19 results on '"Dirks, Peter"'
Search Results
2. A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation
- Author
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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
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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
3. A non-coding single nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation
- Author
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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
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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.
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- 2022
4. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
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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
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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.
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- 2022
5. The transcriptional landscape of Shh medulloblastoma.
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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
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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. Translating Basic Science Discoveries into Improved Outcomes for Glioblastoma
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Dirks, Peter B, Gilbert, Mark R, Holland, Eric C, Maher, Elizabeth A, and Weiss, William A
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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.
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- 2020
7. Roadmap for the Emerging Field of Cancer Neuroscience
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Monje, Michelle, Borniger, Jeremy C, D’Silva, Nisha J, Deneen, Benjamin, Dirks, Peter B, Fattahi, Faranak, Frenette, Paul S, Garzia, Livia, Gutmann, David H, Hanahan, Douglas, Hervey-Jumper, Shawn L, Hondermarck, Hubert, Hurov, Jonathan B, Kepecs, Adam, Knox, Sarah M, Lloyd, Alison C, Magnon, Claire, Saloman, Jami L, Segal, Rosalind A, Sloan, Erica K, Sun, Xin, Taylor, Michael D, Tracey, Kevin J, Trotman, Lloyd C, Tuveson, David A, Wang, Timothy C, White, Ruth A, and Winkler, Frank
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Neurosciences ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,Humans ,Neoplasms ,Nervous System ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - 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.
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- 2020
8. Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis
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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
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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
9. A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor
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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
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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
10. A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases
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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
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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.
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- 2018
11. Comprehensive Analysis of Hypermutation in Human Cancer
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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
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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.
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- 2017
12. Intertumoral Heterogeneity within Medulloblastoma Subgroups
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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
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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.
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- 2017
13. Subgroup-specific structural variation across 1,000 medulloblastoma genomes.
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Northcott, Paul A, Shih, David JH, Peacock, John, Garzia, Livia, Morrissy, A Sorana, Zichner, Thomas, Stütz, Adrian M, Korshunov, Andrey, Reimand, Jüri, Schumacher, Steven E, Beroukhim, Rameen, Ellison, David W, Marshall, Christian R, Lionel, Anath C, Mack, Stephen, Dubuc, Adrian, Yao, Yuan, Ramaswamy, Vijay, Luu, Betty, Rolider, Adi, Cavalli, Florence MG, Wang, Xin, Remke, Marc, Wu, Xiaochong, Chiu, Readman YB, Chu, Andy, Chuah, Eric, Corbett, Richard D, Hoad, Gemma R, Jackman, Shaun D, Li, Yisu, Lo, Allan, Mungall, Karen L, Nip, Ka Ming, Qian, Jenny Q, Raymond, Anthony GJ, Thiessen, Nina T, Varhol, Richard J, Birol, Inanc, Moore, Richard A, Mungall, Andrew J, Holt, Robert, Kawauchi, Daisuke, Roussel, Martine F, Kool, Marcel, Jones, David TW, Witt, Hendrick, Fernandez-L, Africa, Kenney, Anna M, Wechsler-Reya, Robert J, Dirks, Peter, Aviv, Tzvi, Grajkowska, Wieslawa A, Perek-Polnik, Marta, Haberler, Christine C, Delattre, Olivier, Reynaud, Stéphanie S, Doz, François F, Pernet-Fattet, Sarah S, Cho, Byung-Kyu, Kim, Seung-Ki, Wang, Kyu-Chang, Scheurlen, Wolfram, Eberhart, Charles G, Fèvre-Montange, Michelle, Jouvet, Anne, Pollack, Ian F, Fan, Xing, Muraszko, Karin M, Gillespie, G Yancey, Di Rocco, Concezio, Massimi, Luca, Michiels, Erna MC, Kloosterhof, Nanne K, French, Pim J, Kros, Johan M, Olson, James M, Ellenbogen, Richard G, Zitterbart, Karel, Kren, Leos, Thompson, Reid C, Cooper, Michael K, Lach, Boleslaw, McLendon, Roger E, Bigner, Darell D, Fontebasso, Adam, Albrecht, Steffen, Jabado, Nada, Lindsey, Janet C, Bailey, Simon, Gupta, Nalin, Weiss, William A, Bognár, László, Klekner, Almos, Van Meter, Timothy E, Kumabe, Toshihiro, Tominaga, Teiji, Elbabaa, Samer K, Leonard, Jeffrey R, and Rubin, Joshua B
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Humans ,Medulloblastoma ,Cerebellar Neoplasms ,Translocation ,Genetic ,Transforming Growth Factor beta ,Proteins ,Carrier Proteins ,NF-kappa B ,Oncogene Proteins ,Fusion ,Nerve Tissue Proteins ,Genomics ,Signal Transduction ,Gene Duplication ,Genes ,myc ,Genome ,Human ,Child ,Hedgehog Proteins ,Genomic Structural Variation ,DNA Copy Number Variations ,RNA ,Long Noncoding ,Pediatric ,Neurosciences ,Genetics ,Brain Disorders ,Pediatric Research Initiative ,Brain Cancer ,Cancer ,Rare Diseases ,Pediatric Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,General Science & Technology - 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 Parkinson's 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.
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- 2012
14. Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity
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Meyer, Mona, Reimand, Jüri, Lan, Xiaoyang, Head, Renee, Zhu, Xueming, Kushida, Michelle, Bayani, Jane, Pressey, Jessica C., Lionel, Anath C., Clarke, Ian D., Cusimano, Michael, Squire, Jeremy A., Scherer, Stephen W., Bernstein, Mark, Woodin, Melanie A., Bader, Gary D., and Dirks, Peter B.
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- 2015
15. Brain Tumour Stem Cells: The Undercurrents of Human Brain Cancer and Their Relationship to Neural Stem Cells
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Dirks, Peter B.
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- 2008
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16. Pan-cancer analysis of non-coding transcripts reveals the prognostic onco-lncRNA HOXA10-AS in gliomas.
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Isaev, Keren, Jiang, Lingyan, Wu, Shuai, Lee, Christian A., Watters, Valérie, Fort, Victoire, Tsai, Ricky, Coutinho, Fiona J., Hussein, Samer M.I., Zhang, Jie, Wu, Jinsong, Dirks, Peter B., Schramek, Daniel, and Reimand, Jüri
- Abstract
Long non-coding RNAs (lncRNAs) are increasingly recognized as functional units in cancer and powerful biomarkers; however, most remain uncharacterized. Here, we analyze 5,592 prognostic lncRNAs in 9,446 cancers of 30 types using machine learning. We identify 166 lncRNAs whose expression correlates with survival and improves the accuracy of common clinical variables, molecular features, and cancer subtypes. Prognostic lncRNAs are often characterized by switch-like expression patterns. In low-grade gliomas, HOXA10-AS activation is a robust marker of poor prognosis that complements IDH1/2 mutations, as validated in another retrospective cohort, and correlates with developmental pathways in tumor transcriptomes. Loss- and gain-of-function studies in patient-derived glioma cells, organoids, and xenograft models identify HOXA10-AS as a potent onco-lncRNA that regulates cell proliferation, contact inhibition, invasion, Hippo signaling, and mitotic and neuro-developmental pathways. Our study underscores the pan-cancer potential of the non-coding transcriptome for identifying biomarkers and regulators of cancer progression. [Display omitted] • AI-supported pan-cancer catalog of prognostic long non-coding RNAs (lncRNAs) • Switch-like lncRNA expression highlights avenues for biomarker and mechanistic studies • The onco-lncRNA HOXA10-AS in glioma regulates cell proliferation and invasion • HOXA10-AS expression indicates poor prognosis in IDH-wild-type and IDH-mutant glioma Pan-cancer analysis of lncRNAs by Isaev et al. reveals prognostic transcripts with characteristic switch-like expression and a landscape of functional and pathway associations. Detailed experimental and clinical validation highlights the onco-lncRNA HOXA10-AS whose activation in glioma associates with poor patient prognosis and cell proliferation and invasion phenotypes in cell lines, xenografts, and organoids. [ABSTRACT FROM AUTHOR]
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- 2021
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17. Cancer and Stem Cell Biology: How Tightly Intertwined?
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Kim, Carla F. and Dirks, Peter B.
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STEM cells ,CANCER cells ,CANCER ,CONFERENCES & conventions - Abstract
Ever since the discovery of cancer stem cells in leukemia and, more recently, in solid tumors, enormous attention has been paid to the apparent stem cell nature of cancer. These concepts were the focus of the "Stem Cells and Cancer" symposium held recently at the University of California, San Francisco, and the inspiration for this overview of current research and important questions emerging in this area. [ABSTRACT FROM AUTHOR]
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- 2008
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18. The transcriptional landscape of Shh medulloblastoma
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Jaume Mora, Erwin G. Van Meir, Olivier Delattre, Diala Abd-Rabbo, Almos Klekner, Peter Hauser, Roger E. McLendon, Amulya A. Nageswara Rao, David Malkin, James M. Olson, Boleslaw Lach, A. Sorana Morrissy, Xiaoyun Zhang, John J.Y. Lee, Steven J.M. Jones, Young Shin Ra, Ulrich Schüller, Miklós Garami, Joanna J. Phillips, Betty Luu, Hamza Farooq, Johan M. Kros, Karel Zitterbart, Michael K. Cooper, Raul Suarez, William A. Weiss, Quang M. Trinh, Ana Guerreiro Stucklin, Tomoko Shofuda, Carmen de Torres, Marco A. Marra, Enrique López-Aguilar, Hiromichi Suzuki, Patryk Skowron, Eric Bouffet, Karen Mungall, Evan Y. Wang, Tina Zheng, Maria C. Vladoiu, Julien Masliah-Planchon, Ian F. Pollack, Wai Sang Poon, Liam D. Hendrikse, Claudia C. Faria, Yu Chang Wang, Kay Ka Wai Li, Carlos Gilberto Carlotti, Joshua B. Rubin, Gary D. Bader, Aaron Gillmor, Caterina Giannini, Uri Tabori, Shin Jung, Franck Bourdeaut, Chi-chung Hui, Avesta Rastan, Reid C. Thompson, Jennifer A. Chan, Nada Jabado, David Meyronet, Rajeev Vibhakar, Jiannis Ragoussis, Michelle Ly, Olivier Ayrault, Charles G. Eberhart, Andrew J. Mungall, Wiesława Grajkowska, Xiaochong Wu, Jüri Reimand, Ho Keung Ng, Vernon Fong, Michael D. Taylor, Seung-Ki Kim, Florence M.G. Cavalli, Carolina Nor, Helen He Zhu, Eric M. Thompson, Borja L. Holgado, David Zagzag, Craig Daniels, Gelareh Zadeh, Haig Djambazian, G. Yancey Gillespie, Peter B. Dirks, Richard A. Moore, John A. Calarco, Shizhong Dai, Vijay Ramaswamy, Lincoln Stein, Pierre Bérubé, Pim J. French, Toshihiro Kumabe, James Loukides, Swneke D. Bailey, Linda M. Liau, Ronald L. Hamilton, Francois P. Doz, Maria Luisa Garrè, László Bognár, The Hospital for sick children [Toronto] (SickKids), The Wellcome Trust Sanger Institute [Cambridge], Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation, radiobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurology, Pathology, Repositório da Universidade de Lisboa, Skowron, Patryk, Farooq, Hamza, Cavalli, Florence M G, Morrissy, A Sorana, Ly, Michelle, Hendrikse, Liam D, Wang, Evan Y, Djambazian, Haig, Zhu, Helen, Mungall, Karen L, Trinh, Quang M, Zheng, Tina, Dai, Shizhong, Stucklin, Ana S Guerreiro, Vladoiu, Maria C, Fong, Vernon, Holgado, Borja L, Nor, Carolina, Wu, Xiaochong, Abd-Rabbo, Diala, Bérubé, Pierre, Wang, Yu Chang, Luu, Betty, Suarez, Raul A, Rastan, Avesta, Gillmor, Aaron H, Lee, John J Y, Zhang, Xiao Yun, Daniels, Craig, Dirks, Peter, Malkin, David, Bouffet, Eric, Tabori, Uri, Loukides, Jame, Doz, François P, Bourdeaut, Franck, Delattre, Olivier O, Masliah-Planchon, Julien, Ayrault, Olivier, Kim, Seung-Ki, Meyronet, David, Grajkowska, Wieslawa A, Carlotti, Carlos G, de Torres, Carmen, Mora, Jaume, Eberhart, Charles G, Van Meir, Erwin G, Kumabe, Toshihiro, French, Pim J, Kros, Johan M, Jabado, Nada, Lach, Boleslaw, Pollack, Ian F, Hamilton, Ronald L, Rao, Amulya A Nageswara, Giannini, Caterina, Olson, James M, Bognár, László, Klekner, Almo, Zitterbart, Karel, Phillips, Joanna J, Thompson, Reid C, Cooper, Michael K, Rubin, Joshua B, Liau, Linda M, Garami, Mikló, Hauser, Peter, Li, Kay Ka Wai, Ng, Ho-Keung, Poon, Wai Sang, Yancey Gillespie, G, Chan, Jennifer A, Jung, Shin, McLendon, Roger E, Thompson, Eric M, Zagzag, David, Vibhakar, Rajeev, Ra, Young Shin, Garre, Maria Luisa, Schüller, Ulrich, Shofuda, Tomoko, Faria, Claudia C, López-Aguilar, Enrique, Zadeh, Gelareh, Hui, Chi-Chung, Ramaswamy, Vijay, Bailey, Swneke D, Jones, Steven J, Mungall, Andrew J, Moore, Richard A, Calarco, John A, Stein, Lincoln D, Bader, Gary D, Reimand, Jüri, Ragoussis, Jianni, Weiss, William A, Marra, Marco A, Suzuki, Hiromichi, and Taylor, Michael D
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0301 basic medicine ,Male ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,General Physics and Astronomy ,ComputingMilieux_LEGALASPECTSOFCOMPUTING ,Genome informatics ,Transcriptome ,0302 clinical medicine ,Genetics research ,2.1 Biological and endogenous factors ,Gene Regulatory Networks ,Sonic hedgehog ,Aetiology ,Child ,Cancer ,Regulation of gene expression ,Pediatric ,Multidisciplinary ,Gene Regulatory Network ,biology ,Middle Aged ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Child, Preschool ,embryonic structures ,Female ,TRANSDUÇÃO DE SINAL CELULAR ,Hedgehog Protein ,Human ,Signal Transduction ,Biotechnology ,Adult ,Pediatric Research Initiative ,animal structures ,Adolescent ,Pediatric Cancer ,Science ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Computational biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Paediatric cancer ,03 medical and health sciences ,Young Adult ,Rare Diseases ,SDG 3 - Good Health and Well-being ,Clinical Research ,GLI2 ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,GNAS complex locus ,medicine ,Genetics ,Humans ,Hedgehog Proteins ,Cerebellar Neoplasms ,Preschool ,neoplasms ,Gene ,Medulloblastoma ,Neoplastic ,Cerebellar Neoplasm ,Human Genome ,Neurosciences ,Infant ,Genetic Variation ,General Chemistry ,medicine.disease ,Brain Disorders ,CNS cancer ,Brain Cancer ,030104 developmental biology ,PTCH1 ,Gene Expression Regulation ,biology.protein - Abstract
Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention., Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.
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- 2021
19. Monoallelic Expression Determines Oncogenic Progression and Outcome in Benign and Malignant Brain Tumors.
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Walker, Erin J., Zhang, Cindy, Castelo-Branco, Pedro, Hawkins, Cynthia, Wilson, Wes, Zhukova, Nataliya, Alon, Noa, Novokmet, Ana, Baskin, Berivan, Ray, Peter, Knobbe, Christiane, Dirks, Peter, Taylor, Michael D., Croul, Sidney, Malkin, David, and Tabori, Uri
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- *
GENOMICS , *DNA , *RNA , *GENOMES , *CANCER - Abstract
Although monoallelic expression (MAE) is a frequent genomic event in normal tissues, its role in tumorigenesis remains unclear. Here we carried out single-nucleotide polymorphism arrays on DNA and RNA from a large cohort of pediatric and adult brain tumor tissues to determine the genome-wide rate of MAE, its role in specific cancer-related genes, and the clinical consequences of MAE in brain tumors. We also used targeted genotyping to examine the role of tumor-related genes in brain tumor development and specifically examined the clinical consequences of MAE at TP53 and IDH1. The genome-wide rate of tumor MAE was higher than in previously described normal tissue and increased with specific tumor grade. Oncogenes, but not tumor suppressors, exhibited significantly higher MAE in high-grade compared with low-grade tumors. This method identified nine novel genes highly associated with MAE. Within cancer-related genes, MAE was gene specific; hTERT was most significantly affected, with a higher frequency of MAE in adult and advanced tumors. Clinically, MAE at TP53 exists only in mutated tumors and increases with tumor aggressiveness. MAE toward the normal allele at IDH1 conferred worse survival even in IDH1 mutated tumors. Taken together, our findings suggest that MAE is tumor and gene specific, frequent in brain tumor subtypes, and may be associated with tumor progression/aggressiveness. Further exploration of MAE at relevant genes may contribute to better understanding of tumor development and determine survival in brain tumor patients. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
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