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Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma.
Fontebasso, Adam M; Papillon-Cavanagh, Simon; Schwartzentruber, Jeremy; Nikbakht, Hamid; Gerges, Noha; Fiset, Pierre-Olivier; Bechet, Denise; Faury, Damien; De Jay, Nicolas; Ramkissoon, Lori A; Corcoran, Aoife; Jones, David T W; Sturm, Dominik; Johann, Pascal; Tomita, Tadanori; Goldman, Stewart; Nagib, Mahmoud; Bendel, Anne; Goumnerova, Liliana; Bowers, Daniel C; Leonard, Jeffrey R; Rubin, Joshua B; Alden, Tord; Browd, Samuel; Geyer, J Russell; Leary, Sarah; Jallo, George; Cohen, Kenneth; Gupta, Nalin; Prados, Michael D; Carret, Anne-Sophie; Ellezam, Benjamin; Crevier, Louis; Klekner, Almos; Bognar, Laszlo; Hauser, Peter; Garami, Miklos; Myseros, John; Dong, Zhifeng; Siegel, Peter M; Malkin, Hayley; Ligon, Azra H; Albrecht, Steffen; Pfister, Stefan M; Ligon, Keith L; Majewski, Jacek; Jabado, Nada; Kieran, Mark W.
Affiliation
  • Fontebasso AM; 1] Division of Experimental Medicine, Montreal Children's Hospital, McGill University and McGill University Health Centre, Montreal, Quebec, Canada. [2].
  • Papillon-Cavanagh S; 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2].
  • Schwartzentruber J; 1] Wellcome Trust Sanger Institute, Hinxton, UK. [2].
  • Nikbakht H; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
  • Gerges N; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
  • Fiset PO; Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
  • Bechet D; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
  • Faury D; 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2] Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
  • De Jay N; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
  • Ramkissoon LA; Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Corcoran A; Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Jones DT; Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Sturm D; Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Johann P; Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Tomita T; Department of Neurological Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois, USA.
  • Goldman S; Department of Pediatrics Hematology-Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois, USA.
  • Nagib M; Clinical Pediatric Neurosurgical Oncology, Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, USA.
  • Bendel A; Department of Pediatric Hematology-Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA.
  • Goumnerova L; 1] Department of Neurosurgery, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA.
  • Bowers DC; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  • Leonard JR; Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.
  • Rubin JB; Department of Pediatrics, Hematology-Oncology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.
  • Alden T; Department of Neurological Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois, USA.
  • Browd S; Department of Neurosurgery, Seattle Children's Hospital, Seattle, Washington, USA.
  • Geyer JR; Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, Washington, USA.
  • Leary S; Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, Washington, USA.
  • Jallo G; Department of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA.
  • Cohen K; Department of Pediatric Hematology-Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
  • Gupta N; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Prados MD; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Carret AS; Department of Hematology-Oncology, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.
  • Ellezam B; Department of Pathology, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.
  • Crevier L; Department of Neurosurgery, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.
  • Klekner A; Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
  • Bognar L; Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
  • Hauser P; 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary.
  • Garami M; 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary.
  • Myseros J; Department of Neurosurgery, Children's National Medical Center, Washington, DC, USA.
  • Dong Z; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
  • Siegel PM; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
  • Malkin H; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Ligon AH; 1] Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
  • Albrecht S; Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
  • Pfister SM; Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Ligon KL; 1] Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. [4] Department of Path
  • Majewski J; 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2].
  • Jabado N; 1] Division of Experimental Medicine, Montreal Children's Hospital, McGill University and McGill University Health Centre, Montreal, Quebec, Canada. [2] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [3] Department of Pediatrics, McGill University, Montreal, Quebec, Canad
  • Kieran MW; 1] Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3] Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA. [4].
Nat Genet ; 46(5): 462-6, 2014 May.
Article in En | MEDLINE | ID: mdl-24705250
ABSTRACT
Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Astrocytoma / Brain Neoplasms / Gene Expression Regulation, Neoplastic / Genome, Human / Activin Receptors, Type I / Mutation Limits: Animals / Child / Humans Language: En Journal: Nat Genet Journal subject: GENETICA MEDICA Year: 2014 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Astrocytoma / Brain Neoplasms / Gene Expression Regulation, Neoplastic / Genome, Human / Activin Receptors, Type I / Mutation Limits: Animals / Child / Humans Language: En Journal: Nat Genet Journal subject: GENETICA MEDICA Year: 2014 Document type: Article