Search

Your search keyword '"Dirks, Peter"' showing total 431 results
Start Over Author "Dirks, Peter" Search Limiters Available in Library Collection
431 results on '"Dirks, Peter"'

1. Pediatric Moyamoya Revascularization Perioperative Care: A Modified Delphi Study.

Author

Sun, Lisa, Jordan, Lori, Smith, Edward, Aldana, Philipp, Kirschen, Matthew, Guilliams, Kristin, Gupta, Nalin, Steinberg, Gary, Fox, Christine, Harrar, Dana, Lee, Sarah, Chung, Melissa, Dirks, Peter, Dlamini, Nomazulu, Maher, Cormac, Lehman, Laura, Hong, Sue, Strahle, Jennifer, Pineda, Jose, Beslow, Lauren, Rasmussen, Lindsey, Mailo, Janette, Piatt, Joseph, Lang, Shih-Shan, Adelson, P, Dewan, Michael, Mineyko, Aleksandra, McClugage, Samuel, Vadivelu, Sudhakar, Dowling, Michael, and Hersh, David

Subjects
Cerebral revascularization, Children, Delphi technique, Ischemic stroke, Moyamoya disease, Pediatric stroke, Perioperative care, Child, Humans, Delphi Technique, Moyamoya Disease, Stroke, Perioperative Care, Postoperative Care, Cerebral Revascularization, Treatment Outcome, Retrospective Studies
Abstract

BACKGROUND: Surgical revascularization decreases the long-term risk of stroke in children with moyamoya arteriopathy but can be associated with an increased risk of stroke during the perioperative period. Evidence-based approaches to optimize perioperative management are limited and practice varies widely. Using a modified Delphi process, we sought to establish expert consensus on key components of the perioperative care of children with moyamoya undergoing indirect revascularization surgery and identify areas of equipoise to define future research priorities. METHODS: Thirty neurologists, neurosurgeons, and intensivists practicing in North America with expertise in the management of pediatric moyamoya were invited to participate in a three-round, modified Delphi process consisting of a 138-item practice patterns survey, anonymous electronic evaluation of 88 consensus statements on a 5-point Likert scale, and a virtual group meeting during which statements were discussed, revised, and reassessed. Consensus was defined as ≥ 80% agreement or disagreement. RESULTS: Thirty-nine statements regarding perioperative pediatric moyamoya care for indirect revascularization surgery reached consensus. Salient areas of consensus included the following: (1) children at a high risk for stroke and those with sickle cell disease should be preadmitted prior to indirect revascularization; (2) intravenous isotonic fluids should be administered in all patients for at least 4 h before and 24 h after surgery; (3) aspirin should not be discontinued in the immediate preoperative and postoperative periods; (4) arterial lines for blood pressure monitoring should be continued for at least 24 h after surgery and until active interventions to achieve blood pressure goals are not needed; (5) postoperative care should include hourly vital signs for at least 24 h, hourly neurologic assessments for at least 12 h, adequate pain control, maintaining normoxia and normothermia, and avoiding hypotension; and (6) intravenous fluid bolus administration should be considered the first-line intervention for new focal neurologic deficits following indirect revascularization surgery. CONCLUSIONS: In the absence of data supporting specific care practices before and after indirect revascularization surgery in children with moyamoya, this Delphi process defined areas of consensus among neurosurgeons, neurologists, and intensivists with moyamoya expertise. Research priorities identified include determining the role of continuous electroencephalography in postoperative moyamoya care, optimal perioperative blood pressure and hemoglobin targets, and the role of supplemental oxygen for treatment of suspected postoperative ischemia.

Published
2024

2. Single-cell atlas of the human brain vasculature across development, adulthood and disease

Author

Wälchli, Thomas, Ghobrial, Moheb, Schwab, Marc, Takada, Shigeki, Zhong, Hang, Suntharalingham, Samuel, Vetiska, Sandra, Gonzalez, Daymé Rodrigues, Wu, Ruilin, Rehrauer, Hubert, Dinesh, Anuroopa, Yu, Kai, Chen, Edward L. Y., Bisschop, Jeroen, Farnhammer, Fiona, Mansur, Ann, Kalucka, Joanna, Tirosh, Itay, Regli, Luca, Schaller, Karl, Frei, Karl, Ketela, Troy, Bernstein, Mark, Kongkham, Paul, Carmeliet, Peter, Valiante, Taufik, Dirks, Peter B., Suva, Mario L., Zadeh, Gelareh, Tabar, Viviane, Schlapbach, Ralph, Jackson, Hartland W., De Bock, Katrien, Fish, Jason E., Monnier, Philippe P., Bader, Gary D., and Radovanovic, Ivan

Published
2024
Full Text
View/download PDF

4. A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation

Author

Yanchus, Connor, Drucker, Kristen L, Kollmeyer, Thomas M, Tsai, Ricky, Winick-Ng, Warren, Liang, Minggao, Malik, Ahmad, Pawling, Judy, De Lorenzo, Silvana B, Ali, Asma, Decker, Paul A, Kosel, Matt L, Panda, Arijit, Al-Zahrani, Khalid N, Jiang, Lingyan, Browning, Jared WL, Lowden, Chris, Geuenich, Michael, Hernandez, J Javier, Gosio, Jessica T, Ahmed, Musaddeque, Loganathan, Sampath Kumar, Berman, Jacob, Trcka, Daniel, Michealraj, Kulandaimanuvel Antony, Fortin, Jerome, Carson, Brittany, Hollingsworth, Ethan W, Jacinto, Sandra, Mazrooei, Parisa, Zhou, Lily, Elia, Andrew, Lupien, Mathieu, He, Housheng Hansen, Murphy, Daniel J, Wang, Liguo, Abyzov, Alexej, Dennis, James W, Maass, Philipp G, Campbell, Kieran, Wilson, Michael D, Lachance, Daniel H, Wrensch, Margaret, Wiencke, John, Mak, Tak, Pennacchio, Len A, Dickel, Diane E, Visel, Axel, Wrana, Jeffrey, Taylor, Michael D, Zadeh, Gelareh, Dirks, Peter, Eckel-Passow, Jeanette E, Attisano, Liliana, Pombo, Ana, Ida, Cristiane M, Kvon, Evgeny Z, Jenkins, Robert B, and Schramek, Daniel

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Brain Cancer, Brain Disorders, Human Genome, Neurosciences, Rare Diseases, Genetics, Cancer Genomics, Cancer, 2.1 Biological and endogenous factors, Animals, Brain Neoplasms, Chromosomes, Human, Pair 8, Glioma, Humans, Isocitrate Dehydrogenase, Mice, Mutation, Polymorphism, Single Nucleotide, General Science & Technology
Abstract

Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (IDH)-mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1R132H-driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.

Published
2022

5. 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

6. macroH2A2 antagonizes epigenetic programs of stemness in glioblastoma

Author

Nikolic, Ana, Maule, Francesca, Bobyn, Anna, Ellestad, Katrina, Paik, Seungil, Marhon, Sajid A., Mehdipour, Parinaz, Lun, Xueqing, Chen, Huey-Miin, Mallard, Claire, Hay, Alexander J., Johnston, Michael J., Gafuik, Christopher J., Zemp, Franz J., Shen, Yaoqing, Ninkovic, Nicoletta, Osz, Katalin, Labit, Elodie, Berger, N. Daniel, Brownsey, Duncan K., Kelly, John J., Biernaskie, Jeff, Dirks, Peter B., Derksen, Darren J., Jones, Steven J. M., Senger, Donna L., Chan, Jennifer A., Mahoney, Douglas J., De Carvalho, Daniel D., and Gallo, Marco

Published
2023
Full Text
View/download PDF

7. A non-coding single nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation

Author

Yanchus, Connor, Drucker, Kristen L, Kollmeyer, Thomas M, Tsai, Ricky, Liang, Minggao, Jiang, Lingyan, Pawling, Judy, Ali, Asma, Decker, Paul, Kosel, Matt, Panda, Arijit, Malik, Ahmad, Al-Zahrani, Khalid N, Hernandez, J Javier, Ahmed, Musaddeque, Loganathan, Sampath Kumar, Trcka, Daniel, Michaelraj, Antony, Fortin, Jerome, Mazrooei, Parisa, Zhou, Lily, Elia, Andrew, Lupien, Mathieu, He, Housheng Hansen, Wang, Liguo, Abyzov, Alexej, Dennis, James W, Wilson, Michael D, Wrana, Jeffrey, Lachance, Daniel, Wrensch, Margaret, Wiencke, John, Pennacchio, Len A, Dickel, Diane E, Visel, Axel, Taylor, Michael, Zadeh, Gelareh, Dirks, Peter, Eckel-Passow, Jeanette E, Mak, Tak, Kvon, Evgeny, Jenkins, Robert B, and Schramek, Daniel

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer Genomics, Brain Cancer, Brain Disorders, Rare Diseases, Prevention, Genetics, Human Genome, Cancer, Neurosciences, 2.1 Biological and endogenous factors
Abstract

Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single nucleotide polymorphism rs55705857 (A>G), which confers a 6-fold increased risk of IDH-mutant low-grade glioma (LGG) and is amongst the highest genetic associations with cancer. By fine-mapping the locus, we reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. To functionally test rs55705857, we generated an IDH1 R132H -driven LGG mouse model and show that mutating the highly conserved, orthologous mouse rs55705857 locus dramatically accelerated tumor development from 463 to 172 days and increased penetrance from 30% to 75%. Overall, our work generates new LGG models and reveals mechanisms of the heritable predisposition to lethal glioma in ∼40% of LGG-patients.

Published
2022

8. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Author

Das, Anirban, Sudhaman, Sumedha, Morgenstern, Daniel, Coblentz, Ailish, Chung, Jiil, Stone, Simone C, Alsafwani, Noor, Liu, Zhihui Amy, Karsaneh, Ola Abu Al, Soleimani, Shirin, Ladany, Hagay, Chen, David, Zatzman, Matthew, Cabric, Vanja, Nobre, Liana, Bianchi, Vanessa, Edwards, Melissa, Sambira Nahum, Lauren C, Ercan, Ayse B, Nabbi, Arash, Constantini, Shlomi, Dvir, Rina, Yalon-Oren, Michal, Campino, Gadi Abebe, Caspi, Shani, Larouche, Valerie, Reddy, Alyssa, Osborn, Michael, Mason, Gary, Lindhorst, Scott, Bronsema, Annika, Magimairajan, Vanan, Opocher, Enrico, De Mola, Rebecca Loret, Sabel, Magnus, Frojd, Charlotta, Sumerauer, David, Samuel, David, Cole, Kristina, Chiaravalli, Stefano, Massimino, Maura, Tomboc, Patrick, Ziegler, David S, George, Ben, Van Damme, An, Hijiya, Nobuko, Gass, David, McGee, Rose B, Mordechai, Oz, Bowers, Daniel C, Laetsch, Theodore W, Lossos, Alexander, Blumenthal, Deborah T, Sarosiek, Tomasz, Yen, Lee Yi, Knipstein, Jeffrey, Bendel, Anne, Hoffman, Lindsey M, Luna-Fineman, Sandra, Zimmermann, Stefanie, Scheers, Isabelle, Nichols, Kim E, Zapotocky, Michal, Hansford, Jordan R, Maris, John M, Dirks, Peter, Taylor, Michael D, Kulkarni, Abhaya V, Shroff, Manohar, Tsang, Derek S, Villani, Anita, Xu, Wei, Aronson, Melyssa, Durno, Carol, Shlien, Adam, Malkin, David, Getz, Gad, Maruvka, Yosef E, Ohashi, Pamela S, Hawkins, Cynthia, Pugh, Trevor J, Bouffet, Eric, and Tabori, Uri

Subjects
Rare Diseases, Pediatric, Cancer, Neurosciences, Pediatric Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Adolescent, Adult, B7-H1 Antigen, Biomarkers, Tumor, Child, DNA Repair, DNA Replication, Female, Germ-Line Mutation, Humans, Immune Checkpoint Inhibitors, Male, Neoplasms, Prospective Studies, Retrospective Studies, Survival Analysis, Tumor Microenvironment, Young Adult, Medical and Health Sciences, Immunology
Abstract

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.

Published
2022

9. 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

10. Translating Basic Science Discoveries into Improved Outcomes for Glioblastoma

Author

Dirks, Peter B, Gilbert, Mark R, Holland, Eric C, Maher, Elizabeth A, and Weiss, William A

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Brain Cancer, Brain Disorders, Neurosciences, Cancer, Antineoplastic Agents, Glioblastoma, Humans, Molecular Targeted Therapy, Translational Research, Biomedical, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

Members of the scientific and clinical neuro-oncology community met in April 2019 to discuss the current challenges and opportunities associated with translating basic science discoveries in glioblastoma for improved survival of patients. A summary of key points of these discussions is presented in this article.

Published
2020

11. Roadmap for the Emerging Field of Cancer Neuroscience.

Author

Monje, Michelle, Borniger, Jeremy, DSilva, Nisha, Deneen, Benjamin, Dirks, Peter, Fattahi, Faranak, Frenette, Paul, Garzia, Livia, Gutmann, David, Hanahan, Douglas, Hervey-Jumper, Shawn, Hondermarck, Hubert, Hurov, Jonathan, Kepecs, Adam, Lloyd, Alison, Magnon, Claire, Saloman, Jami, Segal, Rosalind, Sloan, Erica, Sun, Xin, Taylor, Michael, Tracey, Kevin, Trotman, Lloyd, Tuveson, David, Wang, Timothy, White, Ruth, Winkler, Frank, and Knox, Sarah

Subjects
Humans, Neoplasms, Nervous System, Neurosciences
Abstract

Mounting evidence indicates that the nervous system plays a central role in cancer pathogenesis. In turn, cancers and cancer therapies can alter nervous system form and function. This Commentary seeks to describe the burgeoning field of cancer neuroscience and encourage multidisciplinary collaboration for the study of cancer-nervous system interactions.

Published
2020

12. Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis

Author

Huang, Miller, Tailor, Jignesh, Zhen, Qiqi, Gillmor, Aaron H, Miller, Matthew L, Weishaupt, Holger, Chen, Justin, Zheng, Tina, Nash, Emily K, McHenry, Lauren K, An, Zhenyi, Ye, Fubaiyang, Takashima, Yasuhiro, Clarke, James, Ayetey, Harold, Cavalli, Florence MG, Luu, Betty, Moriarity, Branden S, Ilkhanizadeh, Shirin, Chavez, Lukas, Yu, Chunying, Kurian, Kathreena M, Magnaldo, Thierry, Sevenet, Nicolas, Koch, Philipp, Pollard, Steven M, Dirks, Peter, Snyder, Michael P, Largaespada, David A, Cho, Yoon Jae, Phillips, Joanna J, Swartling, Fredrik J, Morrissy, A Sorana, Kool, Marcel, Pfister, Stefan M, Taylor, Michael D, Smith, Austin, and Weiss, William A

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Human Genome, Brain Disorders, Regenerative Medicine, Pediatric, Pediatric Cancer, Stem Cell Research, Transplantation, Biotechnology, Rare Diseases, Stem Cell Research - Nonembryonic - Human, Cancer, Neurosciences, Stem Cell Research - Nonembryonic - Non-Human, Brain Cancer, Development of treatments and therapeutic interventions, 5.2 Cellular and gene therapies, Animals, Basal Cell Nevus Syndrome, Brain Neoplasms, Carcinogenesis, DEAD-box RNA Helicases, Disease Models, Animal, Genetic Engineering, Genetic Predisposition to Disease, Humans, Medulloblastoma, Mice, Mice, SCID, N-Myc Proto-Oncogene Protein, Neoplasm Proteins, Neural Stem Cells, Neuroepithelial Cells, Patched-1 Receptor, Pluripotent Stem Cells, Stem Cell Transplantation, Transplantation, Heterologous, SHH, human pluripotent stem cells, medulloblastoma, neuroepithelial stem cells, Biological Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predisposed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.

Published
2019

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

Author

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

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

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

Published
2019

17. A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases

Author

Garzia, Livia, Kijima, Noriyuki, Morrissy, A Sorana, De Antonellis, Pasqualino, Guerreiro-Stucklin, Ana, Holgado, Borja L, Wu, Xiaochong, Wang, Xin, Parsons, Michael, Zayne, Kory, Manno, Alex, Kuzan-Fischer, Claudia, Nor, Carolina, Donovan, Laura K, Liu, Jessica, Qin, Lei, Garancher, Alexandra, Liu, Kun-Wei, Mansouri, Sheila, Luu, Betty, Thompson, Yuan Yao, Ramaswamy, Vijay, Peacock, John, Farooq, Hamza, Skowron, Patryk, Shih, David JH, Li, Angela, Ensan, Sherine, Robbins, Clinton S, Cybulsky, Myron, Mitra, Siddhartha, Ma, Yussanne, Moore, Richard, Mungall, Andy, Cho, Yoon-Jae, Weiss, William A, Chan, Jennifer A, Hawkins, Cynthia E, Massimino, Maura, Jabado, Nada, Zapotocky, Michal, Sumerauer, David, Bouffet, Eric, Dirks, Peter, Tabori, Uri, Sorensen, Poul HB, Brastianos, Priscilla K, Aldape, Kenneth, Jones, Steven JM, Marra, Marco A, Woodgett, James R, Wechsler-Reya, Robert J, Fults, Daniel W, and Taylor, Michael D

Subjects
Brain Cancer, Cancer, Neurosciences, Pediatric Cancer, Pediatric, Rare Diseases, Brain Disorders, Allografts, Animals, Cell Line, Tumor, Chemokine CCL2, Chromosomes, Human, Pair 10, Female, Humans, Male, Medulloblastoma, Meningeal Neoplasms, Mice, SCID, Neoplastic Cells, Circulating, Parabiosis, brain tumors, circulating tumor cells, medulloblastoma, metastases, pediatric cancer, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.

Published
2018

18. Comprehensive Analysis of Hypermutation in Human Cancer

Author

Campbell, Brittany B, Light, Nicholas, Fabrizio, David, Zatzman, Matthew, Fuligni, Fabio, de Borja, Richard, Davidson, Scott, Edwards, Melissa, Elvin, Julia A, Hodel, Karl P, Zahurancik, Walter J, Suo, Zucai, Lipman, Tatiana, Wimmer, Katharina, Kratz, Christian P, Bowers, Daniel C, Laetsch, Theodore W, Dunn, Gavin P, Johanns, Tanner M, Grimmer, Matthew R, Smirnov, Ivan V, Larouche, Valérie, Samuel, David, Bronsema, Annika, Osborn, Michael, Stearns, Duncan, Raman, Pichai, Cole, Kristina A, Storm, Phillip B, Yalon, Michal, Opocher, Enrico, Mason, Gary, Thomas, Gregory A, Sabel, Magnus, George, Ben, Ziegler, David S, Lindhorst, Scott, Issai, Vanan Magimairajan, Constantini, Shlomi, Toledano, Helen, Elhasid, Ronit, Farah, Roula, Dvir, Rina, Dirks, Peter, Huang, Annie, Galati, Melissa A, Chung, Jiil, Ramaswamy, Vijay, Irwin, Meredith S, Aronson, Melyssa, Durno, Carol, Taylor, Michael D, Rechavi, Gideon, Maris, John M, Bouffet, Eric, Hawkins, Cynthia, Costello, Joseph F, Meyn, M Stephen, Pursell, Zachary F, Malkin, David, Tabori, Uri, and Shlien, Adam

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Human Genome, Cancer, Rare Diseases, Cancer Genomics, 2.1 Biological and endogenous factors, Good Health and Well Being, Adult, Child, Cluster Analysis, DNA Polymerase II, DNA Polymerase III, DNA Replication, Humans, Mutation, Neoplasms, Poly-ADP-Ribose Binding Proteins, DNA repair, DNA replication, cancer genomics, cancer predisposition, hypermutation, immune checkpoint inhibitors, mismatch repair, mutator, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.

Published
2017

19. 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
Full Text
View/download PDF

20. 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

21. The white matter is a pro-differentiative niche for glioblastoma

Author

Brooks, Lucy J., Clements, Melanie P., Burden, Jemima J., Kocher, Daniela, Richards, Luca, Devesa, Sara Castro, Zakka, Leila, Woodberry, Megan, Ellis, Michael, Jaunmuktane, Zane, Brandner, Sebastian, Morrison, Gillian, Pollard, Steven M., Dirks, Peter B., Marguerat, Samuel, and Parrinello, Simona

Published
2021
Full Text
View/download PDF

22. PRMT5 inhibition disrupts splicing and stemness in glioblastoma

Author

Sachamitr, Patty, Ho, Jolene C., Ciamponi, Felipe E., Ba-Alawi, Wail, Coutinho, Fiona J., Guilhamon, Paul, Kushida, Michelle M., Cavalli, Florence M. G., Lee, Lilian, Rastegar, Naghmeh, Vu, Victoria, Sánchez-Osuna, María, Coulombe-Huntington, Jasmin, Kanshin, Evgeny, Whetstone, Heather, Durand, Mathieu, Thibault, Philippe, Hart, Kirsten, Mangos, Maria, Veyhl, Joseph, Chen, Wenjun, Tran, Nhat, Duong, Bang-Chi, Aman, Ahmed M., Che, Xinghui, Lan, Xiaoyang, Whitley, Owen, Zaslaver, Olga, Barsyte-Lovejoy, Dalia, Richards, Laura M., Restall, Ian, Caudy, Amy, Röst, Hannes L., Bonday, Zahid Quyoom, Bernstein, Mark, Das, Sunit, Cusimano, Michael D., Spears, Julian, Bader, Gary D., Pugh, Trevor J., Tyers, Mike, Lupien, Mathieu, Haibe-Kains, Benjamin, Artee Luchman, H., Weiss, Samuel, Massirer, Katlin B., Prinos, Panagiotis, Arrowsmith, Cheryl H., and Dirks, Peter B.

Published
2021
Full Text
View/download PDF

24. Norrin mediates tumor-promoting and -suppressive effects in glioblastoma via Notch and Wnt

Author

El-Sehemy, Ahmed, Selvadurai, Hayden, Ortin-Martinez, Arturo, Pokrajac, Neno, Mamatjan, Yasin, Tachibana, Nobuhiko, Rowland, Katherine, Lee, Lilian, Park, Nicole, Aldape, Kenneth, Dirks, Peter, and Wallace, Valerie A.

Subjects
R and D Systems, Neurophysiology, Cancer -- Development and progression, Software industry, Stem cells, Glioblastomas -- Development and progression, Health care industry
Abstract

Glioblastoma multiforme (GBM) contains a subpopulation of cells, GBM stem cells (GSCs), that maintain the bulk tumor and represent a key therapeutic target. Norrin is a Wnt ligand that binds Frizzled class receptor 4 (FZD4) to activate canonical Wnt signaling. Although Norrin, encoded by NDP, has a well-described role in vascular development, its function in human tumorigenesis is largely unexplored. Here, we show that NDP expression is enriched in neurological cancers, including GBM, and its levels positively correlated with survival in a GBM subtype defined by low expression of ASCL1, a proneural factor. We investigated the function of Norrin and FZD4 in GSCs and found that it mediated opposing tumor-suppressive and -promoting effects on [ASCL1.sup.lo] and [ASCL1.sup.hi] GSCs. Consistent with a potential tumor-suppressive effect of Norrin suggested by the tumor outcome data, we found that Norrin signaling through FZD4 inhibited growth in [ASCL1.sup.lo] GSCs. In contrast, in [ASCL1.sup.hi] GSCs Norrin promoted Notch signaling, independently of WNT, to promote tumor progression. Forced ASCL1 expression reversed the tumor-suppressive effects of Norrin in [ASCL1.sup.lo] GSCs. Our results identify Norrin as a modulator of human brain cancer progression and reveal an unanticipated Notch-mediated function of Norrin in regulating cancer stem cell biology. This study identifies an unanticipated role of Norrin in human brain cancer progression. In addition, we provide preclinical evidence suggesting Norrin and canonical Wnt signaling as potential therapeutic targets for GBM subtype-restricted cancer stem cells., Introduction Glioblastoma multiforme (GBM) is the most common malignant brain cancer in adults (1, 2). Consistent with its progressive nature, GBM remains significantly refractory to current therapeutic strategies (3, 4). [...]

Published
2020
Full Text
View/download PDF

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. DNA hypermethylation within TERT promoter upregulates TERT expression in cancer

Author

Lee, Donghyun D., Leao, Ricardo, Komosa, Martin, Gallo, Marco, Zhang, Cindy H., Lipman, Tatiana, Remke, Marc, Heidari, Abolfazl, Nunes, Nuno Miguel, Apolonio, Joana D., Price, Aryeh J., De Mello, Ramon Andrade, Dias, Joao S., Huntsman, David, Hermanns, Thomas, Wild, Peter J., Vanner, Robert, Zadeh, Gelareh, Karamchandani, Jason, Das, Sunit, Taylor, Michael D., Hawkins, Cynthia E., Wasserman, Jonathan D., Figueiredo, Arnaldo, Hamilton, Robert J., Minden, Mark D., Wani, Khalida, Diplas, Bill, Yan, Hai, Aldape, Kenneth, Akbari, Mohammad R., Danesh, Arnavaz, Pugh, Trevor J., Dirks, Peter B., Castelo-Branco, Pedro, and Tabori, Uri

Subjects
Cancer -- Genetic aspects -- Research, Gene mutation -- Research, Methylation -- Genetic aspects, Telomeres -- Research, Health care industry
Abstract

Replicative immortality is a hallmark of cancer cells governed by telomere maintenance. Approximately 90% of human cancers maintain their telomeres by activating telomerase, driven by the transcriptional upregulation of telomerase reverse transcriptase (TERT). Although TERT promoter mutations (TPMs) are a major cancer-associated genetic mechanism of TERT upregulation, many cancers exhibit TERT upregulation without TPMs. In this study, we describe the TERT hypermethylated oncological region (THOR), a 433-bp genomic region encompassing 52 CpG sites located immediately upstream of the TERT core promoter, as a cancer-associated epigenetic mechanism of TERT upregulation. Unmethylated THOR repressed TERT promoter activity regardless of TPM status, and hypermethylation of THOR counteracted this repressive function. THOR methylation analysis in 1,352 human tumors revealed frequent (>45%) cancer-associated DNA hypermethylation in 9 of 11 (82%) tumor types screened. Additionally, THOR hypermethylation, either independently or along with TPMs, accounted for how approximately 90% of human cancers can aberrantly activate telomerase. Thus, we propose that THOR hypermethylation is a prevalent telomerase-activating mechanism in cancer that can act independently of or in conjunction with TPMs, further supporting the utility of THOR hypermethylation as a prognostic biomarker., IntroductionReplicative immortality is an attribute of cancer cells governed by telomere maintenance (1). Telomeres are repetitive nucleoprotein structures that protect chromosomal ends and shorten after each replicative cycle, playing important [...]

Published
2019
Full Text
View/download PDF

29. Stenose du foramen magnum chez un garcon de 5 mois atteint d'achondroplasie

Author

Malhotra, Armaan K., Parker, Whitney, and Dirks, Peter B.

Subjects
Achondroplasia -- Health aspects -- Cases, Company legal issue, Health
Abstract

Un pediatre en milieu communautaire a oriente un garcon de 5 mois vers la clinique de genetique de notre etablissement pour un probleme de petite taille et de macrocephalie. L'accouchement [...]

Published
2023
Full Text
View/download PDF

30. Subgroup-specific structural variation across 1,000 medulloblastoma genomes.

Author

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

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

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

Published
2012

33. Mechanical nanosurgery of chemoresistant glioblastoma using magnetically controlled carbon nanotubes

Author

Wang, Xian, primary, Gong, Zheyuan, additional, Wang, Tiancong, additional, Law, Junhui, additional, Chen, Xin, additional, Wanggou, Siyi, additional, Wang, Jintian, additional, Ying, Binbin, additional, Francisco, Michelle, additional, Dong, Weifan, additional, Xiong, Yi, additional, Fan, Jerry J., additional, MacLeod, Graham, additional, Angers, Stephane, additional, Li, Xuejun, additional, Dirks, Peter B., additional, Liu, Xinyu, additional, Huang, Xi, additional, and Sun, Yu, additional

Published
2023
Full Text
View/download PDF

35. GLUT1 inhibition blocks growth of RB1-positive triple negative breast cancer

Author

Wu, Qin, ba-alawi, Wail, Deblois, Genevieve, Cruickshank, Jennifer, Duan, Shili, Lima-Fernandes, Evelyne, Haight, Jillian, Tonekaboni, Seyed Ali Madani, Fortier, Anne-Marie, Kuasne, Hellen, McKee, Trevor D., Mahmoud, Hassan, Kushida, Michelle, Cameron, Sarina, Dogan-Artun, Nergiz, Chen, WenJun, Nie, Yan, Zhang, Lan Xin, Vellanki, Ravi N., Zhou, Stanley, Prinos, Panagiotis, Wouters, Bradly G., Dirks, Peter B., Done, Susan J., Park, Morag, Cescon, David W., Haibe-Kains, Benjamin, Lupien, Mathieu, and Arrowsmith, Cheryl H.

Published
2020
Full Text
View/download PDF

36. Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling

Author

Mack, Stephen C., Pajtler, Kristian W., Chavez, Lukas, Okonechnikov, Konstantin, Bertrand, Kelsey C., Wang, Xiuxing, Erkek, Serap, Federation, Alexander, Song, Anne, Lee, Christine, Wang, Xin, McDonald, Laura, Morrow, James J., Saiakhova, Alina, Sin-Chan, Patrick, Wu, Qiulian, Michaelraj, Kulandaimanuvel Antony, Miller, Tyler E., Hubert, Christopher G., Ryzhova, Marina, Garzia, Livia, Donovan, Laura, Dombrowski, Stephen, Factor, Daniel C., Luu, Betty, Valentim, Claudia L. L., Gimple, Ryan C., Morton, Andrew, Kim, Leo, Prager, Briana C., Lee, John J. Y., Wu, Xiaochong, Zuccaro, Jennifer, Thompson, Yuan, Holgado, Borja L., Reimand, Jri, Ke, Susan Q., Tropper, Adam, Lai, Sisi, Vijayarajah, Senthuran, Doan, Sylvia, Mahadev, Vaidehi, Mian, Ana Fernandez, Grbner, Susanne N., Lienhard, Matthias, Zapatka, Marc, Huang, Zhiqin, Aldape, Kenneth D., Carcaboso, Angel M., Houghton, Peter J., Keir, Stephen T., Milde, Till, Witt, Hendrik, Li, Yan, Li, Chao-Jun, Bian, Xiu-Wu, Jones, David T. W., Scott, Ian, Singh, Sheila K., Huang, Annie, Dirks, Peter B., Bouffet, Eric, Bradner, James E., Ramaswamy, Vijay, Jabado, Nada, Rutka, James T., Northcott, Paul A., Lupien, Mathieu, Lichter, Peter, Korshunov, Andrey, Scacheri, Peter C., Pfister, Stefan M., Kool, Marcel, Taylor, Michael D., and Rich, Jeremy N.

Subjects
Gliomas -- Physiological aspects -- Genetic aspects -- Care and treatment, Cancer genetics -- Research, Cancer research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Stephen C. Mack [1, 2, 3, 4]; Kristian W. Pajtler [5, 6, 7]; Lukas Chavez [5, 6, 8]; Konstantin Okonechnikov [5, 6]; Kelsey C. Bertrand [1, 2, 9]; Xiuxing [...]

Published
2018
Full Text
View/download PDF

37. Mechanosensitive brain tumor cells construct blood-tumor barrier to mask chemosensitivity

Author

Chen, Xin, primary, Momin, Ali, additional, Wanggou, Siyi, additional, Wang, Xian, additional, Min, Hyun-Kee, additional, Dou, Wenkun, additional, Gong, Zheyuan, additional, Chan, Jade, additional, Dong, Weifan, additional, Fan, Jerry J., additional, Xiong, Yi, additional, Talipova, Kamilia, additional, Zhao, Hongyu, additional, Chen, Yuki X., additional, Veerasammy, Kelly, additional, Fekete, Adam, additional, Kumar, Sachin A., additional, Liu, Hongwei, additional, Yang, Qi, additional, Son, Joe Eun, additional, Dou, Zhengchao, additional, Hu, Malini, additional, Pardis, Parnian, additional, Juraschka, Kyle, additional, Donovan, Laura K., additional, Zhang, Jiao, additional, Ramaswamy, Vijay, additional, Selvadurai, Hayden J., additional, Dirks, Peter B., additional, Taylor, Michael D., additional, Wang, Lu-Yang, additional, Hui, Chi-chung, additional, Abzalimov, Rinat, additional, He, Ye, additional, Sun, Yu, additional, Li, Xuejun, additional, and Huang, Xi, additional

Published
2023
Full Text
View/download PDF

39. EPID-25. THE CLINICAL AND MOLECULAR LANDSCAPE OF GLIOMAS IN ADOLESCENTS AND YOUNG ADULTS

Author

Bennett, Julie, primary, Nobre, Liana, additional, Sheth, Javal, additional, Ryall, Scott, additional, Fang, Karen, additional, Johnson, Monique, additional, Negm, Logine, additional, Chung, Jiil, additional, Komosa, Martin, additional, Nunes, Nuno, additional, Lim-Fat, Mary Jane, additional, Perry, James, additional, Sahgal, Arjun, additional, Detsky, Jay, additional, Bouffet, Eric, additional, Hazrati, Lili-Naz, additional, Dirks, Peter, additional, Ertl-Wagner, Birgit, additional, Kongkham, Paul, additional, Zadeh, Gelareh, additional, Mason, Warren, additional, Cusimano, Michael, additional, Das, Sunit, additional, Gao, Andrew, additional, Tsang, Derek, additional, Nguyen, Lananh, additional, Laperriere, Normand, additional, Keith, Julia, additional, Munoz, David, additional, Tabori, Uri, additional, and Hawkins, Cynthia, additional

Published
2022
Full Text
View/download PDF

42. STEM-16. MACROH2A2 REPRESSES AN EPIGENETIC SELF-RENEWAL NETWORK IN GLIOBLASTOMA STEM CELLS

Author

Nikolic, Ana, primary, Bobyn, Anna, additional, Maule, Francesca, additional, Ellestad, Katrina, additional, Paik, Seungil, additional, Marhon, Sajid, additional, Mehdipour, Parinaz, additional, Lun, Xuequng, additional, Johnston, Michael, additional, Gafiuk, Christopher, additional, Zemp, Franz, additional, Shen, Yaoqing, additional, Ninkovic, Nicoletta, additional, Labit, Elodie, additional, Berger, N Daniel, additional, Brownsey, Duncan, additional, Kelly, John, additional, Biernaskie, Jeff, additional, Dirks, Peter, additional, Derksen, Darren, additional, Jones, Steven J M, additional, Senger, Donna L, additional, Chan, Jennifer, additional, Mahoney, Douglas J, additional, de Carvalho, Daniel, additional, and Gallo, Marco, additional

Published
2022
Full Text
View/download PDF

43. Outcomes of endovascular embolization for Vein of Galen malformations: An individual participant data meta-analysis

Author

Savage, Cody, primary, Hale, Andrew T., additional, Parr, Matthew S., additional, Hedaya, Alexander, additional, Saccomano, Benjamin W., additional, Tsemo, Georges Bouobda, additional, Hafeez, Muhammad U., additional, Tanweer, Omar, additional, Kan, Peter, additional, Solomon, Laurent J., additional, Meila, Dan, additional, Dirks, Peter B., additional, Blount, Jeffrey P., additional, Johnston, James M., additional, Rocque, Brandon G., additional, Rozzelle, Curtis J., additional, Bhatia, Kartik, additional, Muthusami, Prakash, additional, Krings, Timo, additional, and Jones, Jesse, additional

Published
2022
Full Text
View/download PDF

48. LGG-41. The clinical and molecular landscape of gliomas in adolescents and young adults

Author

Bennett, Julie, primary, Nobre, Liana, additional, Sheth, Javal, additional, Ryall, Scott, additional, Fang, Karen, additional, Johnson, Monique, additional, Negm, Logine, additional, Chung, Jiil, additional, Komosa, Martin, additional, Nunes, Nuno M, additional, Fat, Mary Jane Lim, additional, Perry, James, additional, Sahgal, Arjun, additional, Detsky, Jay, additional, Bouffet, Eric, additional, Naz-Hazrati, Lili, additional, Dirks, Peter, additional, Ertl-Wagner, Birgit, additional, Kongkham, Paul, additional, Zadeh, Gelareh, additional, Mason, Warren, additional, Climans, Seth, additional, Cusimano, Michael, additional, Das, Sunit, additional, Gao, Andrew, additional, Tsang, Derek, additional, Nguyen, Lananh, additional, Laperriere, Normand, additional, Keith, Julia, additional, Munoz, David, additional, Tabori, Uri, additional, and Hawkins, Cynthia, additional

Published
2022
Full Text
View/download PDF

49. A brain precursor atlas reveals the acquisition of developmental-like states in adult cerebral tumours

Author

Hamed, Akram A, Kunz, Daniel J, El-Hamamy, Ibrahim, Trinh, Quang M, Subedar, Omar D, Richards, Laura M, Foltz, Warren, Bullivant, Garrett, Ware, Matthaeus, Vladoiu, Maria C, Zhang, Jiao, Raj, Antony M, Pugh, Trevor J, Taylor, Michael D, Teichmann, Sarah A, Stein, Lincoln D, Simons, Benjamin D, Dirks, Peter B, Hamed, Akram A [0000-0001-9239-2942], Kunz, Daniel J [0000-0003-3597-6591], El-Hamamy, Ibrahim [0000-0003-3800-419X], Trinh, Quang M [0000-0002-3602-2290], Richards, Laura M [0000-0003-3414-7628], Vladoiu, Maria C [0000-0001-8644-0581], Taylor, Michael D [0000-0001-7009-3466], Teichmann, Sarah A [0000-0002-6294-6366], Simons, Benjamin D [0000-0002-3875-7071], Dirks, Peter B [0000-0001-5718-6465], Apollo - University of Cambridge Repository, Kunz, Daniel [0000-0003-3597-6591], Teichmann, Sarah [0000-0002-6294-6366], and Simons, Benjamin [0000-0002-3875-7071]

Subjects
64, Telencephalon, Multidisciplinary, Neurogenesis, 631/136/532/2182, article, General Physics and Astronomy, Brain, General Chemistry, Glioma, 13, General Biochemistry, Genetics and Molecular Biology, 49, Mice, 13/100, 692/699/67/1922, Animals, Humans, 64/60, Child, 631/67/71, Cerebrum, 49/91
Abstract

Funder: Canadian Institute of Health Research (155960), Human cerebral cancers are known to contain cell types resembling the varying stages of neural development. However, the basis of this association remains unclear. Here, we map the development of mouse cerebrum across the developmental time-course, from embryonic day 12.5 to postnatal day 365, performing single-cell transcriptomics on >100,000 cells. By comparing this reference atlas to single-cell data from >100 glial tumours of the adult and paediatric human cerebrum, we find that tumour cells have an expression signature that overlaps with temporally restricted, embryonic radial glial precursors (RGPs) and their immediate sublineages. Further, we demonstrate that prenatal transformation of RGPs in a genetic mouse model gives rise to adult cerebral tumours that show an embryonic/juvenile RGP identity. Together, these findings implicate the acquisition of embryonic-like states in the genesis of adult glioma, providing insight into the origins of human glioma, and identifying specific developmental cell types for therapeutic targeting.

Published
2021

50. Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy

Author

Lan, Xiaoyang, Jörg, David J., Cavalli, Florence M. G., Richards, Laura M., Nguyen, Long V., Vanner, Robert J., Guilhamon, Paul, Lee, Lilian, Kushida, Michelle M., Pellacani, Davide, Park, Nicole I., Coutinho, Fiona J., Whetstone, Heather, Selvadurai, Hayden J., Che, Clare, Luu, Betty, Carles, Annaick, Moksa, Michelle, Rastegar, Naghmeh, Head, Renee, Dolma, Sonam, Prinos, Panagiotis, Cusimano, Michael D., Das, Sunit, Bernstein, Mark, Arrowsmith, Cheryl H., Mungall, Andrew J., Moore, Richard A., Ma, Yussanne, Gallo, Marco, Lupien, Mathieu, Pugh, Trevor J., Taylor, Michael D., Hirst, Martin, Eaves, Connie J., Simons, Benjamin D., and Dirks, Peter B.

Published
2017
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results