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1. Failure of human rhombic lip differentiation underlies medulloblastoma formation

Author

Hendrikse, Liam D, Haldipur, Parthiv, Saulnier, Olivier, Millman, Jake, Sjoboen, Alexandria H, Erickson, Anders W, Ong, Winnie, Gordon, Victor, Coudière-Morrison, Ludivine, Mercier, Audrey L, Shokouhian, Mohammad, Suárez, Raúl A, Ly, Michelle, Borlase, Stephanie, Scott, David S, Vladoiu, Maria C, Farooq, Hamza, Sirbu, Olga, Nakashima, Takuma, Nambu, Shohei, Funakoshi, Yusuke, Bahcheli, Alec, Diaz-Mejia, J Javier, Golser, Joseph, Bach, Kathleen, Phuong-Bao, Tram, Skowron, Patryk, Wang, Evan Y, Kumar, Sachin A, Balin, Polina, Visvanathan, Abhirami, Lee, John JY, Ayoub, Ramy, Chen, Xin, Chen, Xiaodi, Mungall, Karen L, Luu, Betty, Bérubé, Pierre, Wang, Yu C, Pfister, Stefan M, Kim, Seung-Ki, Delattre, Olivier, Bourdeaut, Franck, Doz, François, Masliah-Planchon, Julien, Grajkowska, Wieslawa A, Loukides, James, Dirks, Peter, Fèvre-Montange, Michelle, Jouvet, Anne, French, Pim J, Kros, Johan M, Zitterbart, Karel, Bailey, Swneke D, Eberhart, Charles G, Rao, Amulya AN, Giannini, Caterina, Olson, James M, Garami, Miklós, Hauser, Peter, Phillips, Joanna J, Ra, Young S, de Torres, Carmen, Mora, Jaume, Li, Kay KW, Ng, Ho-Keung, Poon, Wai S, Pollack, Ian F, López-Aguilar, Enrique, Gillespie, G Yancey, Van Meter, Timothy E, Shofuda, Tomoko, Vibhakar, Rajeev, Thompson, Reid C, Cooper, Michael K, Rubin, Joshua B, Kumabe, Toshihiro, Jung, Shin, Lach, Boleslaw, Iolascon, Achille, Ferrucci, Veronica, de Antonellis, Pasqualino, Zollo, Massimo, Cinalli, Giuseppe, Robinson, Shenandoah, Stearns, Duncan S, Van Meir, Erwin G, Porrati, Paola, Finocchiaro, Gaetano, Massimino, Maura, Carlotti, Carlos G, Faria, Claudia C, Roussel, Martine F, Boop, Frederick, Chan, Jennifer A, Aldinger, Kimberly A, Razavi, Ferechte, Silvestri, Evelina, McLendon, Roger E, and Thompson, Eric M

Subjects
Stem Cell Research, Brain Disorders, Neurosciences, Rare Diseases, Stem Cell Research - Nonembryonic - Non-Human, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, 2.1 Biological and endogenous factors, Cell Differentiation, Cell Lineage, Cerebellar Neoplasms, Cerebellum, Core Binding Factor alpha Subunits, Hedgehog Proteins, Histone Demethylases, Humans, Ki-67 Antigen, Medulloblastoma, Metencephalon, Muscle Proteins, Mutation, Otx Transcription Factors, Repressor Proteins, T-Box Domain Proteins, Transcription Factors, General Science & Technology
Abstract

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

Published
2022

2. The transcriptional landscape of Shh medulloblastoma.

Author

Skowron, Patryk, Farooq, Hamza, Cavalli, Florence MG, Morrissy, A Sorana, Ly, Michelle, Hendrikse, Liam D, Wang, Evan Y, Djambazian, Haig, Zhu, Helen, Mungall, Karen L, Trinh, Quang M, Zheng, Tina, Dai, Shizhong, Stucklin, Ana S Guerreiro, Vladoiu, Maria C, Fong, Vernon, Holgado, Borja L, Nor, Carolina, Wu, Xiaochong, Abd-Rabbo, Diala, Bérubé, Pierre, Wang, Yu Chang, Luu, Betty, Suarez, Raul A, Rastan, Avesta, Gillmor, Aaron H, Lee, John JY, Zhang, Xiao Yun, Daniels, Craig, Dirks, Peter, Malkin, David, Bouffet, Eric, Tabori, Uri, Loukides, James, Doz, François P, Bourdeaut, Franck, Delattre, Olivier O, Masliah-Planchon, Julien, Ayrault, Olivier, Kim, Seung-Ki, Meyronet, David, Grajkowska, Wieslawa A, Carlotti, Carlos G, de Torres, Carmen, Mora, Jaume, Eberhart, Charles G, Van Meir, Erwin G, Kumabe, Toshihiro, French, Pim J, Kros, Johan M, Jabado, Nada, Lach, Boleslaw, Pollack, Ian F, Hamilton, Ronald L, Rao, Amulya A Nageswara, Giannini, Caterina, Olson, James M, Bognár, László, Klekner, Almos, Zitterbart, Karel, Phillips, Joanna J, Thompson, Reid C, Cooper, Michael K, Rubin, Joshua B, Liau, Linda M, Garami, Miklós, Hauser, Peter, Li, Kay Ka Wai, Ng, Ho-Keung, Poon, Wai Sang, Yancey Gillespie, G, Chan, Jennifer A, Jung, Shin, McLendon, Roger E, Thompson, Eric M, Zagzag, David, Vibhakar, Rajeev, Ra, Young Shin, Garre, Maria Luisa, Schüller, Ulrich, Shofuda, Tomoko, Faria, Claudia C, López-Aguilar, Enrique, Zadeh, Gelareh, Hui, Chi-Chung, Ramaswamy, Vijay, Bailey, Swneke D, Jones, Steven J, Mungall, Andrew J, Moore, Richard A, Calarco, John A, Stein, Lincoln D, Bader, Gary D, Reimand, Jüri, Ragoussis, Jiannis, Weiss, William A, Marra, Marco A, Suzuki, Hiromichi, and Taylor, Michael D

Subjects
Humans, Medulloblastoma, Cerebellar Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Adolescent, Adult, Middle Aged, Child, Child, Preschool, Infant, Female, Male, Hedgehog Proteins, Gene Regulatory Networks, Genetic Variation, Young Adult, Transcriptome, Pediatric Research Initiative, Brain Cancer, Pediatric, Rare Diseases, Genetics, Pediatric Cancer, Clinical Research, Brain Disorders, Neurosciences, Biotechnology, Human Genome, Cancer, 2.1 Biological and endogenous factors
Abstract

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.

Published
2021

3. A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor

Author

Sin-Chan, Patrick, Mumal, Iqra, Suwal, Tannu, Ho, Ben, Fan, Xiaolian, Singh, Irtisha, Du, Yuchen, Lu, Mei, Patel, Neilket, Torchia, Jonathon, Popovski, Dean, Fouladi, Maryam, Guilhamon, Paul, Hansford, Jordan R, Leary, Sarah, Hoffman, Lindsey M, Levy, Jean M Mulcahy, Lassaletta, Alvaro, Solano-Paez, Palma, Rivas, Eloy, Reddy, Alyssa, Gillespie, G Yancey, Gupta, Nalin, Van Meter, Timothy E, Nakamura, Hideo, Wong, Tai-Tong, Ra, Young-Shin, Kim, Seung-Ki, Massimi, Luca, Grundy, Richard G, Fangusaro, Jason, Johnston, Donna, Chan, Jennifer, Lafay-Cousin, Lucie, Hwang, Eugene I, Wang, Yin, Catchpoole, Daniel, Michaud, Jean, Ellezam, Benjamin, Ramanujachar, Ramya, Lindsay, Holly, Taylor, Michael D, Hawkins, Cynthia E, Bouffet, Eric, Jabado, Nada, Singh, Sheila K, Kleinman, Claudia L, Barsyte-Lovejoy, Dalia, Li, Xiao-Nan, Dirks, Peter B, Lin, Charles Y, Mack, Stephen C, Rich, Jeremy N, and Huang, Annie

Subjects
Rare Diseases, Neurosciences, Cancer, Genetics, Biotechnology, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Biomarkers, Tumor, Brain Neoplasms, Cell Cycle, Cell Transformation, Neoplastic, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 2, DNA Copy Number Variations, Enhancer Elements, Genetic, Epigenesis, Genetic, Gene Expression Regulation, Gene Regulatory Networks, Genetic Association Studies, Genetic Predisposition to Disease, Humans, MicroRNAs, Models, Biological, Multigene Family, N-Myc Proto-Oncogene Protein, Neoplasms, Germ Cell and Embryonal, Oncogenes, RNA-Binding Proteins, C19MC, ETMR, LIN28A, MYCN, brain tumor, cell-cycle, epigenetics, microRNA, super-enhancer, therapeutics, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death.

Published
2019

4. Intertumoral Heterogeneity within Medulloblastoma Subgroups

Author

Cavalli, Florence MG, Remke, Marc, Rampasek, Ladislav, Peacock, John, Shih, David JH, Luu, Betty, Garzia, Livia, Torchia, Jonathon, Nor, Carolina, Morrissy, A Sorana, Agnihotri, Sameer, Thompson, Yuan Yao, Kuzan-Fischer, Claudia M, Farooq, Hamza, Isaev, Keren, Daniels, Craig, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Lee, Ji Yeoun, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Vasiljevic, Alexandre, Faure-Conter, Cecile, Jouvet, Anne, Giannini, Caterina, Rao, Amulya A Nageswara, Li, Kay Ka Wai, Ng, Ho-Keung, Eberhart, Charles G, Pollack, Ian F, Hamilton, Ronald L, Gillespie, G Yancey, Olson, James M, Leary, Sarah, Weiss, William A, Lach, Boleslaw, Chambless, Lola B, Thompson, Reid C, Cooper, Michael K, Vibhakar, Rajeev, Hauser, Peter, van Veelen, Marie-Lise C, Kros, Johan M, French, Pim J, Ra, Young Shin, Kumabe, Toshihiro, López-Aguilar, Enrique, Zitterbart, Karel, Sterba, Jaroslav, Finocchiaro, Gaetano, Massimino, Maura, Van Meir, Erwin G, Osuka, Satoru, Shofuda, Tomoko, Klekner, Almos, Zollo, Massimo, Leonard, Jeffrey R, Rubin, Joshua B, Jabado, Nada, Albrecht, Steffen, Mora, Jaume, Van Meter, Timothy E, Jung, Shin, Moore, Andrew S, Hallahan, Andrew R, Chan, Jennifer A, Tirapelli, Daniela PC, Carlotti, Carlos G, Fouladi, Maryam, Pimentel, José, Faria, Claudia C, Saad, Ali G, Massimi, Luca, Liau, Linda M, Wheeler, Helen, Nakamura, Hideo, Elbabaa, Samer K, Perezpeña-Diazconti, Mario, de León, Fernando Chico Ponce, Robinson, Shenandoah, Zapotocky, Michal, Lassaletta, Alvaro, Huang, Annie, Hawkins, Cynthia E, Tabori, Uri, Bouffet, Eric, Bartels, Ute, Dirks, Peter B, Rutka, James T, Bader, Gary D, Reimand, Jüri, Goldenberg, Anna, Ramaswamy, Vijay, and Taylor, Michael D

Subjects
Genetics, Rare Diseases, Pediatric Cancer, Cancer, Brain Cancer, Pediatric Research Initiative, Pediatric, Human Genome, Brain Disorders, Cluster Analysis, Cohort Studies, DNA Copy Number Variations, DNA Methylation, Gene Expression Profiling, Genomics, Humans, Medulloblastoma, Precision Medicine, copy number, gene expression, integrative clustering, medulloblastoma, methylation, subgroups, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

Published
2017

5. Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors

Author

Torchia, Jonathon, Golbourn, Brian, Feng, Shengrui, Ho, Ching, Sin-Chan, Patrick, Vasiljevic, Alexandre, Norman, Joseph D, Guilhamon, Paul, Garzia, Livia, Agamez, Natalia R, Lu, Mei, Chan, Tiffany S, Picard, Daniel, de Antonellis, Pasqualino, Khuong-Quang, Dong-Anh, Planello, Aline C, Zeller, Constanze, Barsyte-Lovejoy, Dalia, Lafay-Cousin, Lucie, Letourneau, Louis, Bourgey, Mathieu, Yu, Man, Gendoo, Deena MA, Dzamba, Misko, Barszczyk, Mark, Medina, Tiago, Riemenschneider, Alexandra N, Morrissy, A Sorana, Ra, Young-Shin, Ramaswamy, Vijay, Remke, Marc, Dunham, Christopher P, Yip, Stephen, Ng, Ho-keung, Lu, Jian-Qiang, Mehta, Vivek, Albrecht, Steffen, Pimentel, Jose, Chan, Jennifer A, Somers, Gino R, Faria, Claudia C, Roque, Lucia, Fouladi, Maryam, Hoffman, Lindsey M, Moore, Andrew S, Wang, Yin, Choi, Seung Ah, Hansford, Jordan R, Catchpoole, Daniel, Birks, Diane K, Foreman, Nicholas K, Strother, Doug, Klekner, Almos, Bognár, Laszló, Garami, Miklós, Hauser, Péter, Hortobágyi, Tibor, Wilson, Beverly, Hukin, Juliette, Carret, Anne-Sophie, Van Meter, Timothy E, Hwang, Eugene I, Gajjar, Amar, Chiou, Shih-Hwa, Nakamura, Hideo, Toledano, Helen, Fried, Iris, Fults, Daniel, Wataya, Takafumi, Fryer, Chris, Eisenstat, David D, Scheinemann, Katrin, Fleming, Adam J, Johnston, Donna L, Michaud, Jean, Zelcer, Shayna, Hammond, Robert, Afzal, Samina, Ramsay, David A, Sirachainan, Nongnuch, Hongeng, Suradej, Larbcharoensub, Noppadol, Grundy, Richard G, Lulla, Rishi R, Fangusaro, Jason R, Druker, Harriet, Bartels, Ute, Grant, Ronald, Malkin, David, McGlade, C Jane, Nicolaides, Theodore, Tihan, Tarik, Phillips, Joanna, Majewski, Jacek, Montpetit, Alexandre, Bourque, Guillaume, Bader, Gary D, Reddy, Alyssa T, Gillespie, G Yancey, and Warmuth-Metz, Monika

Subjects
Genetics, Human Genome, Rare Diseases, Orphan Drug, Cancer, 2.1 Biological and endogenous factors, Development of treatments and therapeutic interventions, Aetiology, 5.1 Pharmaceuticals, Cell Line, Tumor, Cell Proliferation, Cell Survival, Central Nervous System Neoplasms, Chromatin, DNA Methylation, Dasatinib, Epigenesis, Genetic, Epigenomics, Humans, Mutation, Protein Kinase Inhibitors, Pyrimidines, Receptor, Platelet-Derived Growth Factor beta, Rhabdoid Tumor, SMARCB1 Protein, Teratoma, ATRT, enhancer, epigenomics, genomics, rhabdoid tumors, subgroup-specific therapeutics, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

Published
2016

6. Author Correction: Failure of human rhombic lip differentiation underlies medulloblastoma formation

Author

Hendrikse, Liam D., Haldipur, Parthiv, Saulnier, Olivier, Millman, Jake, Sjoboen, Alexandria H., Erickson, Anders W., Ong, Winnie, Gordon, Victor, Coudière-Morrison, Ludivine, Mercier, Audrey L., Shokouhian, Mohammad, Suárez, Raúl A., Ly, Michelle, Borlase, Stephanie, Scott, David S., Vladoiu, Maria C., Farooq, Hamza, Sirbu, Olga, Nakashima, Takuma, Nambu, Shohei, Funakoshi, Yusuke, Bahcheli, Alec, Diaz-Mejia, J. Javier, Golser, Joseph, Bach, Kathleen, Phuong-Bao, Tram, Skowron, Patryk, Wang, Evan Y., Kumar, Sachin A., Balin, Polina, Visvanathan, Abhirami, Lee, John J. Y., Ayoub, Ramy, Chen, Xin, Chen, Xiaodi, Mungall, Karen L., Luu, Betty, Bérubé, Pierre, Wang, Yu C., Pfister, Stefan M., Kim, Seung-Ki, Delattre, Olivier, Bourdeaut, Franck, Doz, François, Masliah-Planchon, Julien, Grajkowska, Wieslawa A., Loukides, James, Dirks, Peter, Fèvre-Montange, Michelle, Jouvet, Anne, French, Pim J., Kros, Johan M., Zitterbart, Karel, Bailey, Swneke D., Eberhart, Charles G., Rao, Amulya A. N., Giannini, Caterina, Olson, James M., Garami, Miklós, Hauser, Peter, Phillips, Joanna J., Ra, Young S., de Torres, Carmen, Mora, Jaume, Li, Kay K. W., Ng, Ho-Keung, Poon, Wai S., Pollack, Ian F., López-Aguilar, Enrique, Gillespie, G. Yancey, Van Meter, Timothy E., Shofuda, Tomoko, Vibhakar, Rajeev, Thompson, Reid C., Cooper, Michael K., Rubin, Joshua B., Kumabe, Toshihiro, Jung, Shin, Lach, Boleslaw, Iolascon, Achille, Ferrucci, Veronica, de Antonellis, Pasqualino, Zollo, Massimo, Cinalli, Giuseppe, Robinson, Shenandoah, Stearns, Duncan S., Van Meir, Erwin G., Porrati, Paola, Finocchiaro, Gaetano, Massimino, Maura, Carlotti, Carlos G., Faria, Claudia C., Roussel, Martine F., Boop, Frederick, Chan, Jennifer A., Aldinger, Kimberly A., Razavi, Ferechte, Silvestri, Evelina, McLendon, Roger E., Thompson, Eric M., Ansari, Marc, Garre, Maria L., Chico, Fernando, Eguía, Pilar, Pérezpeña, Mario, Morrissy, A. Sorana, Cavalli, Florence M. G., Wu, Xiaochong, Daniels, Craig, Rich, Jeremy N., Jones, Steven J. M., Moore, Richard A., Marra, Marco A., Huang, Xi, Reimand, Jüri, Sorensen, Poul H., Wechsler-Reya, Robert J., Weiss, William A., Pugh, Trevor J., Garzia, Livia, Kleinman, Claudia L., Stein, Lincoln D., Jabado, Nada, Malkin, David, Ayrault, Olivier, Golden, Jeffrey A., Ellison, David W., Doble, Brad, Ramaswamy, Vijay, Werbowetski-Ogilvie, Tamra E., Suzuki, Hiromichi, Millen, Kathleen J., and Taylor, Michael D.

Published
2022
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17. Subgroup-specific structural variation across 1,000 medulloblastoma genomes.

Author

Northcott, Paul, Shih, David, Peacock, John, Garzia, Livia, Morrissy, A, Zichner, Thomas, Stütz, Adrian, Korshunov, Andrey, Reimand, Jüri, Schumacher, Steven, Beroukhim, Rameen, Ellison, David, Marshall, Christian, Lionel, Anath, Mack, Stephen, Dubuc, Adrian, Yao, Yuan, Ramaswamy, Vijay, Luu, Betty, Rolider, Adi, Cavalli, Florence, Wang, Xin, Remke, Marc, Wu, Xiaochong, Chiu, Readman, Chu, Andy, Chuah, Eric, Corbett, Richard, Hoad, Gemma, Jackman, Shaun, Li, Yisu, Lo, Allan, Mungall, Karen, Nip, Ka, Qian, Jenny, Raymond, Anthony, Thiessen, Nina, Varhol, Richard, Birol, Inanc, Moore, Richard, Mungall, Andrew, Holt, Robert, Kawauchi, Daisuke, Roussel, Martine, Kool, Marcel, Jones, David, Witt, Hendrick, Fernandez-L, Africa, Kenney, Anna, Wechsler-Reya, Robert, Dirks, Peter, Aviv, Tzvi, Grajkowska, Wieslawa, Perek-Polnik, Marta, Haberler, Christine, Delattre, Olivier, Reynaud, Stéphanie, Doz, François, Pernet-Fattet, Sarah, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Scheurlen, Wolfram, Eberhart, Charles, Fèvre-Montange, Michelle, Jouvet, Anne, Pollack, Ian, Fan, Xing, Muraszko, Karin, Gillespie, G, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna, Kloosterhof, Nanne, French, Pim, Kros, Johan, Olson, James, Ellenbogen, Richard, Zitterbart, Karel, Kren, Leos, Thompson, Reid, Cooper, Michael, Lach, Boleslaw, McLendon, Roger, Bigner, Darell, Fontebasso, Adam, Albrecht, Steffen, Jabado, Nada, Lindsey, Janet, Bailey, Simon, Van Meir, Erwin, Fouladi, Maryam, Nakamura, Hideo, Cinalli, Giuseppe, Garami, Miklós, Hauser, Peter, Saad, Ali, Iolascon, Achille, Jung, Shin, and Carlotti, Carlos

Subjects
Carrier Proteins, Cerebellar Neoplasms, Child, DNA Copy Number Variations, Gene Duplication, Genes, myc, Genome, Human, Genomic Structural Variation, Genomics, Hedgehog Proteins, Humans, Medulloblastoma, NF-kappa B, Nerve Tissue Proteins, Oncogene Proteins, Fusion, Proteins, RNA, Long Noncoding, Signal Transduction, Transforming Growth Factor beta, Translocation, Genetic
Abstract

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinsons disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.

Published
2012

25. Figure S7 from Safety and Efficacy of Intraventricular Immunovirotherapy with Oncolytic HSV-1 for CNS Cancers

Author

Kang, Kyung-Don, primary, Bernstock, Joshua D., primary, Totsch, Stacie K., primary, Gary, Sam E., primary, Rocco, Abbey, primary, Nan, Li, primary, Li, Rong, primary, Etminan, Tina, primary, Han, Xiaosi, primary, Beierle, Elizabeth A., primary, Eisemann, Tanja, primary, Wechsler-Reya, Robert J., primary, Bae, Sejong, primary, Whitley, Richard, primary, Gillespie, G. Yancey, primary, Markert, James M., primary, and Friedman, Gregory K., primary

Published
2023
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26. Data from Safety and Efficacy of Intraventricular Immunovirotherapy with Oncolytic HSV-1 for CNS Cancers

Author

Kang, Kyung-Don, primary, Bernstock, Joshua D., primary, Totsch, Stacie K., primary, Gary, Sam E., primary, Rocco, Abbey, primary, Nan, Li, primary, Li, Rong, primary, Etminan, Tina, primary, Han, Xiaosi, primary, Beierle, Elizabeth A., primary, Eisemann, Tanja, primary, Wechsler-Reya, Robert J., primary, Bae, Sejong, primary, Whitley, Richard, primary, Gillespie, G. Yancey, primary, Markert, James M., primary, and Friedman, Gregory K., primary

Published
2023
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29. List of Contributors

Author

Abraham, Jame, primary, Advani, Anjali, additional, Basse, Per, additional, Bhatia, Shailender, additional, Boland, Patrick M., additional, Chen, Hongbin, additional, Dy, Grace K., additional, Ernstoff, Marc S., additional, Fountzilas, Christos, additional, Friedman, Gregory K., additional, Gillespie, G. Yancey, additional, Hanif, Ahmad, additional, Harrison, Michael R., additional, Inman, Brant A., additional, Ito, Fumito, additional, Iyer, Renuka V., additional, Kalinski, Pawel, additional, Khan, Sumera, additional, Kruse, Megan, additional, Lee, Sunyoung S., additional, Lee, Sylvia, additional, Loecher, Matthew, additional, Maawy, Ali A., additional, Mayor, Paul, additional, McNamara, Megan A., additional, Puzanov, Igor, additional, Ring, Eric K., additional, Sawalha, Yazeed, additional, Starbuck, Kristen, additional, Zhang, Tian, additional, and Zsiros, Emese, additional

Published
2019
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32. Supplementary Figure from Immune Activity and Response Differences of Oncolytic Viral Therapy in Recurrent Glioblastoma: Gene Expression Analyses of a Phase IB Study

Author

Miller, Katherine E., primary, Cassady, Kevin A., primary, Roth, Justin C., primary, Clements, Jennifer, primary, Schieffer, Kathleen M., primary, Leraas, Kristen, primary, Miller, Anthony R., primary, Prasad, Nripesh, primary, Leavenworth, Jianmei W., primary, Aban, Inmaculada B., primary, Whitley, Richard J., primary, Gillespie, G. Yancey, primary, Mardis, Elaine R., primary, and Markert, James M., primary

Published
2023
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33. Data from MARCKS Regulates Growth and Radiation Sensitivity and Is a Novel Prognostic Factor for Glioma

Author

Jarboe, John S., primary, Anderson, Joshua C., primary, Duarte, Christine W., primary, Mehta, Tapan, primary, Nowsheen, Somaira, primary, Hicks, Patricia H., primary, Whitley, Alexander C., primary, Rohrbach, Timothy D., primary, McCubrey, Raymond O., primary, Chiu, Sherard, primary, Burleson, Tamara M., primary, Bonner, James A., primary, Gillespie, G. Yancey, primary, Yang, Eddy S., primary, and Willey, Christopher D., primary

Published
2023
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35. Supplementary Data from Immune Activity and Response Differences of Oncolytic Viral Therapy in Recurrent Glioblastoma: Gene Expression Analyses of a Phase IB Study

Author

Miller, Katherine E., primary, Cassady, Kevin A., primary, Roth, Justin C., primary, Clements, Jennifer, primary, Schieffer, Kathleen M., primary, Leraas, Kristen, primary, Miller, Anthony R., primary, Prasad, Nripesh, primary, Leavenworth, Jianmei W., primary, Aban, Inmaculada B., primary, Whitley, Richard J., primary, Gillespie, G. Yancey, primary, Mardis, Elaine R., primary, and Markert, James M., primary

Published
2023
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36. Supplementary Figure 2 from MARCKS Regulates Growth and Radiation Sensitivity and Is a Novel Prognostic Factor for Glioma

Author

Jarboe, John S., primary, Anderson, Joshua C., primary, Duarte, Christine W., primary, Mehta, Tapan, primary, Nowsheen, Somaira, primary, Hicks, Patricia H., primary, Whitley, Alexander C., primary, Rohrbach, Timothy D., primary, McCubrey, Raymond O., primary, Chiu, Sherard, primary, Burleson, Tamara M., primary, Bonner, James A., primary, Gillespie, G. Yancey, primary, Yang, Eddy S., primary, and Willey, Christopher D., primary

Published
2023
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37. Supplementary Methods and Figure Legends from MARCKS Regulates Growth and Radiation Sensitivity and Is a Novel Prognostic Factor for Glioma

Author

Jarboe, John S., primary, Anderson, Joshua C., primary, Duarte, Christine W., primary, Mehta, Tapan, primary, Nowsheen, Somaira, primary, Hicks, Patricia H., primary, Whitley, Alexander C., primary, Rohrbach, Timothy D., primary, McCubrey, Raymond O., primary, Chiu, Sherard, primary, Burleson, Tamara M., primary, Bonner, James A., primary, Gillespie, G. Yancey, primary, Yang, Eddy S., primary, and Willey, Christopher D., primary

Published
2023
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38. Supplementary Figure 1 from MARCKS Regulates Growth and Radiation Sensitivity and Is a Novel Prognostic Factor for Glioma

Author

Jarboe, John S., primary, Anderson, Joshua C., primary, Duarte, Christine W., primary, Mehta, Tapan, primary, Nowsheen, Somaira, primary, Hicks, Patricia H., primary, Whitley, Alexander C., primary, Rohrbach, Timothy D., primary, McCubrey, Raymond O., primary, Chiu, Sherard, primary, Burleson, Tamara M., primary, Bonner, James A., primary, Gillespie, G. Yancey, primary, Yang, Eddy S., primary, and Willey, Christopher D., primary

Published
2023
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39. Data from Immune Activity and Response Differences of Oncolytic Viral Therapy in Recurrent Glioblastoma: Gene Expression Analyses of a Phase IB Study

Author

Miller, Katherine E., primary, Cassady, Kevin A., primary, Roth, Justin C., primary, Clements, Jennifer, primary, Schieffer, Kathleen M., primary, Leraas, Kristen, primary, Miller, Anthony R., primary, Prasad, Nripesh, primary, Leavenworth, Jianmei W., primary, Aban, Inmaculada B., primary, Whitley, Richard J., primary, Gillespie, G. Yancey, primary, Mardis, Elaine R., primary, and Markert, James M., primary

Published
2023
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40. Supplementary Figure 4 from MARCKS Regulates Growth and Radiation Sensitivity and Is a Novel Prognostic Factor for Glioma

Author

Jarboe, John S., primary, Anderson, Joshua C., primary, Duarte, Christine W., primary, Mehta, Tapan, primary, Nowsheen, Somaira, primary, Hicks, Patricia H., primary, Whitley, Alexander C., primary, Rohrbach, Timothy D., primary, McCubrey, Raymond O., primary, Chiu, Sherard, primary, Burleson, Tamara M., primary, Bonner, James A., primary, Gillespie, G. Yancey, primary, Yang, Eddy S., primary, and Willey, Christopher D., primary

Published
2023
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41. Supplementary Figure 3 from MARCKS Regulates Growth and Radiation Sensitivity and Is a Novel Prognostic Factor for Glioma

Author

Jarboe, John S., primary, Anderson, Joshua C., primary, Duarte, Christine W., primary, Mehta, Tapan, primary, Nowsheen, Somaira, primary, Hicks, Patricia H., primary, Whitley, Alexander C., primary, Rohrbach, Timothy D., primary, McCubrey, Raymond O., primary, Chiu, Sherard, primary, Burleson, Tamara M., primary, Bonner, James A., primary, Gillespie, G. Yancey, primary, Yang, Eddy S., primary, and Willey, Christopher D., primary

Published
2023
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44. An investigation into the effects of childhood atopic eczema on parental stress

Author

Gillespie, G. N.

Subjects
150, Scratching
Abstract

Very little research has examined stress among parents of children with atopic eczema, though stressful events arc widely Implicated In Its actiology. This study Investigated reported stress among 38 parents of children with atopic eczema who had received hospital out-paticnt trcatmcnt within the previous 12 months. Responses of parents on the Parenting Stress Index were compared with published norms. Significantly elevated levels of stress among the study sample were found on the Difficult Child subscale. Total stress scores showed significant positive correlations with parental reports of illness severity. The majority of parents reported problems In relation to the symptom of scratching by their child with eczema. Recent problems with scratching were also found to correlate significantly with parenting stress. A rating scale was developed to allow parents to report on situational variables they associate with increased scratching by their child with eczema. The scale was found to have good test-retest reliability over a oneto-four week period. Three of its subscales (Environmental Sensitivity, Psychological Sensitivity and Negative Coping ) showed acceptable internal consistency. A fourth subscale (Positive Coping) showed poor internal consistency. Ratings on the Negative Coping subscale correlated significantly with parenting stress. A near-significant positive correlation was also found between parenting stress and the Psychological Sensitivity subscale. The methodological limitations of the study are discussed and implications for clinical practice and future research are outlined. The thesis also includes three small-scale research projects completetd during placements In Adult Mental Health, Learning Disabilities and Child and Adolescent services.

Published
1996

46. N-cadherin upregulation mediates adaptive radioresistance in glioblastoma

Author

Osuka, Satoru, Zhu, Dan, Zhang, Zhaobin, Li, Chaoxi, Stackhouse, Christian T., Sampetrean, Oltea, Olson, Jeffrey J., Gillespie, G. Yancey, Saya, Hideyuki, Willey, Christopher D., and Van Meir, Erwin G.

Subjects
Cadherins -- Physiological aspects -- Health aspects, Glioblastoma multiforme -- Development and progression -- Care and treatment, Radiotherapy -- Physiological aspects -- Usage, Insulin-like growth factor 1 -- Physiological aspects -- Health aspects, Health care industry
Abstract

Glioblastoma (GBM) is composed of heterogeneous tumor cell populations, including those with stem cell properties, termed glioma stem cells (GSCs). GSCs are innately less radiation sensitive than the tumor bulk and are believed to drive GBM formation and recurrence after repeated irradiation. However, it is unclear how GSCs adapt to escape the toxicity of repeated irradiation used in clinical practice. To identify important mediators of adaptive radioresistance in GBM, we generated radioresistant human and mouse GSCs by exposing them to repeat cycles of irradiation. Surviving subpopulations acquired strong radioresistance in vivo, which was accompanied by a reduction in cell proliferation and an increase in cell-cell adhesion and N-cadherin expression. Increasing N-cadherin expression rendered parental GSCs radioresistant, reduced their proliferation, and increased their stemness and intercellular adhesive properties. Conversely, radioresistant GSCs lost their acquired phenotypes upon CRISPR/Cas9-mediated knockout of N-cadherin. Mechanistically, elevated N-cadherin expression resulted in the accumulation of [beta]-catenin at the cell surface, which suppressed Wnt/[beta]-catenin proliferative signaling, reduced neural differentiation, and protected against apoptosis through Clusterin secretion. N-cadherin upregulation was induced by radiation-induced IGF1 secretion, and the radiation resistance phenotype could be reverted with picropodophyllin, a clinically applicable blood-brain-barrier permeable IGF1 receptor inhibitor, supporting clinical translation., Introduction Glioblastoma (GBM) is an important health problem and major clinical challenge. GBM is the most aggressive brain tumor in adults, with a median overall survival of less than 2 [...]

Published
2021
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47. Safety and Efficacy of Intraventricular Immunovirotherapy with Oncolytic HSV-1 for CNS Cancers

Author

Kang, Kyung-Don, primary, Bernstock, Joshua D., additional, Totsch, Stacie K., additional, Gary, Sam E., additional, Rocco, Abbey, additional, Nan, Li, additional, Li, Rong, additional, Etminan, Tina, additional, Han, Xiaosi, additional, Beierle, Elizabeth A., additional, Eisemann, Tanja, additional, Wechsler-Reya, Robert J., additional, Bae, Sejong, additional, Whitley, Richard, additional, Gillespie, G. Yancey, additional, Markert, James M., additional, and Friedman, Gregory K., additional

Published
2022
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48. Correlation of higher levels of soluble TNF-R1 with a shorter survival, independent of age, in recurrent glioblastoma

Author

Ahluwalia, Manmeet S., Bou-Anak, Stephanie, Burgett, Monica E., Sarmey, Nehaw, Khosla, Divya, Dahiya, Saurabh, Weil, Robert J., Bae, Eunnyung, Huang, Ping, McGraw, Mary, Grove, Lisa M., Olman, Mitchell A., Prayson, Richard A., Suh, John H., Gillespie, G. Yancey, Barnholtz-Sloan, Jill, Nowacki, Amy S., Barnett, Gene H., and Gladson, Candece L.

Published
2017
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