The Role of Histone Modifying Enzyme SUV420H2 in Pediatric Ependymoma

Total Page:16

File Type:pdf, Size:1020Kb

The Role of Histone Modifying Enzyme SUV420H2 in Pediatric Ependymoma W&M ScholarWorks Undergraduate Honors Theses Theses, Dissertations, & Master Projects 5-2015 The Role of Histone Modifying Enzyme SUV420H2 in Pediatric Ependymoma. Sarah Goggin College of William and Mary Follow this and additional works at: https://scholarworks.wm.edu/honorstheses Part of the Cancer Biology Commons, Genomics Commons, and the Molecular and Cellular Neuroscience Commons Recommended Citation Goggin, Sarah, "The Role of Histone Modifying Enzyme SUV420H2 in Pediatric Ependymoma." (2015). Undergraduate Honors Theses. Paper 215. https://scholarworks.wm.edu/honorstheses/215 This Honors Thesis is brought to you for free and open access by the Theses, Dissertations, & Master Projects at W&M ScholarWorks. It has been accepted for inclusion in Undergraduate Honors Theses by an authorized administrator of W&M ScholarWorks. For more information, please contact [email protected]. Table of Contents ABSTRACT:…………………………………………………………………………………………………………………….3 INTRODUCTION:…………………………………………………………………………………………………………..4 EPIGENETICS IN CANCER………………………………………………………………………………..……….5 GENE EXPRESSION PROFILING IN CANCER…………………………………………………….…………7 GENE EXPRESSION PROFILING IN PEDIATRIC EPENDYMOMA………………………………..…8 WHAT IS PEDIATRIC EPENDYMOMA?……………………………………………………………………………..9 ALTERED CHROMATIN STATES IN CANCER……………………………………………………………..12 ALTERED CHROMATIN STATES IN PEDIATRIC EPENDYMOMA…………………………………13 HISTONE MODIFYING ENZYME SUV4-20H2 EFFECT ON CHROMATIN STATE……………….13 METHODS:……………………………………………………………………………………………………………………16 ANALYSIS OF MICROARRAY DATA…………………………………………………………………………..16 REAL-TIME PCR FOR VALIDATION OF MICROARRAY DATA……………………………….….……18 ANALYSIS OF REAL-TIME PCR DATA………………………………………………………………………..19 CHROMATIN IMMUNOPRECIPITATION……………………………………………………….….………20 REAL-TIME PCR OF CHIP PULLDOWNS (AND ANALYSIS)…………………………………………..23 ChIP-SEQUENCING………………………………………………………………………………….…………….23 RESULTS:………………………………………………………………………………………………………………..……26 THERE ARE SIGNIFICANTLY ALTERED PATTERNS OF GENE EXPRESSION IN SUBTYPES OF PEDIATRIC EPENDYMOMA…………………………………………………………..……26 POOR PROGNOSIS SUBGROUP SHOWS ALTERED EXPRESSION OF GENES RELATED TO CELL CYCLE REGULATION, TUMOR SUPPRESSION, AND DNA REPLICATION AND REPAIR………………………………………………………………………………….…27 MICROARRAY ALTERED EXPRESSION VALIDATED AND REPLICATED IN VCU COHORT OF PEDIATRIC EPENDYMOMA……………………………………………………………..……29 SUV4-20H2 BINDS NEAR TERT PROMOTER…………………………………………………..………….31 H4K20me2 AND H4K20me3 MODIFICATION ARE FOUND NEAR TERT PROMOTER…………………………………………………………………………………………………………..33 ChIP-SEQUENCING EXPERIMENTS……………………………………………………………….…………34 DISCUSSION:……………………………………………………………………………………………………………….36 REFERENCES:………………………………………………………………………………………………………..……41 TABLES:…………………………………………………………………………………………………………………..…..45 Table 1: ChIP-qPCR RESULTS WITH anti-SUV4-20H2 ……………….…………..………………………….……58 Table 2: ChIP-qPCR RESULTS WITH anti-H4K20me2 …………………………………………………..………..61 Table 3: ChIP-qPCR RESULTS WITH anti-H4K20me3 …………………………………..……….……………….62 FIGURES:……………………………………………………………………………………………………………..………45 Figure 1: EPIGENETIC MODIFICATIONS AND CHROMATIN STATE …………………………………….…..45 !1 Figure 2: DIFFERENTIAL EXPRESSION PATTERNS IN GOOD PROGNOSIS AND POOR PROGNOSIS SUBGROUPS OF PE ……………………………………………………………………………46 Figure 3: ALTERED EXPRESSION OF GENES RELATED TO CELL CYCLE REGULATION, TUMOR SUPPRESSION, AS WELL AS DNA REPLICATION AND REPAIR IN POOR PROGNOSIS SUBGROUP………………………………………………………………………………………………………….48 Figure 4: MODEL OF SUV4-20H2 IN CANCER ……………………………………………………………………….50 Figure 5: VCU PE SAMPLES SHOW DIFFERENTIAL EXPRESSION OF SUV4-20H2 AND PROTO- ONCOGENES …………………………………………………………………………………………..………….51 Figure 6: qPCR IN VCU SAMPLES VALIDATES MICROARRAY ALTERED EXPRESSION ……………….53 Figure 7: ANTIBODIES ARE EFFECTIVE FOR USE IN CHROMATIN IMMUNOPRECIPITATION ……55 Figure 8: SCHEMATIC SHOWING GENERAL BINDING REGIONS OF SUV4-20H2 AND OTHER CHROMATIN MODIFIERS ………………………………………………………………………………..……56 Figure 9: SUV4-20H2 BINDS TO CHROMATIN NEAR TERT PROMOTER……………………………………57 Figure 10: H4K20me2 AND H4K20me3 MODIFICATIONS ARE PRESENT IN CHROMATIN NEAR TERT PROMOTER …………………………………………………………………………………………..…59 Figure 11: MODEL FOR DYSREGULATION OF TERT BY SUV4-20H2 LEADING TO PE …………………63 SUPPLEMENTARY MATERIALS: ………………………………………………………………………………65 Supplementary Material-1: PLIER METHOD….…………………………………………………………………….…65 Supplementary Material-2: PERMUTATION TESTING PARAMETERS AND CALCULATIONS..…..……65 Supplementary Material-3: GSEA METHOD OVERVIEW……….……………………………………………….…66 Supplementary Material-4: SAM METHODOLOGY- PRINCIPAL CALCULATIONS…..………………….….66 Supplementary Material-5: AGILENT 2100 BIOANALYZER- RNA 6000 PICO KIT PROTOCOL….….….67 Supplementary Material-6: NANODROP PROTOCOL………………………………………………………………………69 Supplementary Material-7: CHROMATIN IMMUNOPRECIPITATION- SPECIFIC VOLUMES…..………70 Supplementary Material-8: PRIMERS DESIGNED FOR qPCR EXPERIMENTS …………….….………..….70 Supplementary Material-9: ME-DIP AND 450K METHYLATION ARRAY……………………….……………..71 !2 Abstract Cancer is the leading cause of non-accidental death in children. Pediatric ependymomas (PE) are the third most common brain tumor in children. Despite advances leading to better survival outcomes in some cancers, these tumors remain incurable in up to 45% of patients, with recurrent local relapse being the major cause of mortality[18, 19]. Surgical resection is currently the most effective treatment, but over 50% of children whose tumors have been totally resected will still experience tumor recurrence despite aggressive adjuvant therapy [22]. Key molecular events in the pathogenesis of PE have yet to be defined, and understanding these events are proving to be increasingly necessary to developing clinically-relevant applications. In particular, errors in epigenetic regulatory machinery appear to play a substantial role in the pathogenesis of numerous cancers. As such, this research used gene expression profiling data on a large cohort (n=102) of PE samples to search for potential driving mechanisms underlying recurrence and poor prognosis in this cancer. Through this, we developed a model for the role of the histone modifying enzyme SUV4-20H2 in carcinogenesis. SUV4-20H2 confers modifications that lead to chromatin compaction and resultant silencing of genes in component/surrounding DNA. We hypothesized that this enzyme acts to directly regulate proto-oncogenes and that its loss in this cancer leads to their increased expression. We find evidence to support this model for SUV4-20H2 regulation of TERT, the catalytic subunit of telomerase. This holds significant translational value as TERT is strongly associated with recurrence and has been shown to increase tumorigenicity of tumor initiating cells, and a better understanding of it's regulation could lead to development of new therapies. Additionally, these findings implicate a potential broader role of SUV4-20H2 in driving carcinogenesis and warrant further investigation. !3 Introduction Cancer epigenomics is an emerging concentration of clinical cancer research. In conjunction with the field of oncogenomics, research aims to better define genomic, transcriptomic and proteomic differences within individual tumor subtypes and between subtypes and to relate these determined molecular phenotypic patterns to differences in prognosis and treatment response. Studies of cancer genomics led to vast leaps in understanding of the nature and underlying mechanisms of cancer. These new understandings began to point toward errors in regulatory control of essential cell processes as fundamental to cancer development and progression. However, of the key cancer-causing genes identified to date, germline mutations in these genes only account for a small fraction of their observed aberrant expression. This leaves open the question of how these hallmark mutations arise. Further, findings began and continue to emerge indicating the presence of mutations in various components of epigenetic machinery in numerous cancers. Findings such as these point to a substantial role for epigenetics in driving cancer. Research in this area has also been driven by its increasing clinical relevance. One major problem in clinical cancer research to date has been connecting diagnosis to prognosis and treatment response. Significant heterogeneity in both prognosis and treatment response have been found in cancers diagnosed by histology and location, but these remain the two primary diagnostic criteria. As such, research directed at cancer types defined by these criteria is limited in scope and applicability. More recent efforts aimed at identifying classes of transcriptomic patterning have proven far better at predicting prognosis and treatment response and have the potential to reveal more regarding the mechanisms by which malignancies arise. A shift towards gene expression-profile based diagnostics should allow for huge advances in treatment and in research as we begin to be able to categorize cancers by the underlying mechanisms of their malignancy. This thesis examines the altered gene expression patterns in pediatric ependymoma !4 (PE), and subsequently investigates the role of a particular epigenetic factor in its prognosis. This introduction will (1) present an overview of our current understanding of epigenetic states and cancer, (2) identify and justify experimental aims and practices in studying epigenetics in cancer, (3) provide background on the specific malignancy being studied and explain why it is an excellent candidate for investigation, and (4) describe in
Recommended publications
  • Ependymomas in Young Children
    Provide d by Ependymomas in Young Children Lead Contributors: Su Gülsün Berrak, MD Rejin Kebudi, MD Istanbul University, Oncology Institute Istanbul, Turkey Ibrahim Qaddoumi, MD, MS St. Jude Children’s Research Hospital Memphis, Tennessee, United States of America A. Epidemiology Ependymomas are the third most common type of brain tumor that affects children. 1 In a recent study of Turkish children, ependymomas accounted for approximately 13.6% of all brain tumors.2 More than 50% of all patients with ependymomas are younger than 5 years of age, and 70-80% are younger than 8 years of age at the time of clinical presentation. 3–5 A. References 1Blaney S, Kun LE, Hunter J, Rorke-Adams LB, Lau C, Strother D, Pollack IF. Tumors of the Central Nervous System. In: Pizzo PA, Poplack DG, eds. Principles and practice of pediatric oncology . Philadelphia: Lippincott Williams & Wilkins;2006:786–864 2Kutluk T, Yesilipek A, on behalf of Turkish Pediatric Oncology Group/Turkish Pediatric Hematology Association. Pediatric Cancer Registry. National Cancer Congress, 2007 3Goldwein JW, Leahy JM, Packer RJ, et al. Intracranial ependymomas in children. Int J Radiat Oncol Biol Phys. 1990; 19:1497–1502. 4Gilles F, Sobel E, Tavaré C, et al. Age-related changes in diagnoses, histological features, and survival in children with brain tumors: 1930–1979. The Childhood Brain Tumor Consortium. Neurosurgery. 1995; 37:1056–1068. 5Polednak A, Flannery J. Brain, other central nervous system, and eye cancer. Cancer. 1995; 75:330–337. B. Clinical Signs and Symptoms Most children with ependymomas present with localized disease. The predominant location for this tumor is the posterior fossa; the main clinical signs and symptoms in young children with this tumor are irritability, lethargy, and gait disturbance.
    [Show full text]
  • Targeted Therapy with Sirolimus and Nivolumab in a Child with Refractory Multifocal Anaplastic Ependymoma
    Case Report Targeted Therapy with Sirolimus and Nivolumab in a Child with Refractory Multifocal Anaplastic Ependymoma Katia Perruccio 1,*, Angela Mastronuzzi 2 , Marco Lupattelli 3, Francesco Arcioni 1, Ilaria Capolsini 1, Carla Cerri 1, Grazia M. I. Gurdo 1, Maria Speranza Massei 1, Elena Mastrodicasa 1 and Maurizio Caniglia 1 1 Pediatric Oncology Hematology, Santa Maria della Misericordia Hospital, 06156 Perugia, Italy; [email protected] (F.A.); [email protected] (I.C.); [email protected] (C.C.); [email protected] (G.M.I.G.); [email protected] (M.S.M.); [email protected] (E.M.); [email protected] (M.C.) 2 Department of Hematology Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, 00165 Rome, Italy; [email protected] 3 Radiotherapy Department, Santa Maria della Misericordia Hospital, 06156 Perugia, Italy; [email protected] * Correspondence: [email protected] Abstract: Pediatric ependymoma (EPN) is the third most common central nervous system (CNS) tumor, with 90% arising intracranially. Management typically involves maximal surgical resection and radiotherapy, but patients’ outcome is poor. Moreover, there are only a few therapeutical options available for recurrent or refractory disease. In this report, we present the case of a 7-year-old girl with relapsed refractory multifocal grade III EPN who failed conventional treatments and experienced Citation: Perruccio, K.; Mastronuzzi, a stable and durable response to the immune checkpoint inhibitor (ICPI) nivolumab in association A.; Lupattelli, M.; Arcioni, F.; Capolsini, I.; Cerri, C.; Gurdo, G.M.I.; with the mammalian target of rapamycin (m-TOR) inhibitor sirolimus.
    [Show full text]
  • SIOP Ependymoma II Protocol V3.1 22 April 2020 Clean
    Ependymoma Program II FINAL Protocol Version 3. 1 April 22 th , 2020 An international clinical program for the diagnosis and treatment of children, adolescents and young adults with ependymoma Final Version 3.1_ April 22 nd , 2020 Sponsor: Centre Léon Bérard Sponsor Protocol Number: ET-13-002 EudraCT Number: 2013-002766-39 VHP number: VHP358 (VHP201385) Page | 1 CONFIDENTIAL Ependymoma Program II FINAL Protocol Version 3. 1 April 22 th , 2020 SIGNATURE PAGE SIOP EPENDYMOMA II – An international Clinical Program for the diagnosis and treatment of children, adolescents and young adults with ependymoma Protocol version 3.1 dated April 22 nd , 2020 This protocol has been approved by: Name: Dr David PEROL Trial Role: Medical and scientific coordinator Signature: _______________________________ Date: 22-Apr-2020 This protocol describes the SIOP Ependymoma Program II and provides information about procedures for patients taking part in this trial. The protocol should not be used as a guide for treatment of patients not taking part in the SIOP Ependymoma Program II. CONFIDENTIALITY NOTE: This trial protocol is the property of the authoring Coordinating Investigators and is protected by copyright. The content of the trial protocol and the case report forms is confidential and oral or written disclosure to any uninvolved / third parties (without previous written agreement by one of the international or national coordinating investigators) is prohibited. Page | 2 CONFIDENTIAL Ependymoma Program II FINAL Protocol Version 3. 1 April 22 th , 2020 AMENDMENTS
    [Show full text]
  • Cell Ecosystem and Signaling Pathways of Primary and Metastatic Pediatric Posterior Fossa Ependymoma
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.10.244483; this version posted August 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Cell Ecosystem and Signaling Pathways of Primary and Metastatic Pediatric Posterior Fossa Ependymoma Rachael Aubin*,1, Emma C. Troisi*,1, Adam N. Alghalith,1, MacLean P. Nasrallah2, Mariarita Santi2,3, and Pablo G. Camara# 1 Department of Genetics and Institute for Biomedical Informatics, 2 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA 3 Department of Pathology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA * These authors contributed equally to this work. # Correspondence to: [email protected] Pediatric ependymoma is a devastating brain cancer marked by its relapsing pattern and lack of effective chemotherapies. This shortage of treatments is partially due to limited knowledge about ependymoma tumorigenic mechanisms. Although there is evidence that ependymoma originates in radial glia, the specific pathways underlying the progression and metastasis of these tumors are unknown. By means of single-cell transcriptomics, immunofluorescence, and in situ hybridization, we show that the expression profile of tumor cells from pediatric ependymomas in the posterior fossa is consistent with an origin in LGR5+ stem cells. Tumor stem cells recapitulate the developmental lineages of radial glia in neurogenic niches, promote an inflammatory microenvironment in cooperation with microglia, and upon metastatic progression initiate a mesenchymal program driven by reactive gliosis and hypoxia-related genes.
    [Show full text]
  • A Review of Radiographic Imaging Findings of Ependymal Tumors Maria Habib Hanna, MD1*, Bansal A, MD2 and Belani P, MD2
    ISSN: 2643-4474 Hanna et al. Neurosurg Cases Rev 2019, 2:028 DOI: 10.23937/2643-4474/1710028 Volume 2 | Issue 2 Neurosurgery - Cases and Reviews Open Access REVIEW ARTICLE A Review of Radiographic Imaging Findings of Ependymal Tumors Maria Habib Hanna, MD1*, Bansal A, MD2 and Belani P, MD2 1Department of Radiology, Weill Cornell Medicine, New York, USA 2 Check for Department of Radiology, Virginia Tech Carilion School of Medicine, Carilion Roanoke Memorial updates Hospital, 1906 Belleview Ave SE, Roanoke, VA 24014, USA *Corresponding author: Maria Habib Hanna, MD, Assistant Professor, Department of Radiology, Weill Cornell Medicine, 525 E 68th St, NY 10065, New York, USA based on imaging. There are, however, imaging features Abstract that can typically be distinguished between the adult Ependymomas are glial tumors that typically arise from the and pediatric patients. For instance, ependymomas in lining of the ventricles or the central canal of the spinal cord. The most common site of occurrence is within the poste- the adult population are typically larger than 4 cm in rior fossa. Subtypes of ependymomas include anaplastic size when they present and often contain cystic com- ependymoma, myxopapillary ependymoma, and subepend- ponents, whereas ependymomas in the pediatric pop- ymoma. Its characteristic imaging features include findings ulation are usually solid and usually smaller in size at of a heterogeneous mass with necrosis, calcifications, cyst- presentation [4]. ic changes, and hemorrhage. Treatment options includes partial resection with or without irradiation. Radiographic features of intracranial ependymomas are summarized in Table 1. Introduction The types of ependymomas to be discussed in this Ependymomas are rare glial tumors that account article include intracranial ependymomas (infra and su- for approximately 7% of all intracranial neoplasms in pratentorial) and spinal (myxopapillary ependymoma).
    [Show full text]
  • Case Report Supratentorial Atypical Ectopic Ependymoma in a Child: a Case Report
    Int J Clin Exp Med 2017;10(10):14827-14833 www.ijcem.com /ISSN:1940-5901/IJCEM0055614 Case Report Supratentorial atypical ectopic ependymoma in a child: a case report Xuanxuan Wu, Ping Liang, Xuan Zhai Department of Neurosurgery, Children’s Hospital of Chongqing Medical University, No.136, Second Zhongshan Road, Yuzhong District, Chongqing City, 400021, P. R. China Received February 21, 2017; Accepted September 13, 2017; Epub October 15, 2017; Published October 30, 2017 Abstract: The aim of this study is to report a rare case of supratentorial ectopic ependymoma in a child with atypical radiologic and pathologic characteristics. A 14-month-old male infant suffered a short spell of sudden unconscious- ness and convulsion of the right limbs, accompanying with vomiting and salivating. A computed tomogrphy (CT) scan revealed a huge slightly low density solid mass locating in the left temporo-parietal junction, within slightly high density component. Magnetic resonance imaging (MRI) scan demonstrated a solid mass, approximately 78×58×58 mm, in the left temporo-parietal region, which had equal intensity on T1 Weighted Image (WI) and slightly higher signal intensity on T2 WI. Tumor had no attachment to the dura mater and no continuity with the ventricular system. The clinical symptom, sign and assistant examination pointed to the diagnosis of the left temporal and parietal low-grade gliomas. The patient underwent transtemporo-parietal craniotomy. The tumor was fish-meat like appear- ance, pink color, approximately 80×70×60 mm, soft texture, a large welldefined lesion, adherent to lateral ventricle but having no attachment to it. The tumor was completely dissected free of the surrounding brain tissue damage.
    [Show full text]
  • Ependymoma Associated with a Good Prognosis in Immune Gene And
    Immune Gene and Cell Enrichment Is Associated with a Good Prognosis in Ependymoma This information is current as Andrew M. Donson, Diane K. Birks, Valerie N. Barton, Qi of September 27, 2021. Wei, Bette K. Kleinschmidt-DeMasters, Michael H. Handler, Allen E. Waziri, Michael Wang and Nicholas K. Foreman J Immunol 2009; 183:7428-7440; Prepublished online 16 November 2009; doi: 10.4049/jimmunol.0902811 Downloaded from http://www.jimmunol.org/content/183/11/7428 References This article cites 51 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/183/11/7428.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 27, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Immune Gene and Cell Enrichment Is Associated with a Good Prognosis in Ependymoma1 Andrew M. Donson,2*§ Diane K.
    [Show full text]
  • Pediatric Ependymoma: a Proteomics Perspective GEORGE TH
    CANCER GENOMICS & PROTEOMICS 14 : 127-136 (2017) doi:10.21873/cgp.20025 Pediatric Ependymoma: A Proteomics Perspective GEORGE TH. TSANGARIS 1, CHRISSA PAPATHANASIOU 2, PANAGIOTIS G. ADAMOPOULOS 3, ANDREAS SCORILAS 4, CONSTANTINOS E. VORGIAS 4, NEOFYTOS PRODROMOU 3, FOTEINI TZORTZATOU STATHOPOULOU 2, DIMITRIOS J. STRAVOPODIS 5 and ATHANASIOS K. ANAGNOSTOPOULOS 1 1Proteomics Research Unit, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; 2Hematology/Oncology Unit, First Department of Pediatrics, University of Athens, Aghia Sophia Children’s Hospital, Athens, Greece; 3Department of Neurosurgery, Aghia Sophia Children’s Hospital, Athens, Greece; 4Department of Biochemistry and Molecular Biology, Faculty of Biology, School of Sciences, National and Kapodistrian University of Athens, Athens, Greece; 5Department of Cell Biology and Biophysics, Faculty of Biology, School of Sciences, National and Kapodistrian University of Athens, Athens, Greece Abstract. Background/Aim: Proteomics based on high- analyzed sample, thus detailing the greater part of the resolution mass spectrometry (MS) is the tool of choice for ependymoma proteome. Identified proteins were found to the analysis of protein presence, modifications and spread throughout all known tumor categories regarding their interactions, with increasing emphasis on the examination of molecular function and subcellular localization. Conclusion: tumor tissues. Application of MS-based proteomics offers a Through the proposed nanoLC-MS/MS method herein we detailed picture of tumor tissue characteristics, facilitating report, for the firs time, the ependymoma proteome database. the appreciation of different tumor entities, whilst providing A large number of similarities regarding proteome content are reliable and fast results for therapeutic marker targeting and revealed compared to other two pediatric brain tumor prognostic factor assessment.
    [Show full text]
  • The Genetic Basis of Intradural Spinal Tumors and Its Impact on Clinical Treatment
    NEUROSURGICAL FOCUS Neurosurg Focus 39 (2):E3, 2015 The genetic basis of intradural spinal tumors and its impact on clinical treatment Michael Karsy, MD, PhD, Jian Guan, MD, Walavan Sivakumar, MD, Jayson A. Neil, MD, Meic H. Schmidt, MD, MBA, and Mark A. Mahan, MD Department of Neurosurgery, Clinical Neurosciences Center, The University of Utah, Salt Lake City, Utah Genetic alterations in the cells of intradural spinal tumors can have a significant impact on the treatment options, coun- seling, and prognosis for patients. Although surgery is the primary therapy for most intradural tumors, radiochemothera- peutic modalities and targeted interventions play an ever-evolving role in treating aggressive cancers and in addressing cancer recurrence in long-term survivors. Recent studies have helped delineate specific genetic and molecular differ- ences between intradural spinal tumors and their intracranial counterparts and have also identified significant variation in therapeutic effects on these tumors. This review discusses the genetic and molecular alterations in the most common intradural spinal tumors in both adult and pediatric patients, including nerve sheath tumors (that is, neurofibroma and schwannoma), meningioma, ependymoma, astrocytoma (that is, low-grade glioma, anaplastic astrocytoma, and glioblas- toma), hemangioblastoma, and medulloblastoma. It also examines the genetics of metastatic tumors to the spinal cord, arising either from the CNS or from systemic sources. Importantly, the impact of this knowledge on therapeutic options
    [Show full text]
  • 1 PI3K Pathway Activation Provides a Novel Therapeutic Target for Pediatric
    Author Manuscript Published OnlineFirst on September 27, 2013; DOI: 10.1158/1078-0432.CCR-13-0222 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. PI3K pathway activation provides a novel therapeutic target for pediatric ependymoma and is an independent marker of progression free survival Hazel A Rogers1, Cerys Mayne1, Rebecca J Chapman1, John-Paul Kilday1, Beth Coyle1, Richard G Grundy1 1Children’s Brain Tumour Research Centre, D Floor Medical School, Queen’s Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK Running title; Therapeutic potential of PI3K pathway in ependymoma Corresponding Author; Dr Hazel Rogers, Children’s Brain Tumour Research Centre, D Floor Medical School, Queen’s Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK Email; [email protected] Tel; +44 (0)115 8230718 Fax; +44 (0)115 8230696 Keywords; ependymoma, brain tumor, PI3K pathway, AKT, Cyclin D1 Financial Support; Funding was provided by the Joseph Foote Trust, Gentleman’s Night Out and the James Tudor Foundation. Conflict of interest; The authors declare that they have no conflict of interest. Word count; 4631 5 figures and 1 table 1 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 27, 2013; DOI: 10.1158/1078-0432.CCR-13-0222 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Translation Relevance Brain tumors are the leading cause of cancer related deaths in children in the UK. Ependymoma is the second most common malignant pediatric tumor of the CNS.
    [Show full text]
  • Koelsche Et Al., Page 1 Distribution of TERT Promoter Mutations In
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2013 Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system Koelsche, C ; Sahm, F ; Capper, D ; Reuss, D ; Sturm, D ; Jones, D T W ; Kool, M ; Northcott, P A ; Wiestler, B ; Böhmer, K ; Meyer, J ; Mawrin, C ; Hartmann, C ; Mittelbronn, M ; Platten, M ; Brokinkel, B ; Seiz, M ; Herold-Mende, C ; Unterberg, A ; Schittenhelm, J ; Weller, M ; Pfister, S ; Wick, W ; Korshunov, A ; von Deimling, A Abstract: Hot spot mutations in the promoter region of telomerase reverse transcriptase (TERT) have recently been described in several human tumor entities. These mutations result in an upregulation of the telomerase complex activity and thus constitute a relevant mechanism for immortalization of tumor cells. Knowledge of the TERT promoter status in tumors is likely to be of interest for molecular classification and as a potential target for therapy. We, therefore, performed a systematic analysisof TERT promoter mutations in 1,515 tumors of the human nervous system and its coverings including 373 pediatric and 1,142 adult patients. We detected a total of 327 mutations. TERT promoter mutations were exceedingly rare in tumors typically encountered in pediatric patients. In entities typically encountered in adult patients TERT promoter mutations were strongly associated with older age (p < 0.0001). Highest mutation frequencies were detected in gliosarcomas (81 %), oligodendrogliomas (78 %), oligoastrocytomas (58 %), primary glioblastomas (54 %), and solitary fibrous tumors (50 %). Related to other molecular alterations, TERT promoter mutations were strongly associated with 1p/19q loss (p < 0.0001), but inversely associated with loss of ATRX expression (p < 0.0001) and IDH1/IDH2 mutations (p < 0.0001).
    [Show full text]
  • Histologic Grade and Extent of Resection Are Associated with Survival in Pediatric Spinal Cord Ependymomas
    Childs Nerv Syst DOI 10.1007/s00381-013-2149-x ORIGINAL PAPER Histologic grade and extent of resection are associated with survival in pediatric spinal cord ependymomas Michael Safaee & Michael C. Oh & Joseph M. Kim & Derick Aranda & Phiroz E. Tarapore & Tene A. Cage & Nalin Gupta & Andrew T. Parsa Received: 15 February 2013 /Accepted: 3 May 2013 # Springer-Verlag Berlin Heidelberg 2013 Abstract Keywords Ependymoma . Spine . Pediatric . Histologic Purpose Prognostic factors affecting outcomes in pediatric grade . Recurrence . Survival spinal cord ependymomas are limited. We sought to inves- tigate potential associations between extent of resection and histologic grade on progression-free survival (PFS) and Introduction overall survival (OS). Methods A comprehensive literature search was performed Ependymomas are among the most common central nervous to identify pediatric patients who underwent surgical resec- system tumors in children and young adults. They range tion for spinal cord ependymomas. Only manuscripts with from subependymomas (Word Health Organization (WHO) clearly defined age, tumor grade, extent of resection, and grade I) and myxopapillary ependymomas (WHO grade I) clinical follow-up were included. to more aggressive anaplastic ependymomas (WHO grade Results A total of 80 patients were identified with a histologic III). Classic ependymomas (WHO grade II) may vary in distribution as follows: 36 % myxopapillary (grade I), 54 % clinical behavior but are generally slow growing and found classical (grade II), and 10 % anaplastic (grade III). There was adjacent to the ventricular wall or within the spinal cord. no association between tumor grade and PFS. The only factor There is a well-described relationship between the anatomic associated with improved PFS was gross total resection location of ependymomas and their histologic grade.
    [Show full text]