title: Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR.
abstract: Embryonal tumors with multilayered rosettes (ETMRs) are rare, deadly pediatric brain tumors characterized by high-level amplification of the microRNA cluster C19MC. We performed integrated genetic and epigenetic analyses of 12 ETMR samples and identified, in all cases, C19MC fusions to TTYH1 driving expression of the microRNAs. ETMR tumors, cell lines and xenografts showed a specific DNA methylation pattern distinct from those of other tumors and normal tissues. We detected extreme overexpression of a previously uncharacterized isoform of DNMT3B originating at an alternative promoter that is active only in the first weeks of neural tube development. Transcriptional and immunohistochemical analyses suggest that C19MC-dependent DNMT3B deregulation is mediated by RBL2, a known repressor of DNMT3B. Transfection with individual C19MC microRNAs resulted in DNMT3B upregulation and RBL2 downregulation in cultured cells. Our data suggest a potential oncogenic re-engagement of an early developmental program in ETMR via epigenetic alteration mediated by an embryonic, brain-specific DNMT3B isoform.
authors: 1] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada. [2] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [3].
authors: Claudia L
authors: CL
authors: Kleinman
authors: 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2].
authors: Noha
authors: N
authors: Gerges
authors: McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors: Simon
authors: S
authors: Papillon-Cavanagh
authors: Division of Hematology-Oncology, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Patrick
authors: P
authors: Sin-Chan
authors: McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors: Albena
authors: A
authors: Pramatarova
authors: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors: Dong-Anh Khuong
authors: DA
authors: Quang
authors: McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors: Véronique
authors: V
authors: Adoue
authors: McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors: Stephan
authors: S
authors: Busche
authors: McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors: Maxime
authors: M
authors: Caron
authors: McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors: Haig
authors: H
authors: Djambazian
authors: McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors: Amandine
authors: A
authors: Bemmo
authors: Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
authors: Adam M
authors: AM
authors: Fontebasso
authors: Division of Hematology-Oncology, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Tara
authors: T
authors: Spence
authors: McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors: Jeremy
authors: J
authors: Schwartzentruber
authors: Department of Pathology, McGill University Health Centre, Montreal, Quebec, Canada.
authors: Steffen
authors: S
authors: Albrecht
authors: Second Department of Paediatrics, Semmelweis University, Budapest, Hungary.
authors: Peter
authors: P
authors: Hauser
authors: Second Department of Paediatrics, Semmelweis University, Budapest, Hungary.
authors: Miklos
authors: M
authors: Garami
authors: Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
authors: Almos
authors: A
authors: Klekner
authors: Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
authors: Laszlo
authors: L
authors: Bognar
authors: Division of Neurosurgery, Department of Surgery, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
authors: Jose-Luis
authors: JL
authors: Montes
authors: McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors: Alfredo
authors: A
authors: Staffa
authors: McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors: Alexandre
authors: A
authors: Montpetit
authors: McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors: Pierre
authors: P
authors: Berube
authors: Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland.
authors: Magdalena
authors: M
authors: Zakrzewska
authors: Department of Neurosurgery, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland.
authors: Krzysztof
authors: K
authors: Zakrzewski
authors: Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland.
authors: Pawel P
authors: PP
authors: Liberski
authors: Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors: Zhifeng
authors: Z
authors: Dong
authors: Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors: Peter M
authors: PM
authors: Siegel
authors: Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors: Thomas
authors: T
authors: Duchaine
authors: Department of Pathology & Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Christian
authors: C
authors: Perotti
authors: Division of Pediatric Hematology-Oncology, Department of Pediatrics, McGill University and the McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
authors: Adam
authors: A
authors: Fleming
authors: Division of Pediatric Hematology-Oncology, Department of Pediatrics, McGill University and the McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
authors: Damien
authors: D
authors: Faury
authors: Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Marc
authors: M
authors: Remke
authors: Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Marco
authors: M
authors: Gallo
authors: Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Peter
authors: P
authors: Dirks
authors: Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Michael D
authors: MD
authors: Taylor
authors: 1] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada. [2] Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors: Robert
authors: R
authors: Sladek
authors: McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors: Tomi
authors: T
authors: Pastinen
authors: Department of Pathology & Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Jennifer A
authors: JA
authors: Chan
authors: 1] Division of Hematology-Oncology, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Program in Cell Biology, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada. [3].
authors: Annie
authors: A
authors: Huang
authors: 1] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada. [2] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [3].
authors: Jacek
authors: J
authors: Majewski
authors: 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2] Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada. [3].
authors: Nada
authors: N
authors: Jabado
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics*; D002675:Child, Preschool; D002888:Chromosomes, Human, Pair 19; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D050939:Gene Fusion; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics*; D020033:Protein Isoforms; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D008565:Membrane Proteins; D035683:MicroRNAs; D020033:Protein Isoforms; D050717:Retinoblastoma-Like Protein p130; D000097584:DNA Methyltransferase 3B; C493837:RBL2 protein, human; C417913:TTYH1 protein, human