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2. Triptolide and its prodrug Minnelide target high-risk MYC-amplified medulloblastoma in preclinical models

Author

Rodriguez-Blanco, Jezabel, Salvador, April D., Suter, Robert K., Swiderska-Syn, Marzena, Palomo-Caturla, Isabel, Kliebe, Valentin, Shahani, Pritika, Peterson, Kendell, Turos-Cabal, Maria, Vieira, Megan E., Wynn, Daniel T., Howell, Ashley J., Yang, Fan, Ban, Yuguang, McCrea, Heather J., Zindy, Frederique, Danis, Etienne, Vibhakar, Rajeev, Jermakowicz, Anna, Martin, Vanesa, Coss, Christopher C., Harris, Brent T., de Cubas, Aguirre, Chen, X. Steven, Barnoud, Thibaut, Roussel, Martine F., Ayad, Nagi G., and Robbins, David J.

Subjects
Medulloblastoma -- Care and treatment -- Patient outcomes -- Models, Prodrugs -- Dosage and administration -- Testing, Chemotherapy, Combination -- Dosage and administration -- Testing, Health care industry
Abstract

Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance therapeutic approaches that benefit such high-risk patients. Minnelide, a clinically relevant analog of the natural product triptolide, has oncostatic activity in both preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, this compound has not been evaluated in MB. Utilizing a bioinformatic data set that integrates cellular drug response data with gene expression, we predicted that Group 3 (G3) MB, which has a poor 5-year survival, would be sensitive to triptolide/Minnelide. We subsequently showed that both triptolide and Minnelide attenuate the viability of G3 MB cells ex vivo. Transcriptomic analyses identified MYC signaling, a pathologically relevant driver of G3 MB, as a downstream target of this class of drugs. We validated this MYC dependency in G3 MB cells and showed that triptolide exerts its efficacy by reducing both MYC transcription and MYC protein stability. Importantly, Minnelide acted on MYC to reduce tumor growth and leptomeningeal spread, which resulted in improved survival of G3 MB animal models. Moreover, Minnelide improved the efficacy of adjuvant chemotherapy, further highlighting its potential for the treatment of MYC-driven G3 MB., Introduction Nervous system tumors are the leading cause of cancer-related death in children (1), with medulloblastoma (MB) being the most common malignant form (2). Over the last decade, genomic stratification [...]

Published
2024
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3. 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

4. Subgroup and subtype-specific outcomes in adult medulloblastoma.

Author

Coltin, Hallie, Sundaresan, Lakshmikirupa, Smith, Kyle, Skowron, Patryk, Massimi, Luca, Eberhart, Charles, Schreck, Karisa, Gupta, Nalin, Weiss, William, Tirapelli, Daniela, Carlotti, Carlos, Li, Kay, Ryzhova, Marina, Golanov, Andrey, Zheludkova, Olga, Absalyamova, Oksana, Okonechnikov, Konstantin, Stichel, Damian, von Deimling, Andreas, Giannini, Caterina, Raskin, Scott, Van Meir, Erwin, Chan, Jennifer, Fults, Daniel, Chambless, Lola, Kim, Seung-Ki, Vasiljevic, Alexandre, Faure-Conter, Cecile, Vibhakar, Rajeev, Jung, Shin, Leary, Sarah, Mora, Jaume, McLendon, Roger, Pollack, Ian, Hauser, Peter, Grajkowska, Wieslawa, Rubin, Joshua, van Veelen, Marie-Lise, French, Pim, Kros, Johan, Liau, Linda, Pfister, Stefan, Kool, Marcel, Kijima, Noriyuki, Taylor, Michael, Packer, Roger, Northcott, Paul, Korshunov, Andrey, and Ramaswamy, Vijay

Subjects
Adult, DNA methylation profiling, Medulloblastoma, Molecular groups, Risk stratification, Adolescent, Adult, Biomarkers, Tumor, Cerebellar Neoplasms, Cohort Studies, Female, Humans, Male, Medulloblastoma, Progression-Free Survival, Risk Factors, Young Adult
Abstract

Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p

Published
2021

5. 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

6. Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG

Author

Balakrishnan, Ilango, Danis, Etienne, Pierce, Angela, Madhavan, Krishna, Wang, Dong, Dahl, Nathan, Sanford, Bridget, Birks, Diane K, Davidson, Nate, Metselaar, Dennis S, Meel, Michaël Hananja, Lemma, Rakeb, Donson, Andrew, Vijmasi, Trinka, Katagi, Hiroaki, Sola, Ismail, Fosmire, Susan, Alimova, Irina, Steiner, Jenna, Gilani, Ahmed, Hulleman, Esther, Serkova, Natalie J, Hashizume, Rintaro, Hawkins, Cynthia, Carcaboso, Angel M, Gupta, Nalin, Monje, Michelle, Jabado, Nada, Jones, Kenneth, Foreman, Nicholas, Green, Adam, Vibhakar, Rajeev, and Venkataraman, Sujatha

Subjects
Biochemistry and Cell Biology, Biological Sciences, Rare Diseases, Genetics, Stem Cell Research, Biotechnology, Cancer, Brain Disorders, Stem Cell Research - Nonembryonic - Non-Human, Brain Cancer, Aging, Astrocytoma, Brain Stem Neoplasms, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Child, Child, Preschool, Chromatin, Diffuse Intrinsic Pontine Glioma, Epigenomics, Female, Glioma, Histones, Humans, Lysine, Male, Mutation, Neoplasm Recurrence, Local, Polycomb Repressive Complex 1, BH3 mimetics, BMI1, DIPG, H3K27M mutant, H3WT, PTC 028, RNAi screen, SASP, senescence, Bmi1, PTC028, Medical Physiology, Biological sciences
Abstract

Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo.

Published
2020

7. Advancing biology-based therapeutic approaches for atypical teratoid rhabdoid tumors.

Author

Hoffman, Lindsey M, Richardson, Elizabeth Anne, Ho, Ben, Margol, Ashley, Reddy, Alyssa, Lafay-Cousin, Lucie, Chi, Susan, Slavc, Irene, Judkins, Alexander, Hasselblatt, Martin, Bourdeaut, Franck, Frühwald, Michael C, Vibhakar, Rajeev, Bouffet, Eric, and Huang, Annie

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Genetics, Human Genome, Orphan Drug, Cancer, Aetiology, 2.1 Biological and endogenous factors, Epigenomics, Humans, Neoplasms, Neuroepithelial, Rhabdoid Tumor, SMARCB1 Protein, ATRT, enhancer, epigenomics, rhabdoid tumors, subgroup-specific therapeutics, ATRT, enhancer, epigenomics, rhabdoid tumors, Neurosciences, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

Atypical teratoid rhabdoid tumor (ATRT) is a rare, highly malignant central nervous system cancer arising in infants and younger children, historically considered to be homogeneous, monogenic, and incurable. Recent use of intensified therapies has modestly improved survival for ATRT; however, a majority of patients will still succumb to their disease. While ATRTs almost universally exhibit loss of SMARCB1 (BAF47/INI1/SNF5), recent whole genome, transcriptome, and epigenomic analyses of large cohorts reveal previously underappreciated molecular heterogeneity. These discoveries provide novel insights into how SMARCB1 loss drives oncogenesis and confer specific therapeutic vulnerabilities, raising exciting prospects for molecularly stratified treatment for patients with ATRT.

Published
2020

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

11. Author Correction: scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy

Author

Ocasio, Jennifer Karin, Babcock, Benjamin, Malawsky, Daniel, Weir, Seth J., Loo, Lipin, Simon, Jeremy M., Zylka, Mark J., Hwang, Duhyeong, Dismuke, Taylor, Sokolsky, Marina, Rosen, Elias P., Vibhakar, Rajeev, Zhang, Jiao, Saulnier, Olivier, Vladoiu, Maria, El-Hamamy, Ibrahim, Stein, Lincoln D., Taylor, Michael D., Smith, Kyle S., Northcott, Paul A., Colaneri, Alejandro, Wilhelmsen, Kirk, and Gershon, Timothy R.

Published
2022
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13. Multi-pronged analysis of pediatric low-grade glioma reveals a unique tumor microenvironment associated with BRAF alterations

Author

Zahedi, Shadi, primary, Riemondy, Kent, additional, Griesinger, Andrea M., additional, Donson, Andrew M., additional, Fu, Rui, additional, Crespo, Michele, additional, DeSisto, John, additional, Groat, Madeline M., additional, Bratbak, Emil, additional, Green, Adam, additional, Hankinson, Todd C., additional, Handler, Michael, additional, Vibhakar, Rajeev, additional, Willard, Nicholas, additional, Foreman, Nicholas K., additional, and Levy, Jean Mulcahy, additional

Published
2024
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14. Transcriptional Regulation of Protein Synthesis by Mediator Kinase in MYC-driven Medulloblastoma

Author

Wang, Dong, primary, Ritz, Caitlin, additional, Pierce, Angela, additional, Brunt, Breauna, additional, Luo, Yuhuan, additional, Dahl, Nathan, additional, Venkataraman, Sujatha, additional, Danis, Etienne, additional, Kuś, Kamil, additional, Mazan, Milena, additional, Rzymski, Tomasz, additional, Veo, Bethany, additional, and Vibhakar, Rajeev, additional

Published
2024
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16. Development of Chromosome 1q+ Specific Treatment for Highest Risk Pediatric Posterior Fossa Ependymoma

Author

Griesinger, Andrea M., primary, Calzadilla, Annaliese J., additional, Grimaldo, Enrique, additional, Donson, Andrew M., additional, Amani, Vladimir, additional, Pierce, Angela M., additional, Steiner, Jenna, additional, Kargar, Soudabeh, additional, Serkova, Natalie J., additional, Bertrand, Kelsey C., additional, Wright, Karen D., additional, Vibhakar, Rajeev, additional, Hankinson, Todd, additional, Handler, Michael, additional, Lindsay, Holly B., additional, Foreman, Nicholas K., additional, and Dorris, Kathleen, additional

Published
2024
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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: 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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19. 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

21. Comprehensive molecular characterization of pediatric radiation-induced high-grade glioma

Author

DeSisto, John, Lucas, Jr., John T., Xu, Ke, Donson, Andrew, Lin, Tong, Sanford, Bridget, Wu, Gang, Tran, Quynh T., Hedges, Dale, Hsu, Chih-Yang, Armstrong, Gregory T., Arnold, Michael, Bhatia, Smita, Flannery, Patrick, Lemma, Rakeb, Hardie, Lakotah, Schüller, Ulrich, Venkataraman, Sujatha, Hoffman, Lindsey M., Dorris, Kathleen, Mulcahy Levy, Jean M., Hankinson, Todd C., Handler, Michael, Liu, Arthur K., Foreman, Nicholas, Vibhakar, Rajeev, Jones, Kenneth, Allen, Sariah, Zhang, Jinghui, Baker, Suzanne J., Merchant, Thomas E., Orr, Brent A., and Green, Adam L.

Published
2021
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24. BPTF regulates growth of adult and pediatric high-grade glioma through the MYC pathway

Author

Green, Adam L., DeSisto, John, Flannery, Patrick, Lemma, Rakeb, Knox, Aaron, Lemieux, Madeleine, Sanford, Bridget, O’Rourke, Rebecca, Ramkissoon, Shakti, Jones, Kristen, Perry, Jennifer, Hui, Xu, Moroze, Erin, Balakrishnan, Ilango, O’Neill, Allison F., Dunn, Katherine, DeRyckere, Deborah, Danis, Etienne, Safadi, Aaron, Gilani, Ahmed, Hubbell-Engler, Benjamin, Nuss, Zachary, Levy, Jean M. Mulcahy, Serkova, Natalie, Venkataraman, Sujatha, Graham, Douglas K., Foreman, Nicholas, Ligon, Keith, Jones, Ken, Kung, Andrew L., and Vibhakar, Rajeev

Published
2020
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25. Cytogenetic prognostication within medulloblastoma subgroups.

Author

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

Subjects
Adolescent, Biomarkers, Tumor, Child, Child, Preschool, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 14, Cytogenetics, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Hedgehog Proteins, Humans, In Situ Hybridization, Fluorescence, Infant, Kruppel-Like Transcription Factors, Male, Medulloblastoma, Nuclear Proteins, Predictive Value of Tests, Prognosis, Proportional Hazards Models, Proto-Oncogene Proteins c-myc, Reproducibility of Results, Risk Assessment, Risk Factors, Tissue Array Analysis, Wnt Proteins, Young Adult, Zinc Finger Protein Gli2
Abstract

PURPOSE: Medulloblastoma 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 METHODS: Molecular 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. RESULTS: Subgroup 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. CONCLUSION: Combining 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

27. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma.

Author

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

Subjects
Adolescent, Adult, Brain Neoplasms, Child, Child, Preschool, DNA Mutational Analysis, Female, Gene Expression Profiling, Genotype, Humans, Infant, Male, Medulloblastoma, Middle Aged, Mutation, Prognosis, Promoter Regions, Genetic, Telomerase
Abstract

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in

Published
2013

28. Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma

Author

Dubuc, Adrian M, Remke, Marc, Korshunov, Andrey, Northcott, Paul A, Zhan, Shing H, Mendez-Lago, Maria, Kool, Marcel, Jones, David TW, Unterberger, Alexander, Morrissy, A Sorana, Shih, David, Peacock, John, Ramaswamy, Vijay, Rolider, Adi, Wang, Xin, Witt, Hendrik, Hielscher, Thomas, Hawkins, Cynthia, Vibhakar, Rajeev, Croul, Sidney, Rutka, James T, Weiss, William A, Jones, Steven JM, Eberhart, Charles G, Marra, Marco A, Pfister, Stefan M, and Taylor, Michael D

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Pediatric, Human Genome, Brain Disorders, Cancer, Genetics, Rare Diseases, Pediatric Cancer, Brain Cancer, Base Sequence, Cerebellar Neoplasms, Cohort Studies, DNA-Binding Proteins, Female, Genetic Predisposition to Disease, Genome, Histone Demethylases, Histone Methyltransferases, Histone-Lysine N-Methyltransferase, Humans, Lysine, Male, Medulloblastoma, Methylation, Mutation, Neoplasm Proteins, Nuclear Proteins, Polymorphism, Single Nucleotide, MLL2, KDM6A, Histone lysine methylation, PRC2, Clinical Sciences, Neurosciences, Neurology & Neurosurgery
Abstract

Recent sequencing efforts have described the mutational landscape of the pediatric brain tumor medulloblastoma. Although MLL2 is among the most frequent somatic single nucleotide variants (SNV), the clinical and biological significance of these mutations remains uncharacterized. Through targeted re-sequencing, we identified mutations of MLL2 in 8 % (14/175) of MBs, the majority of which were loss of function. Notably, we also report mutations affecting the MLL2-binding partner KDM6A, in 4 % (7/175) of tumors. While MLL2 mutations were independent of age, gender, histological subtype, M-stage or molecular subgroup, KDM6A mutations were most commonly identified in Group 4 MBs, and were mutually exclusive with MLL2 mutations. Immunohistochemical staining for H3K4me3 and H3K27me3, the chromatin effectors of MLL2 and KDM6A activity, respectively, demonstrated alterations of the histone code in 24 % (53/220) of MBs across all subgroups. Correlating these MLL2- and KDM6A-driven histone marks with prognosis, we identified populations of MB with improved (K4+/K27-) and dismal (K4-/K27-) outcomes, observed primarily within Group 3 and 4 MBs. Group 3 and 4 MBs demonstrate somatic copy number aberrations, and transcriptional profiles that converge on modifiers of H3K27-methylation (EZH2, KDM6A, KDM6B), leading to silencing of PRC2-target genes. As PRC2-mediated aberrant methylation of H3K27 has recently been targeted for therapy in other diseases, it represents an actionable target for a substantial percentage of medulloblastoma patients with aggressive forms of the disease.

Published
2013

29. 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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30. EYA2 Tyrosine Phosphatase Inhibition Reduces MYC and Prevents Medulloblastoma Progression

Author

Wolin, Arthur R, primary, Vincent, Melanie Y, additional, Hotz, Taylor, additional, Purdy, Stephen C, additional, Rosenbaum, Sheera R, additional, Hughes, Connor J, additional, Hsu, Jessica Y, additional, Oliphant, Michael U J, additional, Armstrong, Brock, additional, Wessells, Veronica, additional, Varella-Garcia, Marileila, additional, Galbraith, Matthew D, additional, Pierce, Angela, additional, Wang, Dong, additional, Venkataraman, Sujatha, additional, Danis, Etienne, additional, Veo, Bethany, additional, Serkova, Natalie, additional, Espinosa, Joaquin M, additional, Gustafson, Daniel L, additional, Vibhakar, Rajeev, additional, and Ford, Heide L, additional

Published
2023
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32. XRT-06. RAPID PTEFB-DEPENDENT TRANSCRIPTIONAL REORGANIZATION UNDERPINS THE GLIOMA ADAPTIVE RESPONSE TO RADIOTHERAPY

Author

Walker, Faye, primary, Sobral, Lays Martin, additional, Danis, Etienne, additional, Sanford, Bridget, additional, Balakrishnan, Ilango, additional, Wang, Dong, additional, Pierce, Angela, additional, Karam, Sana, additional, Serkova, Natalie, additional, Foreman, Nicholas, additional, Venkataraman, Sujatha, additional, Dowell, Robin, additional, Vibhakar, Rajeev, additional, and Dahl, Nathan, additional

Published
2023
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33. scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy

Author

Ocasio, Jennifer Karin, Babcock, Benjamin, Malawsky, Daniel, Weir, Seth J., Loo, Lipin, Simon, Jeremy M., Zylka, Mark J., Hwang, Duhyeong, Dismuke, Taylor, Sokolsky, Marina, Rosen, Elias P., Vibhakar, Rajeev, Zhang, Jiao, Saulnier, Olivier, Vladoiu, Maria, El-Hamamy, Ibrahim, Stein, Lincoln D., Taylor, Michael D., Smith, Kyle S., Northcott, Paul A., Colaneri, Alejandro, Wilhelmsen, Kirk, and Gershon, Timothy R.

Published
2019
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36. A novel preclinical model of craniospinal irradiation in pediatric diffuse midline glioma demonstrates decreased metastatic disease

Author

Knox, Aaron J., primary, Van Court, Benjamin, additional, Oweida, Ayman, additional, Barsh, Elinor, additional, DeSisto, John, additional, Flannery, Patrick, additional, Lemma, Rakeb, additional, Chatwin, Hannah, additional, Vibhakar, Rajeev, additional, Dorris, Kathleen, additional, Serkova, Natalie J., additional, Karam, Sana D., additional, Gilani, Ahmed, additional, and Green, Adam L., additional

Published
2023
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37. Figure S1 from A Small-Molecule Inhibitor of WEE1, AZD1775, Synergizes with Olaparib by Impairing Homologous Recombination and Enhancing DNA Damage and Apoptosis in Acute Leukemia

Author

Garcia, Tamara B., primary, Snedeker, Jonathan C., primary, Baturin, Dmitry, primary, Gardner, Lori, primary, Fosmire, Susan P., primary, Zhou, Chengjing, primary, Jordan, Craig T., primary, Venkataraman, Sujatha, primary, Vibhakar, Rajeev, primary, and Porter, Christopher C., primary

Published
2023
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38. Supp. Table 2 from Exportin 1 Inhibition Induces Nerve Growth Factor Receptor Expression to Inhibit the NF-κB Pathway in Preclinical Models of Pediatric High-Grade Glioma

Author

DeSisto, John A., primary, Flannery, Patrick, primary, Lemma, Rakeb, primary, Pathak, Amrita, primary, Mestnik, Shelby, primary, Philips, Natalie, primary, Bales, Natalie J., primary, Kashyap, Trinayan, primary, Moroze, Erin, primary, Venkataraman, Sujatha, primary, Kung, Andrew L., primary, Carter, Bruce D., primary, Landesman, Yosef, primary, Vibhakar, Rajeev, primary, and Green, Adam L., primary

Published
2023
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39. Supplemental Figure Legends from Interleukin-6/STAT3 Pathway Signaling Drives an Inflammatory Phenotype in Group A Ependymoma

Author

Griesinger, Andrea M., primary, Josephson, Rebecca J., primary, Donson, Andrew M., primary, Mulcahy Levy, Jean M., primary, Amani, Vladimir, primary, Birks, Diane K., primary, Hoffman, Lindsey M., primary, Furtek, Steffanie L., primary, Reigan, Phillip, primary, Handler, Michael H., primary, Vibhakar, Rajeev, primary, and Foreman, Nicholas K., primary

Published
2023
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40. Supplementary Figure 5 from Interleukin-6/STAT3 Pathway Signaling Drives an Inflammatory Phenotype in Group A Ependymoma

Author

Griesinger, Andrea M., primary, Josephson, Rebecca J., primary, Donson, Andrew M., primary, Mulcahy Levy, Jean M., primary, Amani, Vladimir, primary, Birks, Diane K., primary, Hoffman, Lindsey M., primary, Furtek, Steffanie L., primary, Reigan, Phillip, primary, Handler, Michael H., primary, Vibhakar, Rajeev, primary, and Foreman, Nicholas K., primary

Published
2023
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41. Data from Identification of FDA-Approved Oncology Drugs with Selective Potency in High-Risk Childhood Ependymoma

Author

Donson, Andrew M., primary, Amani, Vladimir, primary, Warner, Elliot A., primary, Griesinger, Andrea M., primary, Witt, Davis A., primary, Levy, Jean M. Mulcahy, primary, Hoffman, Lindsey M., primary, Hankinson, Todd C., primary, Handler, Michael H., primary, Vibhakar, Rajeev, primary, Dorris, Kathleen, primary, and Foreman, Nicholas K., primary

Published
2023
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42. Data from Interleukin-6/STAT3 Pathway Signaling Drives an Inflammatory Phenotype in Group A Ependymoma

Author

Griesinger, Andrea M., primary, Josephson, Rebecca J., primary, Donson, Andrew M., primary, Mulcahy Levy, Jean M., primary, Amani, Vladimir, primary, Birks, Diane K., primary, Hoffman, Lindsey M., primary, Furtek, Steffanie L., primary, Reigan, Phillip, primary, Handler, Michael H., primary, Vibhakar, Rajeev, primary, and Foreman, Nicholas K., primary

Published
2023
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43. Supplementary Data from Identification of FDA-Approved Oncology Drugs with Selective Potency in High-Risk Childhood Ependymoma

Author

Donson, Andrew M., primary, Amani, Vladimir, primary, Warner, Elliot A., primary, Griesinger, Andrea M., primary, Witt, Davis A., primary, Levy, Jean M. Mulcahy, primary, Hoffman, Lindsey M., primary, Hankinson, Todd C., primary, Handler, Michael H., primary, Vibhakar, Rajeev, primary, Dorris, Kathleen, primary, and Foreman, Nicholas K., primary

Published
2023
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44. Supp. Figures from Exportin 1 Inhibition Induces Nerve Growth Factor Receptor Expression to Inhibit the NF-κB Pathway in Preclinical Models of Pediatric High-Grade Glioma

Author

DeSisto, John A., primary, Flannery, Patrick, primary, Lemma, Rakeb, primary, Pathak, Amrita, primary, Mestnik, Shelby, primary, Philips, Natalie, primary, Bales, Natalie J., primary, Kashyap, Trinayan, primary, Moroze, Erin, primary, Venkataraman, Sujatha, primary, Kung, Andrew L., primary, Carter, Bruce D., primary, Landesman, Yosef, primary, Vibhakar, Rajeev, primary, and Green, Adam L., primary

Published
2023
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45. Supplementary Figure 6 from Interleukin-6/STAT3 Pathway Signaling Drives an Inflammatory Phenotype in Group A Ependymoma

Author

Griesinger, Andrea M., primary, Josephson, Rebecca J., primary, Donson, Andrew M., primary, Mulcahy Levy, Jean M., primary, Amani, Vladimir, primary, Birks, Diane K., primary, Hoffman, Lindsey M., primary, Furtek, Steffanie L., primary, Reigan, Phillip, primary, Handler, Michael H., primary, Vibhakar, Rajeev, primary, and Foreman, Nicholas K., primary

Published
2023
Full Text
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46. Supplementary Figure 1 from Interleukin-6/STAT3 Pathway Signaling Drives an Inflammatory Phenotype in Group A Ependymoma

Author

Griesinger, Andrea M., primary, Josephson, Rebecca J., primary, Donson, Andrew M., primary, Mulcahy Levy, Jean M., primary, Amani, Vladimir, primary, Birks, Diane K., primary, Hoffman, Lindsey M., primary, Furtek, Steffanie L., primary, Reigan, Phillip, primary, Handler, Michael H., primary, Vibhakar, Rajeev, primary, and Foreman, Nicholas K., primary

Published
2023
Full Text
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47. Supplementary Figure 2 from Identification of FDA-Approved Oncology Drugs with Selective Potency in High-Risk Childhood Ependymoma

Author

Donson, Andrew M., primary, Amani, Vladimir, primary, Warner, Elliot A., primary, Griesinger, Andrea M., primary, Witt, Davis A., primary, Levy, Jean M. Mulcahy, primary, Hoffman, Lindsey M., primary, Hankinson, Todd C., primary, Handler, Michael H., primary, Vibhakar, Rajeev, primary, Dorris, Kathleen, primary, and Foreman, Nicholas K., primary

Published
2023
Full Text
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48. Supp. Table 3 from Exportin 1 Inhibition Induces Nerve Growth Factor Receptor Expression to Inhibit the NF-κB Pathway in Preclinical Models of Pediatric High-Grade Glioma

Author

DeSisto, John A., primary, Flannery, Patrick, primary, Lemma, Rakeb, primary, Pathak, Amrita, primary, Mestnik, Shelby, primary, Philips, Natalie, primary, Bales, Natalie J., primary, Kashyap, Trinayan, primary, Moroze, Erin, primary, Venkataraman, Sujatha, primary, Kung, Andrew L., primary, Carter, Bruce D., primary, Landesman, Yosef, primary, Vibhakar, Rajeev, primary, and Green, Adam L., primary

Published
2023
Full Text
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49. Supplementary figure 1 from Identification of FDA-Approved Oncology Drugs with Selective Potency in High-Risk Childhood Ependymoma

Author

Donson, Andrew M., primary, Amani, Vladimir, primary, Warner, Elliot A., primary, Griesinger, Andrea M., primary, Witt, Davis A., primary, Levy, Jean M. Mulcahy, primary, Hoffman, Lindsey M., primary, Hankinson, Todd C., primary, Handler, Michael H., primary, Vibhakar, Rajeev, primary, Dorris, Kathleen, primary, and Foreman, Nicholas K., primary

Published
2023
Full Text
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50. Data from Exportin 1 Inhibition Induces Nerve Growth Factor Receptor Expression to Inhibit the NF-κB Pathway in Preclinical Models of Pediatric High-Grade Glioma

Author

DeSisto, John A., primary, Flannery, Patrick, primary, Lemma, Rakeb, primary, Pathak, Amrita, primary, Mestnik, Shelby, primary, Philips, Natalie, primary, Bales, Natalie J., primary, Kashyap, Trinayan, primary, Moroze, Erin, primary, Venkataraman, Sujatha, primary, Kung, Andrew L., primary, Carter, Bruce D., primary, Landesman, Yosef, primary, Vibhakar, Rajeev, primary, and Green, Adam L., primary

Published
2023
Full Text
View/download PDF

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