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Nat Genet. 2014 May;46(5):462-6. doi: 10.1038/ng.2950. Epub 2014 Apr 6.

Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma.

Author information

1
1] Division of Experimental Medicine, Montreal Children's Hospital, McGill University and McGill University Health Centre, Montreal, Quebec, Canada. [2].
2
1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2].
3
1] Wellcome Trust Sanger Institute, Hinxton, UK. [2].
4
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
5
Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
6
1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2] Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
7
Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
8
Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
9
Department of Neurological Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois, USA.
10
Department of Pediatrics Hematology-Oncology, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois, USA.
11
Clinical Pediatric Neurosurgical Oncology, Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, USA.
12
Department of Pediatric Hematology-Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA.
13
1] Department of Neurosurgery, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA.
14
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
15
Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.
16
Department of Pediatrics, Hematology-Oncology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.
17
Department of Neurosurgery, Seattle Children's Hospital, Seattle, Washington, USA.
18
Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, Washington, USA.
19
Department of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA.
20
Department of Pediatric Hematology-Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
21
Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
22
Department of Hematology-Oncology, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.
23
Department of Pathology, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.
24
Department of Neurosurgery, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.
25
Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
26
2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary.
27
Department of Neurosurgery, Children's National Medical Center, Washington, DC, USA.
28
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
29
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
30
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.
31
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 Pathology, Boston Children's Hospital, Boston, Massachusetts, USA. [5].
32
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, Canada. [4].
33
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].

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.

PMID:
24705250
PMCID:
PMC4282994
DOI:
10.1038/ng.2950
[Indexed for MEDLINE]
Free PMC Article

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