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3. Integrative multi-omics reveals two biologically distinct groups of pilocytic astrocytoma

Author

Picard, Daniel, Felsberg, Jörg, Langini, Maike, Stachura, Paweł, Qin, Nan, Macas, Jadranka, Reiss, Yvonne, Bartl, Jasmin, Selt, Florian, Sigaud, Romain, Meyer, Frauke-D., Stefanski, Anja, Stühler, Kai, Roque, Lucia, Roque, Rafael, Pandyra, Aleksandra A., Brozou, Triantafyllia, Knobbe-Thomsen, Christiane, Plate, Karl H., Roesch, Alexander, Milde, Till, Reifenberger, Guido, Leprivier, Gabriel, Faria, Claudia C., and Remke, Marc

Published
2023
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4. 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

7. 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

8. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma

Author

Nobre, Liana, Zapotocky, Michal, Khan, Sara, Fukuoka, Kohei, Fonseca, Adriana, McKeown, Tara, Sumerauer, David, Vicha, Ales, Grajkowska, Wieslawa A, Trubicka, Joanna, Li, Kay Ka Wai, Ng, Ho-Keung, Massimi, Luca, Lee, Ji Yeoun, Kim, Seung-Ki, Zelcer, Shayna, Vasiljevic, Alexandre, Faure-Conter, Cécile, Hauser, Peter, Lach, Boleslaw, van Veelen-Vincent, Marie-Lise, French, Pim J, Van Meir, Erwin G, Weiss, William A, Gupta, Nalin, Pollack, Ian F, Hamilton, Ronald L, Rao, Amulya A Nageswara, Giannini, Caterina, Rubin, Joshua B, Moore, Andrew S, Chambless, Lola B, Vibhakar, Rajeev, Ra, Young Shin, Massimino, Maura, McLendon, Roger E, Wheeler, Helen, Zollo, Massimo, Ferruci, Veronica, Kumabe, Toshihiro, Faria, Claudia C, Sterba, Jaroslav, Jung, Shin, López-Aguilar, Enrique, Mora, Jaume, Carlotti, Carlos G, Olson, James M, Leary, Sarah, Cain, Jason, Krskova, Lenka, Zamecnik, Josef, Hawkins, Cynthia E, Tabori, Uri, Huang, Annie, Bartels, Ute, Northcott, Paul A, Taylor, Michael D, Yip, Stephen, Hansford, Jordan R, Bouffet, Eric, and Ramaswamy, Vijay

Subjects
Cancer, Clinical Research, Evaluation of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adolescent, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Cerebellar Neoplasms, Child, Cyclophosphamide, Female, Humans, Ifosfamide, Male, Medulloblastoma, Middle Aged, Neoplasm Recurrence, Local, Progression-Free Survival, medulloblastoma, WNT, genomics, cyclophosphamide, chemotherapy, prognosis, survival
Abstract

Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.

Published
2020

9. Medulloblastoma has a global impact on health related quality of life: Findings from an international cohort

Author

Medeiros, Cynthia B, Moxon‐Emre, Iska, Scantlebury, Nadia, Malkin, David, Ramaswamy, Vijay, Decker, Alexandra, Law, Nicole, Kumabe, Toshihiro, Leonard, Jeffrey, Rubin, Josh, Jung, Shin, Kim, Seung‐Ki, Gupta, Nalin, Weiss, William, Faria, Claudia C, Vibhakar, Rajeev, Lafay‐Cousin, Lucie, Chan, Jennifer, Kros, Johan M, Janzen, Laura, Taylor, Michael D, Bouffet, Eric, and Mabbott, Donald J

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Cancer, Brain Cancer, Clinical Research, Brain Disorders, Pain Research, Rare Diseases, Pediatric, Neurosciences, 7.1 Individual care needs, Management of diseases and conditions, Good Health and Well Being, Adolescent, Antineoplastic Combined Chemotherapy Protocols, Cancer Survivors, Cerebellar Neoplasms, Child, Child, Preschool, Cohort Studies, Combined Modality Therapy, Craniospinal Irradiation, Female, Follow-Up Studies, Global Health, Health Status, Humans, Infant, Male, Medulloblastoma, Prognosis, Quality of Life, Surveys and Questionnaires, Survival Rate, development, medulloblastoma, pediatric psychology, quality of life, survivors of childhood cancer, Biochemistry and Cell Biology, Oncology and Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundUnderstanding the global impact of medulloblastoma on health related quality of life (HRQL) is critical to characterizing the broad impact of this disease and realizing the benefits of modern treatments. We evaluated HRQL in an international cohort of pediatric medulloblastoma patients.MethodsSeventy-six patients were selected from 10 sites across North America, Europe, and Asia, who participated in the Medulloblastoma Advanced Genomics International Consortium (MAGIC). The Health Utilities Index (HUI) was administered to patients and/or parents at each site. Responses were used to determine overall HRQL and attributes (ie specific subdomains). The impact of various demographic and medical variables on HRQL was considered-including molecular subgroup.ResultsThe majority of patients reported having moderate or severe overall burden of morbidity for both the HUI2 and HUI3 (HUI2 = 60%; HUI3 = 72.1%) when proxy-assessed. Self-care in the HUI2 was rated as higher (ie better outcome) for patients from Western versus Eastern sites, P = .02. Patients with nonmetastatic status had higher values (ie better outcomes) for the HUI3 hearing, HUI3 pain, and HUI2 pain, all P

Published
2020

10. Medulloblastoma has a global impact on health related quality of life: Findings from an international cohort.

Author

de Medeiros, Cynthia B, Moxon-Emre, Iska, Scantlebury, Nadia, Malkin, David, Ramaswamy, Vijay, Decker, Alexandra, Law, Nicole, Kumabe, Toshihiro, Leonard, Jeffrey, Rubin, Josh, Jung, Shin, Kim, Seung-Ki, Gupta, Nalin, Weiss, William, Faria, Claudia C, Vibhakar, Rajeev, Lafay-Cousin, Lucie, Chan, Jennifer, Kros, Johan M, Janzen, Laura, Taylor, Michael D, Bouffet, Eric, and Mabbott, Donald J

Subjects
Humans, Medulloblastoma, Cerebellar Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Prognosis, Combined Modality Therapy, Survival Rate, Cohort Studies, Follow-Up Studies, Health Status, Quality of Life, Adolescent, Child, Child, Preschool, Infant, Female, Male, Craniospinal Irradiation, Global Health, Surveys and Questionnaires, Cancer Survivors, development, medulloblastoma, pediatric psychology, quality of life, survivors of childhood cancer, Pediatric, Brain Cancer, Pain Research, Brain Disorders, Rare Diseases, Clinical Research, Cancer, Neurosciences, 7.1 Individual care needs, Biochemistry and Cell Biology, Oncology and Carcinogenesis
Abstract

BackgroundUnderstanding the global impact of medulloblastoma on health related quality of life (HRQL) is critical to characterizing the broad impact of this disease and realizing the benefits of modern treatments. We evaluated HRQL in an international cohort of pediatric medulloblastoma patients.MethodsSeventy-six patients were selected from 10 sites across North America, Europe, and Asia, who participated in the Medulloblastoma Advanced Genomics International Consortium (MAGIC). The Health Utilities Index (HUI) was administered to patients and/or parents at each site. Responses were used to determine overall HRQL and attributes (ie specific subdomains). The impact of various demographic and medical variables on HRQL was considered-including molecular subgroup.ResultsThe majority of patients reported having moderate or severe overall burden of morbidity for both the HUI2 and HUI3 (HUI2 = 60%; HUI3 = 72.1%) when proxy-assessed. Self-care in the HUI2 was rated as higher (ie better outcome) for patients from Western versus Eastern sites, P = .02. Patients with nonmetastatic status had higher values (ie better outcomes) for the HUI3 hearing, HUI3 pain, and HUI2 pain, all P

Published
2020

12. Contributors

Author

Aghajani, Samira, primary, Ahmadi, Mazaher, additional, Akimitsu, Nobuyoshi, additional, Aldecoa, Iban, additional, Alves, José Luís, additional, Aran, Veronica, additional, Archilla, Ivan, additional, Arrieta, Oscar, additional, Arora, Geetanjali, additional, Bal, C.S., additional, Balaña, Carmen, additional, Balça-Silva, Joana, additional, Barbosa, Marcos, additional, Basso, João, additional, Behrooz, Amir Barzegar, additional, Bramini, Mattia, additional, Bruno, Francesco, additional, Cabral, Célia, additional, Cardona, Andrés F., additional, Carrato, Cristina, additional, Casalino, Simona, additional, Cascão, Rita, additional, Castagnola, Valentina, additional, Castañer Llanes, Sara, additional, Castelo-Branco, Miguel, additional, Clark, Courtney, additional, Coelho-Santos, Vanessa, additional, Cook, Alexander B., additional, Costa, Bárbara, additional, Costa, Bruno M., additional, Costa, Gustavo, additional, Costabile, Gabriella, additional, Cova, Tânia F.G.G., additional, Dabiri, Seyed Mohammad Hossein, additional, Daher, Ahmad, additional, Delgado, Jéssica, additional, Díaz-Lanza, Ana María, additional, Domenech, Marta, additional, Domínguez-Martín, Eva María, additional, Dubois, Luiz Gustavo, additional, Duskey, Jason T., additional, Efferth, Thomas, additional, Faria, Claudia C., additional, Fortuna, Ana, additional, Garcia-Robledo, Juan Esteban, additional, Ghavami, Saeid, additional, Gimeno, Alfredo, additional, Gomes, Célia M.F., additional, Guerreiro, Joana F., additional, Halder, Ankit, additional, Hernandez, Ainhoa, additional, Hernández Santana, Electra Eduina, additional, Kesari, Santosh, additional, Lopez-Rueda, Antonio, additional, Madrakian, Tayyebeh, additional, Magalhães, Mariana, additional, Manadas, Bruno, additional, Martins, Cláudia, additional, Matias, Diana, additional, Mendes, Filipa, additional, Mendes, Maria, additional, Miller, Donald W., additional, Moran, Teresa, additional, Moreira, Ana, additional, Moreno, Montse, additional, Moschetta, Matteo, additional, Mosquera, Andrés, additional, Moura-Neto, Vivaldo, additional, Mukherjee, Arani, additional, Nunes, Sandra C.C., additional, Oleaga, Laura, additional, Ordoñez, Camila, additional, Pacheco, Catarina, additional, Pais, Alberto A.C.C., additional, Paulo, António, additional, Pellerino, Alessia, additional, Pereira, Mariana, additional, Pineda, Estela, additional, Pinto, Catarina I.G., additional, Prakash, Prasoon, additional, Pronello, Edoardo, additional, Puig, Josep, additional, Ribalta, Teresa, additional, Rijo, Patrícia, additional, Rojas, Katerina, additional, Rudà, Roberta, additional, Saba, Luca, additional, Sarmento, Bruno, additional, Schlich, Michele, additional, Sengupta, Shreoshi, additional, Silva, Fernando, additional, Silva, Francisco, additional, Somasundaram, Kumaravel, additional, Sousa, João, additional, Srivastava, Sanjeeva, additional, Tosi, Giovanni, additional, Trevisani, Martina, additional, Vale, Nuno, additional, Varela, Carla, additional, Verma, Ayushi, additional, Vieito, Maria, additional, Vitorino, Carla, additional, Vitorino, Rui, additional, Walsh, Tavia, additional, and Yathindranath, Vinith, additional

Published
2023
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13. Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Author

Monteiro, Cátia, Miarka, Lauritz, Perea-García, María, Priego, Neibla, García-Gómez, Pedro, Álvaro-Espinosa, Laura, de Pablos-Aragoneses, Ana, Yebra, Natalia, Retana, Diana, Baena, Patricia, Fustero-Torre, Coral, Graña-Castro, Osvaldo, Troulé, Kevin, Caleiras, Eduardo, Tezanos, Patricia, Muela, Pablo, Cintado, Elisa, Trejo, José Luis, Sepúlveda, Juan Manuel, González-León, Pedro, Jiménez-Roldán, Luis, Moreno, Luis Miguel, Esteban, Olga, Pérez-Núñez, Ángel, Hernández-Lain, Aurelio, Mazarico Gallego, José, Ferrer, Irene, Suárez, Rocío, Garrido-Martín, Eva M., Paz-Ares, Luis, Dalmasso, Celine, Cohen-Jonathan Moyal, Elizabeth, Siegfried, Aurore, Hegarty, Aisling, Keelan, Stephen, Varešlija, Damir, Young, Leonie S., Mohme, Malte, Goy, Yvonne, Wikman, Harriet, Fernández-Alén, Jose, Blasco, Guillermo, Alcázar, Lucía, Cabañuz, Clara, Grivennikov, Sergei I., Ianus, Andrada, Shemesh, Noam, Faria, Claudia C., Lee, Rebecca, Lorigan, Paul, Le Rhun, Emilie, Weller, Michael, Soffietti, Riccardo, Bertero, Luca, Ricardi, Umberto, Bosch-Barrera, Joaquim, Sais, Elia, Teixidor, Eduard, Hernández-Martínez, Alejandro, Calvo, Alfonso, Aristu, Javier, Martin, Santiago M., Gonzalez, Alvaro, Adler, Omer, Erez, Neta, and Valiente, Manuel

Published
2022
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15. Heterogeneity within the PF-EPN-B ependymoma subgroup

Author

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

Subjects
Genetics, Cancer, Clinical Research, Rare Diseases, Human Genome, Brain Cancer, Brain Disorders, Adolescent, Adult, Age Factors, Child, Cohort Studies, DNA Copy Number Variations, DNA Methylation, Ependymoma, Female, Gene Expression Profiling, Humans, Infratentorial Neoplasms, Kaplan-Meier Estimate, Male, Microarray Analysis, Middle Aged, Young Adult, Posterior fossa, Subgrouping, PFB, PFA, Clustering, Clinical Sciences, Neurosciences, Neurology & Neurosurgery
Abstract

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

Published
2018

16. Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors

Author

Blümel, Lena, Qin, Nan, Berlandi, Johannes, Paisana, Eunice, Cascão, Rita, Custódia, Carlos, Pauck, David, Picard, Daniel, Langini, Maike, Stühler, Kai, Meyer, Frauke-Dorothee, Göbbels, Sarah, Malzkorn, Bastian, Liebau, Max C., Barata, João T., Jeibmann, Astrid, Kerl, Kornelius, Erkek, Serap, Kool, Marcel, Pfister, Stefan M., Johann, Pascal D., Frühwald, Michael C., Borkhardt, Arndt, Reifenberger, Guido, Faria, Claudia C., Fischer, Ute, Hasselblatt, Martin, Bartl, Jasmin, and Remke, Marc

Published
2022
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17. 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

18. Author Correction: Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma

Author

Donovan, Laura K., Delaidelli, Alberto, Joseph, Sujith K., Bielamowicz, Kevin, Fousek, Kristen, Holgado, Borja L., Manno, Alex, Srikanthan, Dilakshan, Gad, Ahmed Z., Van Ommeren, Randy, Przelicki, David, Richman, Cory, Ramaswamy, Vijay, Daniels, Craig, Pallota, Jonelle G., Douglas, Tajana, Joynt, Alyssa C. M., Haapasalo, Joonas, Nor, Carolina, Vladoiu, Maria C., Kuzan-Fischer, Claudia M., Garzia, Livia, Mack, Stephen C., Varadharajan, Srinidhi, Baker, Matthew L., Hendrikse, Liam, Ly, Michelle, Kharas, Kaitlin, Balin, Polina, Wu, Xiaochong, Qin, Lei, Huang, Ning, Stucklin, Ana Guerreiro, Morrissy, A. Sorana, Cavalli, Florence M. G., Luu, Betty, Suarez, Raul, De Antonellis, Pasqualino, Michealraj, Antony, Rastan, Avesta, Hegde, Meenakshi, Komosa, Martin, Sirbu, Olga, Kumar, Sachin A., Abdullaev, Zied, Faria, Claudia C., Yip, Stephen, Hukin, Juliette, Tabori, Uri, Hawkins, Cynthia, Aldape, Ken, Daugaard, Mads, Maris, John M., Sorensen, Poul H., Ahmed, Nabil, and Taylor, Michael D.

Published
2021
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19. Cadherin Expression Profiles Define Glioblastoma Differentiation and Patient Prognosis.

Author

Noronha, Carolina, Ribeiro, Ana Sofia, Carvalho, Rita, Mendes, Nuno, Reis, Joaquim, Faria, Claudia C., Taipa, Ricardo, and Paredes, Joana

Subjects
GLYCOPROTEIN analysis, GLIOMAS, DIAGNOSTIC imaging, RESEARCH funding, EPITHELIAL-mesenchymal transition, CANCER relapse, BRAIN, MESENCHYMAL stem cells, TRANSCRIPTION factors, GENE expression, IMMUNOHISTOCHEMISTRY, GENE expression profiling, SURVIVAL analysis (Biometry), STAINS & staining (Microscopy), PHENOTYPES
Abstract

Simple Summary: Epithelial to mesenchymal transition (EMT) programme is central to various cancers, however how this programme applies to glioblastoma, an aggressive primary brain tumor, remains unknown. In particular, the cadherin switch which involves E-cadherin down-regulation and N-cadherin upregulation, is considered a marker of the EMT in epithelial cancers. Given the knowledge gap in the EMT and cadherins expression in GBM, we studied these proteins (E-, P- and N-cadherin) expression in a large cohort of GBM, extensively characterized with clinical, imaging, neuropathological, treatment and survival data. Our results propose that cadherin expression subgroups reflect an EMT-like programme in GBM and predict patient prognosis. Cadherins are cell–cell adhesion proteins which have been strongly implicated in cancer invasion, dissemination and metastasis capacity; thus, they are key players in the epithelial-to-mesenchymal transition (EMT) program. However, their role in glioblastoma (GBM), a primary central nervous system aggressive tumor, remains to be clarified. N-, E- and P-cadherin expression was analyzed on a large series of GBMs, characterized with clinical, imaging and neuropathological parameters, as well as with patients' survival data. In addition, cadherins' expression was studied in match-recurrent cases. Using TCGA data, cadherin expression profiles were also evaluated according to GBM transcription subtypes. N-cadherin expression was observed in 81.5% of GBM, followed by E-cadherin in 31% and P-cadherin in 20.8%. Upon tumor recurrence, P-cadherin was the only significantly upregulated cadherin compared with the primary tumor, being positive in 65.8% of the cases. Actually, P-cadherin gain was observed in 51.4% of matched primary-recurrent cases. Cadherins' co-expression was also explored. Interestingly, E- and N-cadherin co-expression identified a GBM subgroup with frequent epithelial differentiation and a significant survival benefit. On the other hand, subgroups with P-cadherin expression carried the worse prognosis. P- and N-cadherin co-expression correlated with the presence of a mesenchymal phenotype. Expressions of isolated P-cadherin or E- and P-cadherin co-expression were associated with imaging characteristics of aggressiveness, to highly heterogeneous tumors, an d to worse patient survival. Classical cadherins co-expression subgroups present consistent clinical, imaging, neuropathological and survival differences, which probably reflect different states of an EMT-like program in GBM. [ABSTRACT FROM AUTHOR]

Published
2024
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20. 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

21. Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis.

Author

Ramaswamy, Vijay, Hielscher, Thomas, Mack, Stephen C, Lassaletta, Alvaro, Lin, Tong, Pajtler, Kristian W, Jones, David TW, Luu, Betty, Cavalli, Florence MG, Aldape, Kenneth, Remke, Marc, Mynarek, Martin, Rutkowski, Stefan, Gururangan, Sridharan, McLendon, Roger E, Lipp, Eric S, Dunham, Christopher, Hukin, Juliette, Eisenstat, David D, Fulton, Dorcas, van Landeghem, Frank KH, Santi, Mariarita, van Veelen, Marie-Lise C, Van Meir, Erwin G, Osuka, Satoru, Fan, Xing, Muraszko, Karin M, Tirapelli, Daniela PC, Oba-Shinjo, Sueli M, Marie, Suely KN, Carlotti, Carlos G, Lee, Ji Yeoun, Rao, Amulya A Nageswara, Giannini, Caterina, Faria, Claudia C, Nunes, Sofia, Mora, Jaume, Hamilton, Ronald L, Hauser, Peter, Jabado, Nada, Petrecca, Kevin, Jung, Shin, Massimi, Luca, Zollo, Massimo, Cinalli, Giuseppe, Bognár, László, Klekner, Almos, Hortobágyi, Tibor, Leary, Sarah, Ermoian, Ralph P, Olson, James M, Leonard, Jeffrey R, Gardner, Corrine, Grajkowska, Wieslawa A, Chambless, Lola B, Cain, Jason, Eberhart, Charles G, Ahsan, Sama, Massimino, Maura, Giangaspero, Felice, Buttarelli, Francesca R, Packer, Roger J, Emery, Lyndsey, Yong, William H, Soto, Horacio, Liau, Linda M, Everson, Richard, Grossbach, Andrew, Shalaby, Tarek, Grotzer, Michael, Karajannis, Matthias A, Zagzag, David, Wheeler, Helen, von Hoff, Katja, Alonso, Marta M, Tuñon, Teresa, Schüller, Ulrich, Zitterbart, Karel, Sterba, Jaroslav, Chan, Jennifer A, Guzman, Miguel, Elbabaa, Samer K, Colman, Howard, Dhall, Girish, Fisher, Paul G, Fouladi, Maryam, Gajjar, Amar, Goldman, Stewart, Hwang, Eugene, Kool, Marcel, Ladha, Harshad, Vera-Bolanos, Elizabeth, Wani, Khalida, Lieberman, Frank, Mikkelsen, Tom, Omuro, Antonio M, Pollack, Ian F, Prados, Michael, Robins, H Ian, and Soffietti, Riccardo

Subjects
Humans, Ependymoma, Infratentorial Neoplasms, Combined Modality Therapy, Retrospective Studies, Cohort Studies, Adolescent, Adult, Child, Child, Preschool, Infant, Female, Male, Cytoreduction Surgical Procedures, Rare Diseases, Pediatric Cancer, Cancer, Pediatric, Patient Safety, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposePosterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known.MethodsFour independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses.ResultsMolecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation.ConclusionThe most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence.

Published
2016

22. Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis

Author

Thompson, Eric M, Hielscher, Thomas, Bouffet, Eric, Remke, Marc, Luu, Betty, Gururangan, Sridharan, McLendon, Roger E, Bigner, Darell D, Lipp, Eric S, Perreault, Sebastien, Cho, Yoon-Jae, Grant, Gerald, Kim, Seung-Ki, Lee, Ji Yeoun, Rao, Amulya A Nageswara, Giannini, Caterina, Li, Kay Ka Wai, Ng, Ho-Keung, Yao, Yu, Kumabe, Toshihiro, Tominaga, Teiji, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Low, David CY, Seow, Wan Tew, Chang, Kenneth TE, Mora, Jaume, Pollack, Ian F, Hamilton, Ronald L, Leary, Sarah, Moore, Andrew S, Ingram, Wendy J, Hallahan, Andrew R, Jouvet, Anne, Fèvre-Montange, Michelle, Vasiljevic, Alexandre, Faure-Conter, Cecile, Shofuda, Tomoko, Kagawa, Naoki, Hashimoto, Naoya, Jabado, Nada, Weil, Alexander G, Gayden, Tenzin, Wataya, Takafumi, Shalaby, Tarek, Grotzer, Michael, Zitterbart, Karel, Sterba, Jaroslav, Kren, Leos, Hortobágyi, Tibor, Klekner, Almos, László, Bognár, Pócza, Tímea, Hauser, Peter, Schüller, Ulrich, Jung, Shin, Jang, Woo-Youl, French, Pim J, Kros, Johan M, van Veelen, Marie-Lise C, Massimi, Luca, Leonard, Jeffrey R, Rubin, Joshua B, Vibhakar, Rajeev, Chambless, Lola B, Cooper, Michael K, Thompson, Reid C, Faria, Claudia C, Carvalho, Alice, Nunes, Sofia, Pimentel, José, Fan, Xing, Muraszko, Karin M, López-Aguilar, Enrique, Lyden, David, Garzia, Livia, Shih, David JH, Kijima, Noriyuki, Schneider, Christian, Adamski, Jennifer, Northcott, Paul A, Kool, Marcel, Jones, David TW, Chan, Jennifer A, Nikolic, Ana, Garre, Maria Luisa, Van Meir, Erwin G, Osuka, Satoru, Olson, Jeffrey J, Jahangiri, Arman, Castro, Brandyn A, Gupta, Nalin, Weiss, William A, Moxon-Emre, Iska, Mabbott, Donald J, Lassaletta, Alvaro, Hawkins, Cynthia E, Tabori, Uri, Drake, James, and Kulkarni, Abhaya

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Oncology and Carcinogenesis, Brain Disorders, Rare Diseases, Brain Cancer, Pediatric Research Initiative, Pediatric, Cancer, Adult, Brain Neoplasms, Canada, Child, Child, Preschool, Combined Modality Therapy, Disease Progression, Disease-Free Survival, Female, Humans, Infant, Magnetic Resonance Imaging, Male, Medulloblastoma, Prognosis, Retrospective Studies, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundPatients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner.MethodsWe retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival.FindingsWe included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084).InterpretationThe prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection.FundingCanadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research.

Published
2016

23. 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

24. Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma

Author

Donovan, Laura K., Delaidelli, Alberto, Joseph, Sujith K., Bielamowicz, Kevin, Fousek, Kristen, Holgado, Borja L., Manno, Alex, Srikanthan, Dilakshan, Gad, Ahmed Z., Van Ommeren, Randy, Przelicki, David, Richman, Cory, Ramaswamy, Vijay, Daniels, Craig, Pallota, Jonelle G., Douglas, Tajana, Joynt, Alyssa C.M., Haapasalo, Joonas, Nor, Carolina, Vladoiu, Maria C., Kuzan-Fischer, Claudia M., Garzia, Livia, Mack, Stephen C., Varadharajan, Srinidhi, Baker, Matthew L., Hendrikse, Liam, Ly, Michelle, Kharas, Kaitlin, Balin, Polina, Wu, Xiaochong, Qin, Lei, Huang, Ning, Stucklin, Ana Guerreiro, Morrissy, A. Sorana, Cavalli, Florence M.G., Luu, Betty, Suarez, Raul, De Antonellis, Pasqualino, Michealraj, Antony, Rastan, Avesta, Hegde, Meenakshi, Komosa, Martin, Sirbu, Olga, Kumar, Sachin A., Abdullaev, Zied, Faria, Claudia C., Yip, Stephen, Hukin, Juliette, Tabori, Uri, Hawkins, Cynthia, Aldape, Ken, Daugaard, Mads, Maris, John M., Sorenson, Poul H., Ahmed, Nabil, and Taylor, Michael D.

Subjects
T cells -- Health aspects -- Methods, Medulloblastoma -- Care and treatment, Metastasis -- Care and treatment, Cellular therapy -- Methods -- Health aspects, Immunotherapy -- Methods -- Health aspects, Antigens -- Health aspects, Cerebrospinal fluid -- Health aspects -- Methods, Biological sciences, Health
Abstract

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor [alpha]2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor [alpha]2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans. Intraventricularly delivered monovalent and trivalent CAR T cells exhibit greater therapeutic efficacy as compared with intravenously delivered CAR T cells in medulloblastoma xenograft mouse models and show potency in ependymoma xenograft mouse models., Author(s): Laura K. Donovan [sup.1] [sup.2] , Alberto Delaidelli [sup.3] , Sujith K. Joseph [sup.4] [sup.5] , Kevin Bielamowicz [sup.4] [sup.5] , Kristen Fousek [sup.4] [sup.5] , Borja L. Holgado [...]

Published
2020
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25. 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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26. Cytogenetic prognostication within medulloblastoma subgroups.

Author

Shih, David JH, Northcott, Paul A, Remke, Marc, Korshunov, Andrey, Ramaswamy, Vijay, Kool, Marcel, Luu, Betty, Yao, Yuan, Wang, Xin, Dubuc, Adrian M, Garzia, Livia, Peacock, John, Mack, Stephen C, Wu, Xiaochong, Rolider, Adi, Morrissy, A Sorana, Cavalli, Florence MG, Jones, David TW, Zitterbart, Karel, Faria, Claudia C, Schüller, Ulrich, Kren, Leos, Kumabe, Toshihiro, Tominaga, Teiji, Shin Ra, Young, Garami, Miklós, Hauser, Peter, Chan, Jennifer A, Robinson, Shenandoah, Bognár, László, Klekner, Almos, Saad, Ali G, Liau, Linda M, Albrecht, Steffen, Fontebasso, Adam, Cinalli, Giuseppe, De Antonellis, Pasqualino, Zollo, Massimo, Cooper, Michael K, Thompson, Reid C, Bailey, Simon, Lindsey, Janet C, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna MC, Scherer, Stephen W, Phillips, Joanna J, Gupta, Nalin, Fan, Xing, Muraszko, Karin M, Vibhakar, Rajeev, Eberhart, Charles G, Fouladi, Maryam, Lach, Boleslaw, Jung, Shin, Wechsler-Reya, Robert J, Fèvre-Montange, Michelle, Jouvet, Anne, Jabado, Nada, Pollack, Ian F, Weiss, William A, Lee, Ji-Yeoun, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Leonard, Jeffrey R, Rubin, Joshua B, de Torres, Carmen, Lavarino, Cinzia, Mora, Jaume, Cho, Yoon-Jae, Tabori, Uri, Olson, James M, Gajjar, Amar, Packer, Roger J, Rutkowski, Stefan, Pomeroy, Scott L, French, Pim J, Kloosterhof, Nanne K, Kros, Johan M, Van Meir, Erwin G, Clifford, Steven C, Bourdeaut, Franck, Delattre, Olivier, Doz, François F, Hawkins, Cynthia E, Malkin, David, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Bouffet, Eric, Rutka, James T, Pfister, Stefan M, and Taylor, Michael D

Subjects
Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 14, Humans, Medulloblastoma, Proto-Oncogene Proteins c-myc, Nuclear Proteins, Prognosis, Tissue Array Analysis, In Situ Hybridization, Fluorescence, Proportional Hazards Models, Risk Assessment, Risk Factors, Reproducibility of Results, Predictive Value of Tests, Gene Expression Profiling, Cytogenetics, Gene Expression Regulation, Neoplastic, Adolescent, Child, Child, Preschool, Infant, Female, Male, Wnt Proteins, Kruppel-Like Transcription Factors, Hedgehog Proteins, Young Adult, Biomarkers, Tumor, Zinc Finger Protein Gli2, Rare Diseases, Clinical Research, Pediatric Research Initiative, Cancer, Pediatric Cancer, Brain Disorders, Biotechnology, Pediatric, Patient Safety, Brain Cancer, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, 4.2 Evaluation of markers and technologies, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeMedulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication.Patients and methodsMolecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models.ResultsSubgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas.ConclusionCombining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.

Published
2014

28. Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

Author

Suzuki, Hiromichi, Kumar, Sachin A., Shuai, Shimin, Diaz-Navarro, Ander, Gutierrez-Fernandez, Ana, De Antonellis, Pasqualino, Cavalli, Florence M. G., Juraschka, Kyle, Farooq, Hamza, Shibahara, Ichiyo, Vladoiu, Maria C., Zhang, Jiao, Abeysundara, Namal, Przelicki, David, Skowron, Patryk, Gauer, Nicole, Luu, Betty, Daniels, Craig, Wu, Xiaochong, Forget, Antoine, Momin, Ali, Wang, Jun, Dong, Weifan, Kim, Seung-Ki, Grajkowska, Wieslawa A., Jouvet, Anne, Fèvre-Montange, Michelle, Garrè, Maria Luisa, Nageswara Rao, Amulya A., Giannini, Caterina, Kros, Johan M., French, Pim J., Jabado, Nada, Ng, Ho-Keung, Poon, Wai Sang, Eberhart, Charles G., Pollack, Ian F., Olson, James M., Weiss, William A., Kumabe, Toshihiro, López-Aguilar, Enrique, Lach, Boleslaw, Massimino, Maura, Van Meir, Erwin G., Rubin, Joshua B., Vibhakar, Rajeev, Chambless, Lola B., Kijima, Noriyuki, Klekner, Almos, Bognár, László, Chan, Jennifer A., Faria, Claudia C., Ragoussis, Jiannis, Pfister, Stefan M., Goldenberg, Anna, Wechsler-Reya, Robert J., Bailey, Swneke D., Garzia, Livia, Morrissy, A. Sorana, Marra, Marco A., Huang, Xi, Malkin, David, Ayrault, Olivier, Ramaswamy, Vijay, Puente, Xose S., Calarco, John A., Stein, Lincoln, and Taylor, Michael D.

Published
2019
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29. Nanoparticle-Based Treatment in Glioblastoma

Author

Roque, Diogo, primary, Cruz, Nuno, additional, Ferreira, Hugo Alexandre, additional, Reis, Catarina Pinto, additional, Matela, Nuno, additional, Herculano-Carvalho, Manuel, additional, Cascão, Rita, additional, and Faria, Claudia C., additional

Published
2023
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30. Supplementary Methods and Figure Legends from Foretinib Is Effective Therapy for Metastatic Sonic Hedgehog Medulloblastoma

Author

Faria, Claudia C., primary, Golbourn, Brian J., primary, Dubuc, Adrian M., primary, Remke, Marc, primary, Diaz, Roberto J., primary, Agnihotri, Sameer, primary, Luck, Amanda, primary, Sabha, Nesrin, primary, Olsen, Samantha, primary, Wu, Xiaochong, primary, Garzia, Livia, primary, Ramaswamy, Vijay, primary, Mack, Stephen C., primary, Wang, Xin, primary, Leadley, Michael, primary, Reynaud, Denis, primary, Ermini, Leonardo, primary, Post, Martin, primary, Northcott, Paul A., primary, Pfister, Stefan M., primary, Croul, Sidney E., primary, Kool, Marcel, primary, Korshunov, Andrey, primary, Smith, Christian A., primary, Taylor, Michael D., primary, and Rutka, James T., primary

Published
2023
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31. Supplementary Figure S3 from Foretinib Is Effective Therapy for Metastatic Sonic Hedgehog Medulloblastoma

Author

Faria, Claudia C., primary, Golbourn, Brian J., primary, Dubuc, Adrian M., primary, Remke, Marc, primary, Diaz, Roberto J., primary, Agnihotri, Sameer, primary, Luck, Amanda, primary, Sabha, Nesrin, primary, Olsen, Samantha, primary, Wu, Xiaochong, primary, Garzia, Livia, primary, Ramaswamy, Vijay, primary, Mack, Stephen C., primary, Wang, Xin, primary, Leadley, Michael, primary, Reynaud, Denis, primary, Ermini, Leonardo, primary, Post, Martin, primary, Northcott, Paul A., primary, Pfister, Stefan M., primary, Croul, Sidney E., primary, Kool, Marcel, primary, Korshunov, Andrey, primary, Smith, Christian A., primary, Taylor, Michael D., primary, and Rutka, James T., primary

Published
2023
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32. Data from Foretinib Is Effective Therapy for Metastatic Sonic Hedgehog Medulloblastoma

Author

Faria, Claudia C., primary, Golbourn, Brian J., primary, Dubuc, Adrian M., primary, Remke, Marc, primary, Diaz, Roberto J., primary, Agnihotri, Sameer, primary, Luck, Amanda, primary, Sabha, Nesrin, primary, Olsen, Samantha, primary, Wu, Xiaochong, primary, Garzia, Livia, primary, Ramaswamy, Vijay, primary, Mack, Stephen C., primary, Wang, Xin, primary, Leadley, Michael, primary, Reynaud, Denis, primary, Ermini, Leonardo, primary, Post, Martin, primary, Northcott, Paul A., primary, Pfister, Stefan M., primary, Croul, Sidney E., primary, Kool, Marcel, primary, Korshunov, Andrey, primary, Smith, Christian A., primary, Taylor, Michael D., primary, and Rutka, James T., primary

Published
2023
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33. Supplementary Table S1 from Foretinib Is Effective Therapy for Metastatic Sonic Hedgehog Medulloblastoma

Author

Faria, Claudia C., primary, Golbourn, Brian J., primary, Dubuc, Adrian M., primary, Remke, Marc, primary, Diaz, Roberto J., primary, Agnihotri, Sameer, primary, Luck, Amanda, primary, Sabha, Nesrin, primary, Olsen, Samantha, primary, Wu, Xiaochong, primary, Garzia, Livia, primary, Ramaswamy, Vijay, primary, Mack, Stephen C., primary, Wang, Xin, primary, Leadley, Michael, primary, Reynaud, Denis, primary, Ermini, Leonardo, primary, Post, Martin, primary, Northcott, Paul A., primary, Pfister, Stefan M., primary, Croul, Sidney E., primary, Kool, Marcel, primary, Korshunov, Andrey, primary, Smith, Christian A., primary, Taylor, Michael D., primary, and Rutka, James T., primary

Published
2023
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36. Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis

Author

Torchia, Jonathon, Picard, Daniel, Lafay-Cousin, Lucie, Hawkins, Cynthia E, Kim, Seung-Ki, Letourneau, Louis, Ra, Young-Shin, Ho, King Ching, Chan, Tiffany Sin Yu, Sin-Chan, Patrick, Dunham, Christopher P, Yip, Stephen, Ng, Ho-keung, Lu, Jian-Qiang, Albrecht, Steffen, Pimentel, José, Chan, Jennifer A, Somers, Gino R, Zielenska, Maria, Faria, Claudia C, Roque, Lucia, Baskin, Berivan, Birks, Diane, Foreman, Nick, Strother, Douglas, Klekner, Almos, Garami, Miklos, Hauser, Peter, Hortobágyi, Tibor, Bognár, Laszló, Wilson, Beverly, Hukin, Juliette, Carret, Anne-Sophie, Van Meter, Timothy E, Nakamura, Hideo, Toledano, Helen, Fried, Iris, Fults, Daniel, Wataya, Takafumi, Fryer, Chris, Eisenstat, David D, Scheineman, Katrin, Johnston, Donna, Michaud, Jean, Zelcer, Shayna, Hammond, Robert, Ramsay, David A, Fleming, Adam J, Lulla, Rishi R, Fangusaro, Jason R, Sirachainan, Nongnuch, Larbcharoensub, Noppadol, Hongeng, Suradej, Barakzai, Muhammad Abrar, Montpetit, Alexandre, Stephens, Derek, Grundy, Richard G, Schüller, Ulrich, Nicolaides, Theodore, Tihan, Tarik, Phillips, Joanna, Taylor, Michael D, Rutka, James T, Dirks, Peter, Bader, Gary D, Warmuth-Metz, Monika, Rutkowski, Stefan, Pietsch, Torsten, Judkins, Alexander R, Jabado, Nada, Bouffet, Eric, and Huang, Annie

Published
2015
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37. UBE2C promotes leptomeningeal dissemination and is a therapeutic target in brain metastatic disease

Author

Paisana, Eunice, primary, Cascão, Rita, additional, Custódia, Carlos, additional, Qin, Nan, additional, Picard, Daniel, additional, Pauck, David, additional, Carvalho, Tânia, additional, Ruivo, Pedro, additional, Barreto, Clara, additional, Doutel, Delfim, additional, Cabeçadas, José, additional, Roque, Rafael, additional, Pimentel, José, additional, Miguéns, José, additional, Remke, Marc, additional, Barata, João T., additional, and Faria, Claudia C., additional

Published
2022
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40. Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis

Author

Ramaswamy, Vijay, Remke, Marc, Bouffet, Eric, Faria, Claudia C, Perreault, Sebastien, Cho, Yoon-Jae, Shih, David J, Luu, Betty, Dubuc, Adrian M, Northcott, Paul A, Schüller, Ulrich, Gururangan, Sridharan, McLendon, Roger, Bigner, Darell, Fouladi, Maryam, Ligon, Keith L, Pomeroy, Scott L, Dunn, Sandra, Triscott, Joanna, Jabado, Nada, Fontebasso, Adam, Jones, David T W, Kool, Marcel, Karajannis, Matthias A, Gardner, Sharon L, Zagzag, David, Nunes, Sofia, Pimentel, José, Mora, Jaume, Lipp, Eric, Walter, Andrew W, Ryzhova, Marina, Zheludkova, Olga, Kumirova, Ella, Alshami, Jad, Croul, Sidney E, Rutka, James T, Hawkins, Cynthia, Tabori, Uri, Codispoti, Kari-Elise T, Packer, Roger J, Pfister, Stefan M, Korshunov, Andrey, and Taylor, Michael D

Published
2013
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41. Primary cilia contribute to the aggressiveness of atypical teratoid/rhabdoid tumors

Author

Bluemel, Lena, Qin, Nan, Berlandi, Johannes, Paisana, Eunice, Cascao, Rita, Custodia, Carlos, Pauck, David, Picard, Daniel, Langini, Maike, Stuehler, Kai, Meyer, Frauke-Dorothee, Goebbels, Sarah, Malzkorn, Bastian, Liebau, Max C., Barata, Joao T., Jeibmann, Astrid, Kerl, Kornelius, Erkek, Serap, Kool, Marcel, Pfister, Stefan M., Johann, Pascal D., Fruehwald, Michael C., Borkhardt, Arndt, Reifenberger, Guido, Faria, Claudia C., Fischer, Ute, Hasselblatt, Martin, Bartl, Jasmin, Remke, Marc, Bluemel, Lena, Qin, Nan, Berlandi, Johannes, Paisana, Eunice, Cascao, Rita, Custodia, Carlos, Pauck, David, Picard, Daniel, Langini, Maike, Stuehler, Kai, Meyer, Frauke-Dorothee, Goebbels, Sarah, Malzkorn, Bastian, Liebau, Max C., Barata, Joao T., Jeibmann, Astrid, Kerl, Kornelius, Erkek, Serap, Kool, Marcel, Pfister, Stefan M., Johann, Pascal D., Fruehwald, Michael C., Borkhardt, Arndt, Reifenberger, Guido, Faria, Claudia C., Fischer, Ute, Hasselblatt, Martin, Bartl, Jasmin, and Remke, Marc

Abstract

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant brain tumor in infants that is characterized by loss of nuclear expression of SMARCB1 or SMARCA4 proteins. Recent studies show that AT/RTs comprise three molecular subgroups, namely AT/RT-TYR, AT/RT-MYC and AT/RT-SHH. The subgroups show distinct expression patterns of genes involved in ciliogenesis, however, little is known about the functional roles of primary cilia in the biology of AT/RT. Here, we show that primary cilia are present across all AT/RT subgroups with specific enrichment in AT/RT-TYR patient samples. Furthermore, we demonstrate that primary ciliogenesis contributes to AT/RT biology in vitro and in vivo. Specifically, we observed a significant decrease in proliferation and clonogenicity following disruption of primary ciliogenesis in AT/RT cell line models. Additionally, apoptosis was significantly increased via the induction of STAT1 and DR5 signaling, as detected by proteogenomic profiling. In a Drosophila model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with more than 20% of flies reaching adulthood. We also found significantly extended survival in an orthotopic xenograft mouse model of AT/RT upon disruption of primary ciliogenesis. Taken together, our findings indicate that primary ciliogenesis or its downstream signaling contributes to the aggressiveness of AT/RT and, therefore, may constitute a novel therapeutic target.

Published
2022

42. Intratumoral heterogeneity of MYC drives medulloblastoma metastasis and angiogenesis

Author

Qin, Nan, primary, Paisana, Eunice, additional, Langini, Maike, additional, Picard, Daniel, additional, Malzkorn, Bastian, additional, Custódia, Carlos, additional, Cascão, Rita, additional, Meyer, Frauke-Dorothee, additional, Blümel, Lena, additional, Göbbels, Sarah, additional, Taban, Kübra, additional, Bartl, Jasmin, additional, Bechmann, Nicole, additional, Conrad, Catleen, additional, Gravemeyer, Jan, additional, Becker, Jürgen C, additional, Stefanski, Anja, additional, Puget, Stéphanie, additional, Barata, João T, additional, Stühler, Kai, additional, Fischer, Ute, additional, Felsberg, Jörg, additional, Ayrault, Olivier, additional, Reifenberger, Guido, additional, Borkhardt, Arndt, additional, Eisenhofer, Graeme, additional, Faria, Claudia C, additional, and Remke, Marc, additional

Published
2022
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44. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Author

Remke, Marc, Ramaswamy, Vijay, Peacock, John, Shih, David J. H., Koelsche, Christian, Northcott, Paul A., Hill, Nadia, Cavalli, Florence M. G., Kool, Marcel, Wang, Xin, Mack, Stephen C., Barszczyk, Mark, Morrissy, A. Sorana, Wu, Xiaochong, Agnihotri, Sameer, Luu, Betty, Jones, David T. W., Garzia, Livia, Dubuc, Adrian M., Zhukova, Nataliya, Vanner, Robert, Kros, Johan M., French, Pim J., Van Meir, Erwin G., Vibhakar, Rajeev, Zitterbart, Karel, Chan, Jennifer A., Bognár, László, Klekner, Almos, Lach, Boleslaw, Jung, Shin, Saad, Ali G., Liau, Linda M., Albrecht, Steffen, Zollo, Massimo, Cooper, Michael K., Thompson, Reid C., Delattre, Oliver O., Bourdeaut, Franck, Doz, François F., Garami, Miklós, Hauser, Peter, Carlotti, Carlos G., Van Meter, Timothy E., Massimi, Luca, Fults, Daniel, Pomeroy, Scott L., Kumabe, Toshiro, Ra, Young Shin, Leonard, Jeffrey R., Elbabaa, Samer K., Mora, Jaume, Rubin, Joshua B., Cho, Yoon-Jae, McLendon, Roger E., Bigner, Darell D., Eberhart, Charles G., Fouladi, Maryam, Wechsler-Reya, Robert J., Faria, Claudia C., Croul, Sidney E., Huang, Annie, Bouffet, Eric, Hawkins, Cynthia E., Dirks, Peter B., Weiss, William A., Schüller, Ulrich, Pollack, Ian F., Rutkowski, Stefan, Meyronet, David, Jouvet, Anne, Fèvre-Montange, Michelle, Jabado, Nada, Perek-Polnik, Marta, Grajkowska, Wieslawa A., Kim, Seung-Ki, Rutka, James T., Malkin, David, Tabori, Uri, Pfister, Stefan M., Korshunov, Andrey, von Deimling, Andreas, and Taylor, Michael D.

Published
2013
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45. LMD-12. Ubiquitin Conjugating Enzymes promote leptomeningeal dissemination and decrease survival in patients with brain metastatic disease

Author

Paisana, Eunice, primary, Cascão, Rita, additional, Custódia, Carlos, additional, Qin, Nan, additional, Picard, Daniel, additional, Pauck, David, additional, Carvalho, Tânia, additional, Ruivo, Pedro, additional, Pereira, Pedro, additional, Roque, Rafael, additional, Pimentel, José, additional, Miguéns, José, additional, Remke, Marc, additional, Barata, João T, additional, and Faria, Claudia C, additional

Published
2021
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48. Association of serum brain-specific protein fragments and brain metastases in patients with metastatic breast cancer.

Author

Damaso, Sara, primary, Willumsen, Nicholas, additional, Cavaco, Ana C. Martins, additional, Corredeira, Patrícia, additional, Pacheco, Teresa Raquel Duarte, additional, Costa, Ana Lucia, additional, Faria, Claudia C, additional, Tzara, Ourania, additional, Henriksen, Kim, additional, Karsdal, Morten A., additional, Ali, Suhail M., additional, Leitzel, Kim, additional, Lipton, Allan, additional, and Costa, Luis, additional

Published
2021
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49. Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma

Author

Kumar, Rahul, primary, Smith, Kyle S., additional, Deng, Maximilian, additional, Terhune, Colt, additional, Robinson, Giles W., additional, Orr, Brent A., additional, Liu, Anthony P. Y., additional, Lin, Tong, additional, Billups, Catherine A., additional, Chintagumpala, Murali, additional, Bowers, Daniel C., additional, Hassall, Timothy E., additional, Hansford, Jordan R., additional, Khuong-Quang, Dong Anh, additional, Crawford, John R., additional, Bendel, Anne E., additional, Gururangan, Sridharan, additional, Schroeder, Kristin, additional, Bouffet, Eric, additional, Bartels, Ute, additional, Fisher, Michael J., additional, Cohn, Richard, additional, Partap, Sonia, additional, Kellie, Stewart J., additional, McCowage, Geoffrey, additional, Paulino, Arnold C., additional, Rutkowski, Stefan, additional, Fleischhack, Gudrun, additional, Dhall, Girish, additional, Klesse, Laura J., additional, Leary, Sarah, additional, Nazarian, Javad, additional, Kool, Marcel, additional, Wesseling, Pieter, additional, Ryzhova, Marina, additional, Zheludkova, Olga, additional, Golanov, Andrey V., additional, McLendon, Roger E., additional, Packer, Roger J., additional, Dunham, Christopher, additional, Hukin, Juliette, additional, Fouladi, Maryam, additional, Faria, Claudia C., additional, Pimentel, Jose, additional, Walter, Andrew W., additional, Jabado, Nada, additional, Cho, Yoon-Jae, additional, Perreault, Sebastien, additional, Croul, Sidney E., additional, Zapotocky, Michal, additional, Hawkins, Cynthia, additional, Tabori, Uri, additional, Taylor, Michael D., additional, Pfister, Stefan M., additional, Klimo, Paul, additional, Boop, Frederick A., additional, Ellison, David W., additional, Merchant, Thomas E., additional, Onar-Thomas, Arzu, additional, Korshunov, Andrey, additional, Jones, David T. W., additional, Gajjar, Amar, additional, Ramaswamy, Vijay, additional, and Northcott, Paul A., additional

Published
2021
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50. Subgroup-specific structural variation across 1,000 medulloblastoma genomes

Author

Northcott, Paul A., Shih, David J. H., Peacock, John, Garzia, Livia, Morrissy, Sorana A., Zichner, Thomas, Stütz, Adrian M., Korshunov, Andrey, Reimand, Jüri, Schumacher, Steven E., Beroukhim, Rameen, Ellison, David W., Marshall, Christian R., Lionel, Anath C., Mack, Stephen, Dubuc, Adrian, Yao, Yuan, Ramaswamy, Vijay, Luu, Betty, Rolider, Adi, Cavalli, Florence M. G., Wang, Xin, Remke, Marc, Wu, Xiaochong, Chiu, Readman Y. B., Chu, Andy, Chuah, Eric, Corbett, Richard D., Hoad, Gemma R., Jackman, Shaun D., Li, Yisu, Lo, Allan, Mungall, Karen L., Nip, Ka Ming, Qian, Jenny Q., Raymond, Anthony G. J., Thiessen, Nina, Varhol, Richard J., Birol, Inanc, Moore, Richard A., Mungall, Andrew J., Holt, Robert, Kawauchi, Daisuke, Roussel, Martine F., Kool, Marcel, Jones, David T. W., Witt, Hendrick, Fernandez-L, Africa, Kenney, Anna M., Wechsler-Reya, Robert J., Dirks, Peter, Aviv, Tzvi, Grajkowska, Wieslawa A., Perek-Polnik, Marta, Haberler, Christine C., Delattre, Olivier, Reynaud, Stéphanie S., Doz, François F., Pernet-Fattet, Sarah S., Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Scheurlen, Wolfram, Eberhart, Charles G., Fèvre-Montange, Michelle, Jouvet, Anne, Pollack, Ian F., Fan, Xing, Muraszko, Karin M., Gillespie, Yancey G., Di Rocco, Concezio, Massimi, Luca, Michiels, Erna M. C., Kloosterhof, Nanne K., French, Pim J., Kros, Johan M., Olson, James M., Ellenbogen, Richard G., Zitterbart, Karel, Kren, Leos, Thompson, Reid C., Cooper, Michael K., Lach, Boleslaw, McLendon, Roger E., Bigner, Darell D., Fontebasso, Adam, Albrecht, Steffen, Jabado, Nada, Lindsey, Janet C., Bailey, Simon, Gupta, Nalin, Weiss, William A., Bognár, László, Klekner, Almos, Van Meter, Timothy E., Kumabe, Toshihiro, Tominaga, Teiji, Elbabaa, Samer K., Leonard, Jeffrey R., Rubin, Joshua B., Liau, Linda M., Van Meir, Erwin G., Fouladi, Maryam, Nakamura, Hideo, Cinalli, Giuseppe, Garami, Miklós, Hauser, Peter, Saad, Ali G., Iolascon, Achille, Jung, Shin, Carlotti, Carlos G., Vibhakar, Rajeev, Ra, Young Shin, Robinson, Shenandoah, Zollo, Massimo, Faria, Claudia C., Chan, Jennifer A., Levy, Michael L., Sorensen, Poul H. B., Meyerson, Matthew, Pomeroy, Scott L., Cho, Yoon-Jae, Bader, Gary D., Tabori, Uri, Hawkins, Cynthia E., Bouffet, Eric, Scherer, Stephen W., Rutka, James T., Malkin, David, Clifford, Steven C., Jones, Steven J. M., Korbel, Jan O., Pfister, Stefan M., Marra, Marco A., and Taylor, Michael D.

Published
2012
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