Tarik, Wrensch, Margaret R, and Buffler, Patricia A

Abstract

Epidemiologists routinely conduct centralized single pathology reviews to minimize interobserver diagnostic variability, but this practice does not facilitate the combination of studies across geographic regions and institutions where diagnostic practices differ. A meeting of neuropathologists and epidemiologists focused on brain tumor classification issues in the context of protocol needs for consortial studies (http://epi.grants.cancer.gov/btec/). It resulted in recommendations relevant to brain tumors and possibly other rare disease studies. Two categories of brain tumors have enough general agreement over time, across regions, and between individual pathologists that one can consider using existing diagnostic data without further review: glioblastomas and meningiomas (as long as uniform guidelines such as those provided by the WHO are used). Prospective studies of these tumors benefit from collection of pathology reports, at a minimum recording the pathology department and classification system used in the diagnosis. Other brain tumors, such as oligodendroglioma, are less distinct and require careful histopathologic review for consistent classification across study centers. Epidemiologic study protocols must consider the study specific aims, diagnostic changes that have taken place over time, and other issues unique to the type(s) of tumor being studied. As diagnostic changes are being made rapidly, there are no readily available answers on disease classification issues. It is essential that epidemiologists and neuropathologists collaborate to develop appropriate study designs and protocols for specific hypothesis and populations.

Published
2008
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46. Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas

Author

Bender, Sebastian, primary, Tang, Yujie, additional, Lindroth, Anders M., additional, Hovestadt, Volker, additional, Jones, David T.W., additional, Kool, Marcel, additional, Zapatka, Marc, additional, Northcott, Paul A., additional, Sturm, Dominik, additional, Wang, Wei, additional, Radlwimmer, Bernhard, additional, Højfeldt, Jonas W., additional, Truffaux, Nathalène, additional, Castel, David, additional, Schubert, Simone, additional, Ryzhova, Marina, additional, Şeker-Cin, Huriye, additional, Gronych, Jan, additional, Johann, Pascal David, additional, Stark, Sebastian, additional, Meyer, Jochen, additional, Milde, Till, additional, Schuhmann, Martin, additional, Ebinger, Martin, additional, Monoranu, Camelia-Maria, additional, Ponnuswami, Anitha, additional, Chen, Spenser, additional, Jones, Chris, additional, Witt, Olaf, additional, Collins, V. Peter, additional, von Deimling, Andreas, additional, Jabado, Nada, additional, Puget, Stephanie, additional, Grill, Jacques, additional, Helin, Kristian, additional, Korshunov, Andrey, additional, Lichter, Peter, additional, Monje, Michelle, additional, Plass, Christoph, additional, Cho, Yoon-Jae, additional, and Pfister, Stefan M., additional

Published
2013
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47. The eEF2 Kinase Confers Resistance to Nutrient Deprivation by Blocking Translation Elongation

Author

Leprivier, Gabriel, primary, Remke, Marc, additional, Rotblat, Barak, additional, Dubuc, Adrian, additional, Mateo, Abigail-Rachele F., additional, Kool, Marcel, additional, Agnihotri, Sameer, additional, El-Naggar, Amal, additional, Yu, Bin, additional, Prakash Somasekharan, Syam, additional, Faubert, Brandon, additional, Bridon, Gaëlle, additional, Tognon, Cristina E., additional, Mathers, Joan, additional, Thomas, Ryan, additional, Li, Amy, additional, Barokas, Adi, additional, Kwok, Brian, additional, Bowden, Mary, additional, Smith, Stephanie, additional, Wu, Xiaochong, additional, Korshunov, Andrey, additional, Hielscher, Thomas, additional, Northcott, Paul A., additional, Galpin, Jason D., additional, Ahern, Christopher A., additional, Wang, Ye, additional, McCabe, Martin G., additional, Collins, V. Peter, additional, Jones, Russell G., additional, Pollak, Michael, additional, Delattre, Olivier, additional, Gleave, Martin E., additional, Jan, Eric, additional, Pfister, Stefan M., additional, Proud, Christopher G., additional, Derry, W. Brent, additional, Taylor, Michael D., additional, and Sorensen, Poul H., additional

Published
2013
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48. Abstract 3807: Integrative genomic profiling of pilocytic astrocytomas reveals location specific differential methylation and expression of brain developmental genes.

Author

Lambert, Sally R., primary, Witt, Hendrik, additional, Hovestadt, Volker, additional, Zucknick, Manuela, additional, Kool, Marcel, additional, Pearson, Danita, additional, Korshnov, Andrey, additional, Pfister, Stefan, additional, Collins, V. Peter, additional, and Jones, David T. W., additional

Published
2013
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49. Detailed assessment of copy number alterations revealing homozygous deletions in 1p and 13q in mantle cell lymphoma

Author

Flordal Thelander, Emma, Ichimura, Koichi, Collins, V. Peter, Walsh, Sarah H., Barbany, Gisela, Hagberg, Anette, Laurell, Anna, Rosenquist, Richard, Larsson, Catharina, Lagercrantz, Svetlana, Flordal Thelander, Emma, Ichimura, Koichi, Collins, V. Peter, Walsh, Sarah H., Barbany, Gisela, Hagberg, Anette, Laurell, Anna, Rosenquist, Richard, Larsson, Catharina, and Lagercrantz, Svetlana

Abstract

Mantle cell lymphoma (MCL) is characterized by over-expression of cyclin Dl as a result of the characteristic t(11;14)(q13;q32). However, this translocation alone has proven not to be sufficient for lymphomagenesis, suggesting the involvement of additional alterations. We have characterized 35 cases of MCL by array comparative genomic hybridization with an average resolution of 0.97Mb distributed over the complete human genome. The most common alterations were losses in 1p13.2–p31.1, 6q16.2–q27, 8p21.3, 9p13.2–p24.3, 9q13–q31.3, 11q14.3–q23.3, 13q14.13–q21.31, 13q33.1–q34, and 22q11.23–q13.33 and gains involving 3q21.2–q29, 7p12.1–p22.3, 8q24.13–q24.23, and 18q21.33–q22.3. Four homozygous deletions were identified in totally three patients; two overlapping at 1p32.3, and two adjacent at 13q32.3. The homozygous deletions at 1p32.3 cover the CDKN2C locus (coding for p18), while the region at 13q32.3 does not encompass any known tumor suppressor genes. A gain in 3q was significantly associated with shorter survival (P=0.047).

Published
2007
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