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1. The transcriptional landscape of Shh medulloblastoma

Author

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

Subjects
Science
Abstract

Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.

Published
2021
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2. Failure of human rhombic lip differentiation underlies medulloblastoma formation

Author

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

Subjects
Histone Demethylases, Otx Transcription Factors, Multidisciplinary, Core Binding Factor alpha Subunits, Muscle Proteins, Cell Differentiation, Article, Metencephalon, Repressor Proteins, Ki-67 Antigen, Cerebellum, Mutation, Humans, Cell Lineage, Hedgehog Proteins, Cerebellar Neoplasms, T-Box Domain Proteins, Medulloblastoma, Transcription Factors
Abstract

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. 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

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

Author

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

Subjects
Multidisciplinary
Published
2022

4. Clinical phenotypes and prognostic features of embryonal tumours with multi-layered rosettes: a Rare Brain Tumor Registry study

Author

Milena La Spina, Roona Sinha, Jason E. Cain, Abhaya V. Kulkarni, Nicolas Gottardo, Young-Shin Ra, Jennifer A. Chan, Bryan K. Li, Naureen Mushtaq, Lindsey Hoffman, Maria Joao Gil da Costa, Nada Jabado, Rajeev Vibhakar, Jordan R. Hansford, Palma Solano-Paez, Andrew W. Walter, Anne Bendel, Lili-Naz Hazrati, Michael A. Grotzer, Scott L. Pomeroy, Cynthia Hawkins, Maryam Fouladi, Nicholas Gerber, Ho Keung Ng, Donna L. Johnston, David S. Ziegler, Helen M. Branson, Alexander G. Weil, Tannu Suwal, Jian Qiang Lu, Gino R. Somers, Anna Maria Buccoliero, Ramya Ramanujachar, Ashley Plant, Eloy Rivas, Vanan Magimairajan, Rong Li, Ben Ho, Sandra Camelo-Piragua, Christelle Dufour, Paula Marrano, Uri Tabori, Alyssa Reddy, Sumihito Nobusawa, Jason Fangusaro, James Loukides, Haci Ahmet Demir, Cinzia Lavarino, Angelica Oviedo, Daniel Catchpoole, Yin Wang, Derek Hanson, Joseph Torkildson, Karen Wright, Mette Jorgensen, Nongnuch Sirachainan, Hideo Nakamura, Laetitia Padovani, Luca Massimi, Annie Huang, Rina Dvir, Nalin Gupta, Amy Smith, Sara Khan, Eric Bouffet, Chien-Jui Cheng, Iqra Mumal, Mariko Sato, Jeffery Rubens, Mei Lu, Peter B. Dirks, Jesse Kresak, David Samuel, James T. Rutka, G. Yancey Gillespie, Suzanne Laughlin, Samina Afzal, Salma Al-Karmi, Kuo-Sheng Wu, Claire M. Mazewski, Eugene Hwang, Roger J. Packer, Jean Michaud, Andrew Dodgshun, James M. Drake, Vicente Santa-Maria, Christine Dahl, Sebastian Perreault, Lucie Lafay-Cousin, Frank van Landeghem, Nirav Thacker, Mary Shago, Michael D. Taylor, Derek S. Tsang, Timothy E. Van Meter, Derek Stephens, Adriana Fonseca, Birgit Ertl-Wagner, Mahjouba Boutarbouch, Vijay Ramaswamy, Joanna J. Phillips, Almeida Gonzalez Cv, Jean M. Mulcahy Levy, Benjamin Ellezam, George M. Ibrahim, Nabil Kabbara, Franck Bourdeaut, Violet Shen, Tarik Tihan, Sridharan Gururangan, Tai-Tong Wong, Michal Zapotocky, Michal Yalon-Oren, Helen Toledano, Amar Gajjar, Ute Bartels, Holly Lindsay, Christopher Dunham, Nicolas André, Laura Amariglio, David Scharnhorst, Reuben Antony, Suradej Hongeng, Andres Morales La Madrid, Sharon Low, Paul Wood, Beverly Wilson, Enrica Tan, Peter A. Downie, Dariusz Adamek, Christopher L. Moertel, Alvaro Lassaletta, Chad Jacobsen, Eric H. Raabe, Sarah Leary, Richard Grundy, University of Zurich, Canadian Institutes of Health Research, Canada Research Chairs, Australian Lions Childhood Cancer Research Foundation, Junta de Andalucía, and Asociación Española de Pediatría

Subjects
Oncology, Male, medicine.medical_specialty, medicine.medical_treatment, Brain tumor, 610 Medicine & health, Disease, Neurosurgical Procedures, Internal medicine, Developmental and Educational Psychology, medicine, Humans, RNA, Messenger, Child, Proportional Hazards Models, Chemotherapy, Univariate analysis, business.industry, Brain Neoplasms, Not Otherwise Specified, Hazard ratio, Infant, Newborn, Infant, Neoplasms, Germ Cell and Embryonal, medicine.disease, Prognosis, Phenotype, Combined Modality Therapy, Progression-Free Survival, Radiation therapy, Gene Expression Regulation, Neoplastic, 10036 Medical Clinic, Chemotherapy, Adjuvant, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, Radiotherapy, Adjuvant, business
Abstract

Rare Brain Tumor Registry., [Background] Embryonal tumours with multi-layered rosettes (ETMRs) are a newly recognised, rare paediatric brain tumour with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and scarce clinical data, disease features and determinants of outcomes for these tumours are poorly defined. We did an integrated clinicopathological and molecular analysis of primary ETMRs to define clinical phenotypes, and to identify prognostic factors of survival and key treatment modalities for this orphan disease., [Methods] Paediatric patients with primary ETMRs and tissue available for analyses were identified from the Rare Brain Tumor Consortium global registry. The institutional histopathological diagnoses were centrally re-reviewed as per the current WHO CNS tumour guidelines, using histopathological and molecular assays. Only patients with complete clinical, treatment, and survival data on Nov 30, 2019, were included in clinicopathological analyses. Among patients who received primary multi-modal curative regimens, event-free survival and overall survival were determined using Cox proportional hazard and log-rank analyses. Univariate and multivariable Cox proportional hazard regression was used to estimate hazard ratios (HRs) with 95% CIs for clinical, molecular, or treatment-related prognostic factors., [Findings] 159 patients had a confirmed molecular diagnosis of primary ETMRs (median age at diagnosis 26 months, IQR 18–36) and were included in our clinicopathological analysis. ETMRs were predominantly non-metastatic (94 [73%] of 128 patients), arising from multiple sites; 84 (55%) of 154 were cerebral tumours and 70 (45%) of 154 arose at sites characteristic of other brain tumours. Hallmark C19MC alterations were seen in 144 (91%) of 159 patients; 15 (9%) were ETMR not otherwise specified. In patients treated with curative intent, event-free survival was 57% (95% CI 47–68) at 6 months and 31% (21–42) at 2 years; overall survival was 29% (20–38) at 2 years and 27% (18–37) at 4 years. Overall survival was associated with non-metastatic disease (HR 0·48, 95% CI 0·28–0·80; p=0·0057) and non-brainstem location (0·42 [0·22–0·81]; p=0·013) on univariate analysis, as well as with gross total resection (0·30, 0·16–0·58; p=0·0014), high-dose chemotherapy (0·35, 0·19–0·67; p=0·0020), and radiotherapy (0·21, 0·10–0·41; p, [Interpretation] Prompt molecular diagnosis and post-surgical treatment with intensive multi-modal therapy tailored to patient-specific risk features could improve ETMR survival., Canadian Institute of Health Research, Canada Research Chair Awards, Australian Lions Childhood Cancer Research Foundation, Spanish Society of Pediatrics, Consejería de Salud y Familias de la Junta de Andalucía, Miracle Marnie, Phoebe Rose Rocks, Tali's Funds, Garron Cancer Centre, Grace's Walk, Meagan's Hug, Brainchild, Nelina's Hope, and Jean Martel Foundation.

Published
2021

5. Characterization of a Clival Chordoma Xenograft Model Reveals Tumor Genomic Instability

Author

Daniel Picard, James T. Rutka, Andrew Bondoc, Marc Remke, Michael D. Cusimano, Roberto J. Diaz, Christian A. Smith, James Loukides, Brian Golbourn, Amanda Luck, and Nesrin Sabha

Subjects
Male, musculoskeletal diseases, Brachyury, Apoptosis, Mice, SCID, Biology, Polymorphism, Single Nucleotide, Skull Base Neoplasms, S100 protein, Genomic Instability, Pathology and Forensic Medicine, Mice, 03 medical and health sciences, Cytokeratin, 0302 clinical medicine, Mice, Inbred NOD, FHIT, CDKN2A, Biomarkers, Tumor, Chordoma, Tumor Cells, Cultured, medicine, Animals, Humans, Aged, Cell Proliferation, Severe combined immunodeficiency, Genome, Human, Gene Expression Profiling, medicine.disease, Xenograft Model Antitumor Assays, Gene expression profiling, 030220 oncology & carcinogenesis, Cancer research, 030217 neurology & neurosurgery
Abstract

Patient-derived xenografts retain the genotype of the parent tumors more readily than tumor cells maintained in culture. The two previously reported clival chordoma xenografts were derived from recurrent tumors after radiation. To study the genetics of clival chordoma in the absence of prior radiation exposure we established a patient-derived xenograft at primary resection of a clival chordoma. Epicranial grafting of clival chordoma collected during surgery was performed. Tumor growth was established in a nonobese diabetic/severe combined immunodeficiency mouse and tumors have been passaged serially for seven generations. Physaliferous cell architecture was shown in the regenerated tumors, which stained positive for Brachyury, cytokeratin, and S100 protein. The tumors showed bone invasion. Single-nucleotide polymorphism analysis of the tumor xenograft was compared with the parental tumor. Copy number gain of the T gene (brachyury) and heterozygous loss of cyclin dependent kinase inhibitor 2A (CDKN2A) was observed. Heterozygous loss of the tumor-suppressor fragile histidine triad (FHIT) gene also was observed, although protein expression was preserved. Accumulation of copy number losses and gains as well as increased growth rate was observed over three generations. The patient-derived xenograft reproduces the phenotype of clival chordoma. This model can be used in the future to study chordoma biology and to assess novel treatments.

Published
2018

6. The transcriptional landscape of Shh medulloblastoma

Author

Jaume Mora, Erwin G. Van Meir, Olivier Delattre, Diala Abd-Rabbo, Almos Klekner, Peter Hauser, Roger E. McLendon, Amulya A. Nageswara Rao, David Malkin, James M. Olson, Boleslaw Lach, A. Sorana Morrissy, Xiaoyun Zhang, John J.Y. Lee, Steven J.M. Jones, Young Shin Ra, Ulrich Schüller, Miklós Garami, Joanna J. Phillips, Betty Luu, Hamza Farooq, Johan M. Kros, Karel Zitterbart, Michael K. Cooper, Raul Suarez, William A. Weiss, Quang M. Trinh, Ana Guerreiro Stucklin, Tomoko Shofuda, Carmen de Torres, Marco A. Marra, Enrique López-Aguilar, Hiromichi Suzuki, Patryk Skowron, Eric Bouffet, Karen Mungall, Evan Y. Wang, Tina Zheng, Maria C. Vladoiu, Julien Masliah-Planchon, Ian F. Pollack, Wai Sang Poon, Liam D. Hendrikse, Claudia C. Faria, Yu Chang Wang, Kay Ka Wai Li, Carlos Gilberto Carlotti, Joshua B. Rubin, Gary D. Bader, Aaron Gillmor, Caterina Giannini, Uri Tabori, Shin Jung, Franck Bourdeaut, Chi-chung Hui, Avesta Rastan, Reid C. Thompson, Jennifer A. Chan, Nada Jabado, David Meyronet, Rajeev Vibhakar, Jiannis Ragoussis, Michelle Ly, Olivier Ayrault, Charles G. Eberhart, Andrew J. Mungall, Wiesława Grajkowska, Xiaochong Wu, Jüri Reimand, Ho Keung Ng, Vernon Fong, Michael D. Taylor, Seung-Ki Kim, Florence M.G. Cavalli, Carolina Nor, Helen He Zhu, Eric M. Thompson, Borja L. Holgado, David Zagzag, Craig Daniels, Gelareh Zadeh, Haig Djambazian, G. Yancey Gillespie, Peter B. Dirks, Richard A. Moore, John A. Calarco, Shizhong Dai, Vijay Ramaswamy, Lincoln Stein, Pierre Bérubé, Pim J. French, Toshihiro Kumabe, James Loukides, Swneke D. Bailey, Linda M. Liau, Ronald L. Hamilton, Francois P. Doz, Maria Luisa Garrè, László Bognár, The Hospital for sick children [Toronto] (SickKids), The Wellcome Trust Sanger Institute [Cambridge], Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation, radiobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurology, Pathology, Repositório da Universidade de Lisboa, Skowron, Patryk, Farooq, Hamza, Cavalli, Florence M G, 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 J Y, Zhang, Xiao Yun, Daniels, Craig, Dirks, Peter, Malkin, David, Bouffet, Eric, Tabori, Uri, Loukides, Jame, 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, Almo, Zitterbart, Karel, Phillips, Joanna J, Thompson, Reid C, Cooper, Michael K, Rubin, Joshua B, Liau, Linda M, Garami, Mikló, 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, Jianni, Weiss, William A, Marra, Marco A, Suzuki, Hiromichi, and Taylor, Michael D

Subjects
0301 basic medicine, Male, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, General Physics and Astronomy, ComputingMilieux_LEGALASPECTSOFCOMPUTING, Genome informatics, Transcriptome, 0302 clinical medicine, Genetics research, 2.1 Biological and endogenous factors, Gene Regulatory Networks, Sonic hedgehog, Aetiology, Child, Cancer, Regulation of gene expression, Pediatric, Multidisciplinary, Gene Regulatory Network, biology, Middle Aged, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Child, Preschool, embryonic structures, Female, TRANSDUÇÃO DE SINAL CELULAR, Hedgehog Protein, Human, Signal Transduction, Biotechnology, Adult, Pediatric Research Initiative, animal structures, Adolescent, Pediatric Cancer, Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, Computational biology, Article, General Biochemistry, Genetics and Molecular Biology, Paediatric cancer, 03 medical and health sciences, Young Adult, Rare Diseases, SDG 3 - Good Health and Well-being, Clinical Research, GLI2, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], GNAS complex locus, medicine, Genetics, Humans, Hedgehog Proteins, Cerebellar Neoplasms, Preschool, neoplasms, Gene, Medulloblastoma, Neoplastic, Cerebellar Neoplasm, Human Genome, Neurosciences, Infant, Genetic Variation, General Chemistry, medicine.disease, Brain Disorders, CNS cancer, Brain Cancer, 030104 developmental biology, PTCH1, Gene Expression Regulation, biology.protein
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., Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.

Published
2021

7. Clinical phenotypes and prognostic features of ETMRs (Embryonal Tumor with Multi-layered Rosettes) a new CNS tumor entity: A Rare Brain Tumor Registry study

Author

Christelle Dufour, Paul Wood, Tannu Suwal, Enrica Tan, Gino R. Somers, Christopher L. Moertel, Uri Tabori, Joanna Philips, Jennifer A. Chan, Mette Jorgensen, Nicolas André, CV AlmeidaGonzalez, Palma Solano-Paez, Laura Amariglio, Angelica Oviedo, Amy Smith, Cynthia Hawkins, Vijay Ramaswamy, Chien-Jui Cheng, Sara Khan, Eric Bouffet, Reuben Antony, Peter A. Downie, Vicente Santa-Maria, Scott L. Pomeroy, Maria Joao Gil da Costa, Andrew W. Walter, Samina Afzal, Derek Hanson, Jian-Qiang Lu, Luca Massimi, Jesse Kresak, Joseph Torkildson, Nicolas Gottardo, Helen M. Branson, Frank van Landeghem, Karen Wright, Andres Morales, Jeffery Rubens, Salma Al-Karmi, Adriana Fonseca, Lili-Naz Hazrati, Jean Michaud, Young-Shin Ra, Mahjouba Boutarbouch, Abhaya V. Kulkarni, Lucie Lafay-Cousin, Paula Marrano, Donna L. Johnston, Ben Ho, Chad Jacobsen, Tarik Tihan, Jean M. Mulcahy Levy, David Samuel, Suzanne Laughlin, Naureen Mushtaq, Eric H. Raabe, Sandra Camelo-Piragua, Jordan R. Hansford, Nicholas Gerber, Lindsey M. Hoffman, Andrew Dodgshun, Dariusz Adamek, Derek Stephens, Hideo Nakamura, Nada Jabado, Mei Lu, Brigit Ertl-Wagner, Cinzia Lavarino, James T. Rutka, G. Yancey Gillespie, Sarah Leary, Eugene Hwang, Eloy Rivas, Anne Bendel, Ramya Ramanujachar, Sharon Low, Sridharan Gururangan, Tai-Tong Wong, NG Ho-Keung, James M. Drake, Christine Dahl, Peter B. Dirks, Mary Shago, Alyssa Reddy, Jason Fangusaro, James Loukides, Daniel Catchpoole, Jason E. Cain, Beverly Wilson, Yin Wang, Ahmet Muzaffer Demir, Milena La Spina, Mariko Sato, Sumihito Nobusawa, Nongnuch Sirachainan, Maryam Fouladi, Vanan Magimairajan, Sebastian Perreault, Annie Huang, Kuo-Sheng Wu, David S. Ziegler, Timothy E. Van Meter, Roona Sinha, Maysa Al-Hussaini, George M. Ibrahim, Michael D. Taylor, Derek S. Tsang, Violet Shen, Amar Gajjar, Benjamin Ellezam, Nabil Kabbara, Franck Bourdeaut, Anna Maria Buccoliero, Michal Yalon-Oren, Helen Toledano, Ute Bartels, Holly Lindsay, Christopher Dunham, Nalin Gupta, David Scharnhorst, Michael A. Grotzer, Suradej Hongeng, Rong Li, Michal Zapotocky, Ashley Plant, Pr Laetitia Padovani, Alvaro Lassaletta, Nisreen Amayiri, and Richard Grundy

Subjects
medicine.medical_specialty, Chemotherapy, business.industry, Registry study, medicine.medical_treatment, Brain tumor, Disease, medicine.disease, Phenotype, Gastroenterology, Log-rank test, High dose chemotherapy, Internal medicine, medicine, CNS TUMORS, business
Abstract

BackgroundETMRs are a newly recognized rare paediatric brain tumor with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and limited clinical data, disease features and determinants of outcome are poorly defined. We performed an integrated clinico-pathologic and molecular analyses of 159 primary ETMRs to define clinical phenotypes, identify predictors of survival and critical treatment modalities for this orphan disease.MethodsPrimary ETMR patients were identified from the Rare Brain Tumor Consortium (rarebraintumorconsortium.ca) global registry using histopathologic and molecular assays. Event-Free (EFS) and Overall Survival (OS) for 108 patients treated with curative multi-modal regimens were determined using Cox proportional hazard and log rank analyses.FindingsETMRs were predominantly non-metastatic (73%) tumors arising from multiple sites; 55% were cerebral tumors, 45% arose at sites characteristic of other brain tumors. Hallmark C19MC alterations were seen in 91%; 9% were ETMR-NOS. Survival and hazard analyses showed a 6 month median EFS and 2-4yr OS of 27-29% with metastatic disease (HR=0.44, 95% CI 0.26-0.74; p=0.002) and brainstem location (HR=0.40, 95% CI 0.021-0.75; p=0.005) correlating with adverse OS. Gross total resection (GTR: HR=0.38, 95% CI 0.21-0.68; p=0.001), high dose chemotherapy (HDC: HR=0.55, 95% CI 0.31-0.97; p=0.04) and radiation (RT: HR=0.32, 95% CI 0.16-0.60; p=InterpretationPrompt molecular diagnosis and post-surgical treatment with multi-modal therapy tailored to patient-specific risk features improves ETMR survival.FundingThis work was supported by the Canadian Institute of Health Research Grant No. 137011, Canada Research Chair Awards to AH. Funds from Miracle Marnie, Phoebe Rose Rocks, Tali’s Funds, Garron Cancer Centre, Grace’s Walk, Meagan’s Walk, Nelina’s Hope and Jean Martel Foundation are gratefully acknowledged. SK and PS were respectively supported by the Australian Lions Children’s Cancer Foundation and the Spanish Society of Pediatrics, Consejería de Salud y Familias de la Junta de Andalucía Project EF-0451-2017.

Published
2020
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8. Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma

Author

Samuel Weiss, Leo J.Y. Kim, Xiaochong Wu, Randy Van Ommeren, Yanqing Jiang, Kaitlin Kharas, Evgeny Kanshin, Moloud Ahmadi, Alberto Delaidelli, Geneviève Deblois, David Przelicki, Stephane Angers, Hiromichi Suzuki, Sameer Agnihotri, Bradly G. Wouters, Graham MacLeod, Ricky Tsai, Pasqualino De Antonellis, Michelle Ly, Stacey L. Krumholtz, Paul Guilhamon, James Loukides, Ravi N. Vellanki, Alex Rasnitsyn, Hamza Farooq, Daniel Schramek, Nada Jabado, María Sánchez-Osuna, Laura K. Donovan, Vijay Ramaswamy, Ibrahim El-Hamamy, Joonas Haapasalo, Jeremy N. Rich, Michael D. Taylor, Benjamin A. Garcia, Mike Tyers, Kyle Juraschka, Winnie Ong, Olivier Saulnier, Panagiotis Prinos, John J.Y. Lee, Borja L. Holgado, Olga Sirbu, Craig Daniels, Cheryl H. Arrowsmith, Cory Richman, Poul H. Sorensen, Kulandaimanuvel Antony Michealraj, Sheila K. Singh, Andrea Bajic, Polina Balin, Stephen C. Mack, Betty Luu, Fiona J. Coutinho, Dilakshan Srikanthan, Florence M.G. Cavalli, Sachin Kumar, Evan Y. Wang, Mathieu Lupien, Peter B. Dirks, Maria C. Vladoiu, Lincoln Stein, Livia Garzia, Ahmad Malik, John Wojcik, Avesta Rastan, Michealraj, K. A., Kumar, S. A., Kim, L. J. Y., Cavalli, F. M. G., Przelicki, D., Wojcik, J. B., Delaidelli, A., Bajic, A., Saulnier, O., Macleod, G., Vellanki, R. N., Vladoiu, M. C., Guilhamon, P., Ong, W., Lee, J. J. Y., Jiang, Y., Holgado, B. L., Rasnitsyn, A., Malik, A. A., Tsai, R., Richman, C. M., Juraschka, K., Haapasalo, J., Wang, E. Y., De Antonellis, P., Suzuki, H., Farooq, H., Balin, P., Kharas, K., Van Ommeren, R., Sirbu, O., Rastan, A., Krumholtz, S. L., Ly, M., Ahmadi, M., Deblois, G., Srikanthan, D., Luu, B., Loukides, J., Wu, X., Garzia, L., Ramaswamy, V., Kanshin, E., Sanchez-Osuna, M., El-Hamamy, I., Coutinho, F. J., Prinos, P., Singh, S., Donovan, L. K., Daniels, C., Schramek, D., Tyers, M., Weiss, S., Stein, L. D., Lupien, M., Wouters, B. G., Garcia, B. A., Arrowsmith, C. H., Sorensen, P. H., Angers, S., Jabado, N., Dirks, P. B., Mack, S. C., Agnihotri, S., Rich, J. N., and Taylor, M. D.

Subjects
Epigenomics, Ependymoma, Male, ependymoma, Epigenomic, Somatic cell, cancer metabolism, Infratentorial Neoplasms, Biology, General Biochemistry, Genetics and Molecular Biology, Cell Line, Histones, Brain Neoplasm, 03 medical and health sciences, Epigenome, 0302 clinical medicine, Histone demethylation, Histone methylation, medicine, Animals, Humans, Epigenetics, 030304 developmental biology, hindbrain development, Cell Proliferation, Infratentorial Neoplasm, 0303 health sciences, Brain Neoplasms, Animal, Lysine, Infant, DNA Methylation, medicine.disease, microenvironment, Mice, Inbred C57BL, Histone, Acetylation, paediatric cancer, Mutation, biology.protein, Cancer research, 030217 neurology & neurosurgery, epigenetic, Human
Abstract

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma. Hypoxia reprograms the cellular metabolome and epigenome to promote growth of the most lethal ependymomas.

Published
2020

9. Spatial heterogeneity in medulloblastoma

Author

David T.W. Jones, Yusanne Ma, Xin Wang, Betty Luu, Cynthia Hawkins, Adrian Ally, Marc Remke, John S. Myseros, Nada Jabado, Adam M. Fontebasso, Volker Hovestadt, Michael D. Taylor, Craig Daniels, Borja L. Holgado, Steffen Albrecht, Uri Tabori, David Malkin, Andrey Korshunov, Diana M. Merino, Stuart Horswell, Rebecca Carlsen, James T. Rutka, Daniel Picard, Marco A. Marra, David Shih, Angela Tam, Patrick Plettner, Roger J. Packer, Gary D. Bader, Erin N. Kiehna, Hamza Farooq, Eloi Mercier, John Peacock, Stephen C. Mack, A. Sorana Morrissy, Sameer Agnihotri, Jonathon Torchia, Vijay Ramaswamy, Young Cheng, Kane Tse, Steven J.M. Jones, Laura K. Donovan, Richard A. Moore, Sunit Das, Annie Huang, Nina Thiessen, James Loukides, Darlene Lee, Yisu Li, Marcel Kool, Charles Swanton, Eric Chuah, Tenzin Gayden, Xiaochong Wu, Michael Mayo, Eric Bouffet, Chelsea Mayoh, Peter Lichter, Noreen Dhalla, Brian R. Rood, Jacek Majewski, Ulrich Schüller, Haiyan I. Li, Richard Corbett, Tina Wong, Paul A. Northcott, Pawel Buczkowicz, Florence M.G. Cavalli, Yuan Yao Thompson, William Long, Maria C. Vladoiu, Peter B. Dirks, Hamid Nikbakht, Livia Garzia, Stefan M. Pfister, Jacqueline E. Schein, Simon Papillon-Cavanagh, Andrew J. Mungall, and Jüri Reimand

Subjects
Adult, Male, 0301 basic medicine, renal cell carcinoma, DNA Copy Number Variations, Genome-wide association study, Biology, medulloblastoma, Bioinformatics, Polymorphism, Single Nucleotide, Article, whole exome sequencing, Genetic Heterogeneity, glioblastoma multiforme, 03 medical and health sciences, INDEL Mutation, Renal cell carcinoma, Glioma, Biopsy, gene expression profiling, Genetics, medicine, Cluster Analysis, Humans, Cerebellar Neoplasms, Child, Aged, Aged, 80 and over, Medulloblastoma, Principal Component Analysis, medicine.diagnostic_test, Reverse Transcriptase Polymerase Chain Reaction, business.industry, Genetic heterogeneity, Middle Aged, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, Gene expression profiling, 030104 developmental biology, Child, Preschool, Mutation, Cancer research, Female, Spatial heterogeneity, Personalized medicine, Transcriptome, business, Genome-Wide Association Study
Abstract

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

Published
2017

10. TMOD-10. MOLECULAR CHARACTERIZATION OF A NOVEL HUMAN CLIVAL CHORDOMA XENOGRAFT MODEL DEMONSTRATES INHERENT TUMOR GENOMIC INSTABILITY

Author

Ali Haider, Michael D. Cusimano, Amanda Luck, James T. Rutka, Christian A. Smith, James Loukides, Roberto J. Diaz, Andrew Bondoc, Daniel Picard, Brian Golbourn, Nesrin Sabha, and Marc Remke

Subjects
Genome instability, musculoskeletal diseases, Cancer Research, Brachyury, Pathology, medicine.medical_specialty, Cancer, Biology, medicine.disease, Phenotype, Cytokeratin, Abstracts, Oncology, CDKN2A, Genotype, medicine, Neurology (clinical), Chordoma
Abstract

Patient-derived xenografts (PDXs) retain the genotype of the parental tumors more readily than tumor cells maintained in culture. In order to study the genetics of clival chordoma in the absence of prior radiation we sought to establish a PDX following the primary resection of a clival chordoma. Epicranial grafting of a primary clival chordoma was performed in NOD/SCID mice. Tumors have been passaged serially in mice for 7 generations. Physaliferous cell architecture was demonstrated in the regenerated tumors, which stained positive for Brachyury, Cytokeratin, and S100. The tumors demonstrated bone invasion. Single-nucleotide polymorphism analysis of the tumor xenograft was compared to the parental tumor. We identified homozygous amplification of the T-gene (brachury) and heterozygous loss of CDKN2A. We also identified heterozygous loss of the tumor suppressor FHIT gene, although protein expression was preserved. Accumulation of copy number losses and gains over three generations showed for the first time that there is inherent genomic instability in chordoma. In conclusion, this PDX reproduces the phenotype of clival chordoma. This study is the first to show chromosomal genomic instability in a chordoma that is serially propagated through multiple generations. The genomic instability observed in chordoma may serve as the biological basis for resistance to chemotherapy as is observed for other forms of cancer.

Published
2017

11. Abstract B35: BMP regulation of cancer stem cell quiescence is responsible for chemotherapeutic resistance in glioblastoma

Author

Jeffrey Chan, Angela Celebre, Jason Karamchandani, Sunit Das, Megan YiJun Wu, Karan Dhand, James Loukides, and Jennifer Guan

Subjects
Cancer Research, education.field_of_study, Pathology, medicine.medical_specialty, Temozolomide, Population, Cancer, Biology, medicine.disease, Oncology, SOX2, Cancer stem cell, Glioma, medicine, Cancer research, Stem cell, education, BMP signaling pathway, medicine.drug
Abstract

Introduction: Cancer stem cells (CSCs) represent a distinct cellular population that has been implicated in tumor recurrence following chemotherapy. Accumulating evidence indicates that BMP signaling plays an important role in the regulation of CSCs, and may be involved in the resistance of CSCs to cytotoxic drugs. The role of BMP pathway regulation of the CSC phenotype responsible for treatment resistance in glioblastoma (GBM) has not been explored. Methods: Paraffin-embedded (FFPE) samples from GBM patients were used to evaluate the expression of markers for BMP signaling (pSMAD1/5/8), proliferation (PCNA), and stemness (SOX2) by immunostaining. We tested the self-renewal capacity of primary patient-derived glioma stem cell (GSC) lines using a sphere formation assay. Expression of stemness markers SOX2 and Bmi-1 in BMP4 treated and untreated GSCs, was analyzed by Western blotting. We also performed xenograft transplantation, whereby GSCs were injected intracranially into immunedeficient mice. When tumor formation was confirmed post-injection, mice were administrated EdU and sacrificed at successive time points thereafter. The frequency of all EdU positive cells as well as ID-1positive/ EdU positive cells was quantified from the primary tumor sections throughout the labeling and chase. To study chemoresistance in glioblastoma, GSC lines were treated with graded concentrations of temozolomide (TMZ). Results: We found that pSMAD1/5/8 positive cells in primary patient tumors were largely PCNA-negative. BMP4 treatment inhibited GSC proliferation and self-renewal (sphere-formation), but did not abolish expression of markers of stemness, such as Sox2 and Bmi-1, or tumorigenicity. In our in vivo model, we found ID-1 positive cells retain EdU following a long-term chase. Taken together, these results demonstrate that BMP4-enriched cells possess the characteristics of a quiescent stem cell population. BMP4 treatment protects GSCs against TMZ-induced growth inhibition. Furthermore, pSMAD1/5/8-expressing cells do not possess the DNA damage marker gamma-H2AX following TMZ treatment, suggesting that activation of the BMP pathway protects GSCs against TMZ-induced DNA damage. Conclusion: This study establishes that the BMP signaling pathway is involved in the maintenance of GSC quiescence and may play a role in glioblastoma chemoresistance. Citation Format: Megan YiJun Wu, Angela Celebre, Jeffrey Chan, Jennifer Guan, Karan Dhand, James Loukides, Jason Karamchandani, Sunit Das. BMP regulation of cancer stem cell quiescence is responsible for chemotherapeutic resistance in glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B35.

Published
2015

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