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CNS-PNETs with C19MC amplification and-or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity

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dc.contributor.author Spence T.
dc.contributor.author Sin-Chan P.
dc.contributor.author Picard D.
dc.contributor.author Barszczyk M.
dc.contributor.author Hoss K.
dc.contributor.author Lu M.
dc.contributor.author Kim S.-K.
dc.contributor.author Ra Y.-S.
dc.contributor.author Nakamura H.
dc.contributor.author Fangusaro J.
dc.contributor.author Hwang E.
dc.contributor.author Kiehna E.
dc.contributor.author Toledano H.
dc.contributor.author Wang Y.
dc.contributor.author Shi Q.
dc.contributor.author Johnston D.
dc.contributor.author Michaud J.
dc.contributor.author La Spina M.
dc.contributor.author Buccoliero A.M.
dc.contributor.author Adamek D.
dc.contributor.author Camelo-Piragua S.
dc.contributor.author Peter
dc.contributor.editor
dc.date 2014
dc.date.accessioned 2017-10-05T15:59:40Z
dc.date.available 2017-10-05T15:59:40Z
dc.date.issued 2014
dc.identifier 10.1007/s00401-014-1291-1
dc.identifier.isbn
dc.identifier.issn 00016322
dc.identifier.uri http://hdl.handle.net/10938/19157
dc.description.abstract Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and-or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified-LIN28+ group 1 CNS-PNETs arose predominantly in children 4 years old; a majority arose in the cerebrum but 24 percent (13-54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28-LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28-let7-PI3K-mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity. © 2014 The Author(s).
dc.format.extent
dc.format.extent Pages: (291-303)
dc.language English
dc.publisher Springer Verlag; NEW YORK
dc.relation.ispartof Publication Name: Acta Neuropathologica; Publication Year: 2014; Volume: 128; no. 2; Pages: (291-303);
dc.relation.ispartofseries
dc.relation.uri
dc.source Scopus
dc.subject.other
dc.title CNS-PNETs with C19MC amplification and-or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity
dc.type Article
dc.contributor.affiliation Spence, T., Department of Pediatrics, Hospital for Sick Children, Arthur and Sonia Labatt Brain Tumor Research Centre, 686 Bay Street, Toronto, ON M5G0A4, Canada, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
dc.contributor.affiliation Sin-Chan, P., Department of Pediatrics, Hospital for Sick Children, Arthur and Sonia Labatt Brain Tumor Research Centre, 686 Bay Street, Toronto, ON M5G0A4, Canada, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
dc.contributor.affiliation Picard, D., Department of Pediatrics, Hospital for Sick Children, Arthur and Sonia Labatt Brain Tumor Research Centre, 686 Bay Street, Toronto, ON M5G0A4, Canada
dc.contributor.affiliation Barszczyk, M., Department of Pathology, Hospital for Sick Children, Toronto, ON, Canada
dc.contributor.affiliation Hoss, K., Department of Pediatrics, Hospital for Sick Children, Arthur and Sonia Labatt Brain Tumor Research Centre, 686 Bay Street, Toronto, ON M5G0A4, Canada
dc.contributor.affiliation Lu, M., Department of Pediatrics, Hospital for Sick Children, Arthur and Sonia Labatt Brain Tumor Research Centre, 686 Bay Street, Toronto, ON M5G0A4, Canada
dc.contributor.affiliation Kim, S.-K., Department of Neurosurgery, Seoul National University Children's Hospital, Seoul, South Korea
dc.contributor.affiliation Ra, Y.-S., Department of Neurosurgery, Asan Medical Center, Seoul, South Korea
dc.contributor.affiliation Nakamura, H., Department of Neurosurgery, Kumamoto University, Kumamoto, Japan
dc.contributor.affiliation Fangusaro, J., Division of Pediatric Hematology-Oncology and Stem Cell Transplantation, Children's Memorial Hospital, Chicago, IL, United States
dc.contributor.affiliation Hwang, E., Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, DC, United States
dc.contributor.affiliation Kiehna, E., Department of Neurosurgery, Children's Hospital of Los Angeles, Los Angeles, CA, United States
dc.contributor.affiliation Toledano, H., Oncology Department, Schneider Hospital, Petach Tikva, Israel
dc.contributor.affiliation Wang, Y., Department of Neuropathology, Huashan Hospital, Fudan University, Shanghai, China
dc.contributor.affiliation Shi, Q., Department of Pathology, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
dc.contributor.affiliation Johnston, D., Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada
dc.contributor.affiliation Michaud, J., Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada
dc.contributor.affiliation La Spina, M., Paediatric Haematology and Oncology Division, University of Catania, Sicily, Italy
dc.contributor.affiliation Buccoliero, A.M., Pathology Unit Meyer Children's Hospital, Florence, Italy
dc.contributor.affiliation Adamek, D., Department of Pathomorphology, Jagiellonian University Medical College, Krakow, Poland
dc.contributor.affiliation Camelo-Piragua, S., Department of Pathology, University of Michigan, Ann Arbor, MI, United States
dc.contributor.affiliation Peter Collins, V., Department of Pathology, University of Cambridge, Cambridge, United Kingdom
dc.contributor.affiliation Jones, C., Department of Paediatric Molecular Pathology, Institute of Cancer Research, Sutton, United Kingdom
dc.contributor.affiliation Kabbara, N., Division of Pediatric Hematology Oncology, Rafic Hariri University Hospital, Beirut, Lebanon
dc.contributor.affiliation Jurdi, N., Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon
dc.contributor.affiliation Varlet, P., Medical and Department of Neuropathology, Sainte-Anne Hospital, University Paris V Descartes, Paris, France
dc.contributor.affiliation Perry, A., Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA, United States
dc.contributor.affiliation Scharnhorst, D., Department of Pathology, Children's Hospital Central California, Madera, CA, United States
dc.contributor.affiliation Fan, X., Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
dc.contributor.affiliation Muraszko, K.M., Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States
dc.contributor.affiliation Eberhart, C.G., Division of Pathology, John Hopkins University School of Medicine, Baltimore, MD, United States
dc.contributor.affiliation Ng, H.-K., Department of Anatomical and Cellular Physiology, Chinese University of Hong Kong, Hong Kong, Hong Kong
dc.contributor.affiliation Gururangan, S., Department of Pediatrics, Duke University School of Medicine, Durham, NC, United States
dc.contributor.affiliation Van Meter, T., Department of Pediatrics, Virginia Commonwealth University, Richmond, VA, United States
dc.contributor.affiliation Remke, M., Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, ON, Canada
dc.contributor.affiliation Lafay-Cousin, L., Department of Pediatric Oncology, Alberta Children's Hospital, Calgary, AB, Canada
dc.contributor.affiliation Chan, J.A., Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada
dc.contributor.affiliation Sirachainan, N., Departments of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Bangkok, Thailand
dc.contributor.affiliation Pomeroy, S.L., Department of Neurology, Children's Hospital Boston, Boston, MA, United States
dc.contributor.affiliation Clifford, S.C., Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, United Kingdom
dc.contributor.affiliation Gajjar, A., Neuro-oncology Division, St. Jude Children's Research Hospital, Memphis, TN, United States
dc.contributor.affiliation Shago, M., Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON, Canada
dc.contributor.affiliation Halliday, W., Department of Pathology, Hospital for Sick Children, Toronto, ON, Canada
dc.contributor.affiliation Taylor, M.D., Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, ON, Canada
dc.contributor.affiliation Grundy, R., Children's Brain Tumor Research Centre, Queen's Medical Centre University of Nottingham, Nottingham, United Kingdom
dc.contributor.affiliation Lau, C.C., Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, United States
dc.contributor.affiliation Phillips, J., Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA, United States
dc.contributor.affiliation Bouffet, E., Department of Pediatrics, Hospital for Sick Children, Arthur and Sonia Labatt Brain Tumor Research Centre, 686 Bay Street, Toronto, ON M5G0A4, Canada
dc.contributor.affiliation Dirks, P.B., Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, ON, Canada
dc.contributor.affiliation Hawkins, C.E., Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, Department of Pathology, Hospital for Sick Children, Toronto, ON, Canada
dc.contributor.affiliation Huang, A., Department of Pediatrics, Hospital for Sick Children, Arthur and Sonia Labatt Brain Tumor Research Centre, 686 Bay Street, Toronto, ON M5G0A4, Canada, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
dc.contributor.authorAddress Huang, A.; Department of Pediatrics, Hospital for Sick Children, Arthur and Sonia Labatt Brain Tumor Research Centre, 686 Bay Street, Toronto, ON M5G0A4, Canada; email: annie.huang@sickkids.ca
dc.contributor.authorCorporate University: American University of Beirut Medical Center; Faculty: Faculty of Medicine; Department: Pathology and Laboratory Medicine;
dc.contributor.authorDepartment Pathology and Laboratory Medicine
dc.contributor.authorDivision
dc.contributor.authorEmail annie.huang@sickkids.ca
dc.contributor.authorFaculty Faculty of Medicine
dc.contributor.authorInitials Spence, T
dc.contributor.authorInitials Sin-Chan, P
dc.contributor.authorInitials Picard, D
dc.contributor.authorInitials Barszczyk, M
dc.contributor.authorInitials Hoss, K
dc.contributor.authorInitials Lu, M
dc.contributor.authorInitials Kim, SK
dc.contributor.authorInitials Ra, YS
dc.contributor.authorInitials Nakamura, H
dc.contributor.authorInitials Fangusaro, J
dc.contributor.authorInitials Hwang, E
dc.contributor.authorInitials Kiehna, E
dc.contributor.authorInitials Toledano, H
dc.contributor.authorInitials Wang, Y
dc.contributor.authorInitials Shi, Q
dc.contributor.authorInitials Johnston, D
dc.contributor.authorInitials Michaud, J
dc.contributor.authorInitials La Spina, M
dc.contributor.authorInitials Buccoliero, AM
dc.contributor.authorInitials Adamek, D
dc.contributor.authorInitials Camelo-Piragua, S
dc.contributor.authorInitials Collins, VP
dc.contributor.authorOrcidID
dc.contributor.authorReprintAddress Huang, A (reprint author), Hosp Sick Children, Dept Pediat, Arthur and Sonia Labatt Brain Tumor Res Ctr, Div Hematol Oncol,Peter Gilgan CRL, 686 Bay St,17th Floor,179712, Toronto, ON M5G 0A4, Canada.
dc.contributor.authorResearcherID
dc.contributor.authorUniversity American University of Beirut Medical Center
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dc.description.citedCount 2
dc.description.citedTotWOSCount 2
dc.description.citedWOSCount 2
dc.format.extentCount 13
dc.identifier.articleNo
dc.identifier.coden ANPTA
dc.identifier.pubmedID
dc.identifier.scopusID 84906936263
dc.identifier.url
dc.publisher.address 233 SPRING ST, NEW YORK, NY 10013 USA
dc.relation.ispartofConference
dc.relation.ispartofConferenceCode
dc.relation.ispartofConferenceDate
dc.relation.ispartofConferenceHosting
dc.relation.ispartofConferenceLoc
dc.relation.ispartofConferenceSponsor
dc.relation.ispartofConferenceTitle
dc.relation.ispartofFundingAgency
dc.relation.ispartOfISOAbbr Acta Neuropathol.
dc.relation.ispartOfIssue 2
dc.relation.ispartOfPart
dc.relation.ispartofPubTitle Acta Neuropathologica
dc.relation.ispartofPubTitleAbbr Acta Neuropathol.
dc.relation.ispartOfSpecialIssue
dc.relation.ispartOfSuppl
dc.relation.ispartOfVolume 128
dc.source.ID WOS:000339725800009
dc.type.publication Journal
dc.subject.otherAuthKeyword
dc.subject.otherChemCAS
dc.subject.otherIndex DNA methyltransferase 3B
dc.subject.otherIndex Lin28 protein
dc.subject.otherIndex microRNA
dc.subject.otherIndex protein derivative
dc.subject.otherIndex unclassified drug
dc.subject.otherIndex article
dc.subject.otherIndex brain
dc.subject.otherIndex brain tumor
dc.subject.otherIndex central nervous system tumor
dc.subject.otherIndex child
dc.subject.otherIndex DNA methylation
dc.subject.otherIndex ependymoblastoma
dc.subject.otherIndex female
dc.subject.otherIndex fluorescence in situ hybridization
dc.subject.otherIndex gene expression
dc.subject.otherIndex human
dc.subject.otherIndex human tissue
dc.subject.otherIndex immunohistochemistry
dc.subject.otherIndex major clinical study
dc.subject.otherIndex male
dc.subject.otherIndex neuroectoderm tumor
dc.subject.otherIndex neuroepithelioma
dc.subject.otherIndex preschool child
dc.subject.otherIndex priority journal
dc.subject.otherIndex protein expression
dc.subject.otherKeywordPlus ABUNDANT NEUROPIL
dc.subject.otherKeywordPlus TRUE ROSETTES
dc.subject.otherKeywordPlus EMBRYONAL TUMOR
dc.subject.otherKeywordPlus BRAIN-TUMORS
dc.subject.otherKeywordPlus MULTILAYERED ROSETTES
dc.subject.otherKeywordPlus LIN28-LET-7
dc.subject.otherKeywordPlus SURVIVAL
dc.subject.otherKeywordPlus FEATURES
dc.subject.otherKeywordPlus MARKERS
dc.subject.otherKeywordPlus CANCER
dc.subject.otherWOS Clinical Neurology
dc.subject.otherWOS Neurosciences
dc.subject.otherWOS Pathology


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