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Title[redir]:
Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma | Nature Genetics
Description:
Nada Jabado and colleagues report identification of gain-of-function mutations in ACVR1, which encodes activin A receptor type I, in midline pediatric high-grade astrocytomas. 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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Keywords {🔍}
article, google, scholar, cas, department, pediatric, usa, nature, mutations, university, cancer, childrens, hospital, highgrade, gliomas, mutation, research, boston, supplementary, acvr, histone, access, diffuse, mcgill, montreal, data, midline, canada, authors, tumor, ligon, content, tumors, signaling, nat, quebec, massachusetts, bmp, genes, methylation, pontine, genet, receptor, biol, centre, supported, fund, center, values, cookies,
Topics {✒️}
nature portfolio permissions reprints privacy policy pediatric low-grade gliomas midline high-grade astrocytomas advertising nature 482 nature 455 nature high-throughput sequencing data patient high-grade tumors social media library preparation endogenous gene expression canada research chair brain-specific dnmt3b isoform cell-cycle regulatory genes tumor rna-seq data bone morphogenetic protein regulates β-catenin activity gehan-breslow-wilcoxon testing hedgehog-responsive candidate cell dana-farber cancer institute tgfβ-smad signal transduction cancer research pierre-olivier fiset acvr1 developmental pathway fibrodysplasia ossificans progressiva sequence alignment/map format development fund rosette-forming glioneuronal tumors health research springerlink instant access research fund national research gene fusion discovery permissions content acvr1 mutations transcription factor mybl1 development 139 recurrent somatic alterations chromatin remodelling genes dna methylation profiles global dna methylation human genetics pediatric neuro-oncology bmp receptor signaling recurrent somatic mutations cedars cancer institute pontine area based
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headline:Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma
description:Nada Jabado and colleagues report identification of gain-of-function mutations in ACVR1, which encodes activin A receptor type I, in midline pediatric high-grade astrocytomas. 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.
datePublished:2014-04-06T00:00:00Z
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Genomics
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Cancer Research
Agriculture
Gene Function
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headline:Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma
description:Nada Jabado and colleagues report identification of gain-of-function mutations in ACVR1, which encodes activin A receptor type I, in midline pediatric high-grade astrocytomas. 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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CNS cancer
Genomics
Biomedicine
general
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Cancer Research
Agriculture
Gene Function
Animal Genetics and Genomics
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affiliation:
name:Medical and Health Science Center, University of Debrecen
address:
name:Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
type:PostalAddress
type:Organization
name:Peter Hauser
affiliation:
name:Semmelweis University
address:
name:2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary
type:PostalAddress
type:Organization
name:Miklos Garami
affiliation:
name:Semmelweis University
address:
name:2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary
type:PostalAddress
type:Organization
name:John Myseros
affiliation:
name:Childrenâ²s National Medical Center
address:
name:Department of Neurosurgery, Childrenâ²s National Medical Center, Washington, USA
type:PostalAddress
type:Organization
name:Zhifeng Dong
affiliation:
name:Rosalind and Morris Goodman Cancer Research Centre, McGill University
address:
name:Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Canada
type:PostalAddress
type:Organization
name:Peter M Siegel
url:http://orcid.org/0000-0002-5568-6586
affiliation:
name:Rosalind and Morris Goodman Cancer Research Centre, McGill University
address:
name:Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Canada
type:PostalAddress
type:Organization
name:Hayley Malkin
affiliation:
name:Dana-Farber Cancer Institute
address:
name:Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, USA
type:PostalAddress
type:Organization
name:Azra H Ligon
affiliation:
name:Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute
address:
name:Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, USA
type:PostalAddress
type:Organization
name:Harvard Medical School
address:
name:Harvard Medical School, Boston, USA
type:PostalAddress
type:Organization
name:Brigham and Womenâ²s Hospital
address:
name:Department of Pathology, Brigham and Womenâ²s Hospital, Boston, USA
type:PostalAddress
type:Organization
name:Steffen Albrecht
affiliation:
name:Montreal Childrenâ²s Hospital, McGill University Health Centre
address:
name:Department of Pathology, Montreal Childrenâ²s Hospital, McGill University Health Centre, Montreal, Canada
type:PostalAddress
type:Organization
name:Stefan M Pfister
affiliation:
name:German Cancer Research Center (DKFZ)
address:
name:Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
type:PostalAddress
type:Organization
name:Keith L Ligon
affiliation:
name:Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute
address:
name:Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, USA
type:PostalAddress
type:Organization
name:Harvard Medical School
address:
name:Harvard Medical School, Boston, USA
type:PostalAddress
type:Organization
name:Brigham and Womenâ²s Hospital
address:
name:Department of Pathology, Brigham and Womenâ²s Hospital, Boston, USA
type:PostalAddress
type:Organization
name:Boston Childrenâ²s Hospital
address:
name:Department of Pathology, Boston Childrenâ²s Hospital, Boston, USA
type:PostalAddress
type:Organization
email:[email protected]
name:Jacek Majewski
affiliation:
name:McGill University
address:
name:Department of Human Genetics, McGill University, Montreal, Canada
type:PostalAddress
type:Organization
email:[email protected]
name:Nada Jabado
affiliation:
name:Montreal Childrenâ²s Hospital, McGill University and McGill University Health Centre
address:
name:Division of Experimental Medicine, Montreal Childrenâ²s Hospital, McGill University and McGill University Health Centre, Montreal, Canada
type:PostalAddress
type:Organization
name:McGill University
address:
name:Department of Human Genetics, McGill University, Montreal, Canada
type:PostalAddress
type:Organization
name:McGill University
address:
name:Department of Pediatrics, McGill University, Montreal, Canada
type:PostalAddress
type:Organization
email:[email protected]
name:Mark W Kieran
affiliation:
name:Harvard Medical School
address:
name:Harvard Medical School, Boston, USA
type:PostalAddress
type:Organization
name:Dana-Farber Cancer Institute
address:
name:Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, USA
type:PostalAddress
type:Organization
name:Boston Childrenâ²s Hospital
address:
name:Division of Pediatric Hematology/Oncology, Boston Childrenâ²s Hospital, Boston, USA
type:PostalAddress
type:Organization
email:[email protected]
PostalAddress:
name:Division of Experimental Medicine, Montreal Childrenâ²s Hospital, McGill University and McGill University Health Centre, Montreal, Canada
name:Department of Human Genetics, McGill University, Montreal, Canada
name:Wellcome Trust Sanger Institute, Hinxton, UK
name:Department of Human Genetics, McGill University, Montreal, Canada
name:Department of Human Genetics, McGill University, Montreal, Canada
name:Department of Pathology, Montreal Childrenâ²s Hospital, McGill University Health Centre, Montreal, Canada
name:Department of Human Genetics, McGill University, Montreal, Canada
name:Department of Human Genetics, McGill University, Montreal, Canada
name:Department of Pediatrics, McGill University, Montreal, Canada
name:Department of Human Genetics, McGill University, Montreal, Canada
name:Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, USA
name:Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, USA
name:Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
name:Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
name:Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
name:Department of Neurological Surgery, Ann & Robert H. Lurie Childrenâ²s Hospital of Chicago, Northwestern University, Chicago, USA
name:Department of Pediatrics Hematology-Oncology, Ann & Robert H. Lurie Childrenâ²s Hospital of Chicago, Northwestern University, Chicago, USA
name:Department of Surgery, Clinical Pediatric Neurosurgical Oncology, Boston Childrenâ²s Hospital, Boston, USA
name:Department of Pediatric Hematology-Oncology, Childrenâ²s Hospitals and Clinics of Minnesota, Minneapolis, USA
name:Department of Neurosurgery, Boston Childrenâ²s Hospital, Boston, USA
name:Harvard Medical School, Boston, USA
name:Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, USA
name:Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, USA
name:Department of Pediatrics, Hematology-Oncology, Washington University School of Medicine in St. Louis, St. Louis, USA
name:Department of Neurological Surgery, Ann & Robert H. Lurie Childrenâ²s Hospital of Chicago, Northwestern University, Chicago, USA
name:Department of Neurosurgery, Seattle Childrenâ²s Hospital, Seattle, USA
name:Cancer and Blood Disorders Center, Seattle Childrenâ²s Hospital, Seattle, USA
name:Cancer and Blood Disorders Center, Seattle Childrenâ²s Hospital, Seattle, USA
name:Department of Neurological Surgery, Johns Hopkins Hospital, Baltimore, USA
name:Department of Pediatric Hematology-Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, USA
name:Department of Neurological Surgery, University of California, San Francisco, San Francisco, USA
name:Department of Neurological Surgery, University of California, San Francisco, San Francisco, USA
name:Department of Hematology-Oncology, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Canada
name:Department of Pathology, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Canada
name:Department of Neurosurgery, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Canada
name:Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
name:Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary
name:2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary
name:2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary
name:Department of Neurosurgery, Childrenâ²s National Medical Center, Washington, USA
name:Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Canada
name:Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Canada
name:Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, USA
name:Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, USA
name:Harvard Medical School, Boston, USA
name:Department of Pathology, Brigham and Womenâ²s Hospital, Boston, USA
name:Department of Pathology, Montreal Childrenâ²s Hospital, McGill University Health Centre, Montreal, Canada
name:Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
name:Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, USA
name:Harvard Medical School, Boston, USA
name:Department of Pathology, Brigham and Womenâ²s Hospital, Boston, USA
name:Department of Pathology, Boston Childrenâ²s Hospital, Boston, USA
name:Department of Human Genetics, McGill University, Montreal, Canada
name:Division of Experimental Medicine, Montreal Childrenâ²s Hospital, McGill University and McGill University Health Centre, Montreal, Canada
name:Department of Human Genetics, McGill University, Montreal, Canada
name:Department of Pediatrics, McGill University, Montreal, Canada
name:Harvard Medical School, Boston, USA
name:Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, USA
name:Division of Pediatric Hematology/Oncology, Boston Childrenâ²s Hospital, Boston, USA
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