The transcriptional landscape of Shh medulloblastoma.

Autor: Skowron P; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada., Farooq H; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada., Cavalli FMG; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada., Morrissy AS; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.; Alberta Children's Hospital Research Institute, Calgary, AB, Canada.; Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada., Ly M; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada., Hendrikse LD; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada., Wang EY; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada., Djambazian H; McGill University Genome Centre, McGill University, Montreal, QC, Canada.; Department of Human Genetics, McGill University, Montreal, QC, Canada., Zhu H; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.; Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada., Mungall KL; Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada., Trinh QM; Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada., Zheng T; Department of Neurology, University of California San Francisco, San Francisco, CA, United States., Dai S; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, United States., Stucklin ASG; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada., Vladoiu MC; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada., Fong V; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada., Holgado BL; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada., Nor C; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada., Wu X; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada., Abd-Rabbo D; Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada., Bérubé P; McGill University Genome Centre, McGill University, Montreal, QC, Canada., Wang YC; McGill University Genome Centre, McGill University, Montreal, QC, Canada., Luu B; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada., Suarez RA; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada., Rastan A; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.; Institute of Medical Science, University of Toronto, Toronto, ON, Canada., Gillmor AH; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.; Alberta Children's Hospital Research Institute, Calgary, AB, Canada.; Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada., Lee JJY; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada., Zhang XY; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada., Daniels C; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada., Dirks P; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada., Malkin D; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.; Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada., Bouffet E; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.; Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada., Tabori U; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.; Institute of Medical Science, University of Toronto, Toronto, ON, Canada.; Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada., Loukides J; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada., Doz FP; SIREDO Center (pediatric, adolescent and young adults oncology), Institut Curie, University of Paris, Paris, France., Bourdeaut F; SIREDO Center (pediatric, adolescent and young adults oncology), Institut Curie, University of Paris, Paris, France., Delattre OO; INSERM U 830, Institut Curie, Paris, France., Masliah-Planchon J; Unit of Somatic Genetics, Institut Curie, Paris, France., Ayrault O; PSL Research University, Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Institut Curie, Paris, France., Kim SK; Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul, South Korea., Meyronet D; Hospices Civils de Lyon, Institute of Pathology, University Lyon 1, Department of Cancer Cell Plasticity-INSERM U1052 Cancer Research Center of Lyon, Lyon, France., Grajkowska WA; Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland., Carlotti CG; Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of Sao Paulo, São Paulo, Brazil., de Torres C; Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain., Mora J; Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain., Eberhart CG; Departments of Pathology, Ophthalmology and Oncology, John Hopkins University School of Medicine, Baltimore, MD, United States., Van Meir EG; Department of Hematology & Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, GA, United States., Kumabe T; Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan., French PJ; Department of Neurology, Erasmus University Medical Center, Rotterdam, Netherlands., Kros JM; Department of Pathology, Erasmus University Medical Center, Rotterdam, Netherlands., Jabado N; Division of Experimental Medicine, McGill University, Montreal, QC, Canada., Lach B; Department of Pathology and Molecular Medicine, Division of Anatomical Pathology, McMaster University, Hamilton, ON, Canada.; Department of Pathology and Laboratory Medicine, Hamilton General Hospital, Hamilton, ON, Canada., Pollack IF; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States., Hamilton RL; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States., Rao AAN; Division of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN, United States., Giannini C; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States., Olson JM; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States., Bognár L; Department of Neurosurgery, University of Debrecen, Medical and Health Science Centre, Debrecen, Hungary., Klekner A; Department of Neurosurgery, University of Debrecen, Medical and Health Science Centre, Debrecen, Hungary., Zitterbart K; Department of Pediatric Oncology, Masaryk University School of Medicine, Brno, Czech Republic., Phillips JJ; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, United States.; Department of Pathology, University of California San Francisco, San Francisco, CA, United States., Thompson RC; Department of Neurological Surgery, Vanderbilt Medical Center, Nashville, TN, United States., Cooper MK; Department of Neurology, Vanderbilt Medical Center, Nashville, TN, United States., Rubin JB; Departments of Neuroscience, Washington University School of Medicine in St. Louis, St. Louis, MO, United States., Liau LM; Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California, United States., Garami M; 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary., Hauser P; 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary., Li KKW; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong., Ng HK; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong., Poon WS; Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong., Yancey Gillespie G; Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, United States., Chan JA; Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada., Jung S; Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun, Jeollanam-do, South Korea., McLendon RE; Department of Pathology, Duke University, Durham, NC, United States.; Department of Neurosurgery, Duke University, Durham, NC, United States., Thompson EM; Department of Neurosurgery, Duke University, Durham, NC, United States., Zagzag D; Department of Pathology and Neurosurgery, NYU Grossman School of Medicine and NYU Langone Health, New York, NY, United States., Vibhakar R; Department of Pediatrics, University of Colorado Denver, Aurora, CO, United States., Ra YS; Department of Neurosurgery, University of Ulsan, Asan Medical Center, Seoul, South Korea., Garre ML; U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova, Italy., Schüller U; Institute of Neuropathology, University Medical Center, Hamburg-Eppendorf, Germany.; Research Institute Children's Cancer Center, Hamburg, Germany.; Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf, Germany., Shofuda T; Division of Stem Cell Research, Institute for Clinical Research, Osaka National Hospital, Osaka, Japan., Faria CC; Division of Neurosurgery, Centro Hospitalar Lisboa Norte (CHULN), Hospital de Santa Maria, Lisbon, Portugal.; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal., López-Aguilar E; Division of Pediatric Hematology/Oncology, Hospital Pediatría Centro Médico Nacional century XXI, Mexico City, Mexico., Zadeh G; Division of Neurosurgery, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.; MacFeeters-Hamilton Center for Neuro-Oncology Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada., Hui CC; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada., Ramaswamy V; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.; Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada., Bailey SD; Department of Surgery, Division of Thoracic and Upper Gastrointestinal Surgery, Faculty of Medicine, McGill University, Montreal, QC, Canada.; Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada., Jones SJ; Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.; Department of Molecular Biology & Biochemistry, Simon Fraser University, Burnaby, BC, Canada., Mungall AJ; Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada., Moore RA; Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada., Calarco JA; Department of Cell & Systems Biology, University of Toronto, Toronto, ON, Canada., Stein LD; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.; Adaptive Oncology, Ontario Institute for Cancer Research, Toronto, ON, Canada., Bader GD; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.; The Donnelly Centre, University of Toronto, Toronto, ON, Canada., Reimand J; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.; Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada., Ragoussis J; McGill University Genome Centre, McGill University, Montreal, QC, Canada.; Department of Human Genetics, McGill University, Montreal, QC, Canada., Weiss WA; Department of Neurology, University of California San Francisco, San Francisco, CA, United States.; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, United States.; Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States., Marra MA; Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada., Suzuki H; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada. hisuzuki-ngy@umin.ac.jp.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. hisuzuki-ngy@umin.ac.jp., Taylor MD; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada. mdt.cns@gmail.com.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. mdt.cns@gmail.com.; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. mdt.cns@gmail.com.; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. mdt.cns@gmail.com.; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada. mdt.cns@gmail.com.; Department of Surgery, University of Toronto, Toronto, ON, Canada. mdt.cns@gmail.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Mar 19; Vol. 12 (1), pp. 1749. Date of Electronic Publication: 2021 Mar 19.
DOI: 10.1038/s41467-021-21883-0
Abstrakt: 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.
Databáze: MEDLINE