Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas

The outcome for children with high-grade gliomas (HGG) remains dismal, with a 2-year survival rate of only 10% to 30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in the brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previousl...

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Vydáno v:	Cancer research (Chicago, Ill.) Ročník 73; číslo 20; s. 6219
Hlavní autoři:	Paugh, Barbara S, Zhu, Xiaoyan, Qu, Chunxu, Endersby, Raelene, Diaz, Alexander K, Zhang, Junyuan, Bax, Dorine A, Carvalho, Diana, Reis, Rui M, Onar-Thomas, Arzu, Broniscer, Alberto, Wetmore, Cynthia, Zhang, Jinghui, Jones, Chris, Ellison, David W, Baker, Suzanne J
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 15.10.2013
Témata:	Adolescent Animals Brain Neoplasms - genetics Brain Neoplasms - pathology Child Child, Preschool Gene Expression Profiling Genome-Wide Association Study Glioma - genetics Glioma - pathology Humans Mice Mutation Receptor, Platelet-Derived Growth Factor alpha - genetics Receptor, Platelet-Derived Growth Factor alpha - metabolism
ISSN:	1538-7445, 1538-7445
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Abstract	The outcome for children with high-grade gliomas (HGG) remains dismal, with a 2-year survival rate of only 10% to 30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in the brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet-derived growth factor receptor α (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs. To determine whether PDGFRA is also targeted by more subtle mutations missed by copy number analysis, we sequenced all PDGFRA coding exons from a cohort of pediatric HGGs. Somatic-activating mutations were identified in 14.4% (13 of 90) of nonbrainstem pediatric HGGs and 4.7% (2 of 43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. Forty percent of tumors with mutation showed concurrent amplification, whereas 60% carried heterozygous mutations. Six different mutations impacting different domains all resulted in ligand-independent receptor activation that was blocked by small molecule inhibitors of PDGFR. Expression of mutants in p53-null primary mouse astrocytes conferred a proliferative advantage in vitro and generated HGGs in vivo with complete penetrance when implanted into brain. The gene expression signatures of these murine HGGs reflected the spectrum of human diffuse HGGs. PDGFRA intragenic deletion of exons 8 and 9 were previously shown in adult HGG, but were not detected in 83 nonbrainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFRα in childhood HGG.
AbstractList	The outcome for children with high-grade gliomas (HGG) remains dismal, with a 2-year survival rate of only 10% to 30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in the brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet-derived growth factor receptor α (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs. To determine whether PDGFRA is also targeted by more subtle mutations missed by copy number analysis, we sequenced all PDGFRA coding exons from a cohort of pediatric HGGs. Somatic-activating mutations were identified in 14.4% (13 of 90) of nonbrainstem pediatric HGGs and 4.7% (2 of 43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. Forty percent of tumors with mutation showed concurrent amplification, whereas 60% carried heterozygous mutations. Six different mutations impacting different domains all resulted in ligand-independent receptor activation that was blocked by small molecule inhibitors of PDGFR. Expression of mutants in p53-null primary mouse astrocytes conferred a proliferative advantage in vitro and generated HGGs in vivo with complete penetrance when implanted into brain. The gene expression signatures of these murine HGGs reflected the spectrum of human diffuse HGGs. PDGFRA intragenic deletion of exons 8 and 9 were previously shown in adult HGG, but were not detected in 83 nonbrainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFRα in childhood HGG.The outcome for children with high-grade gliomas (HGG) remains dismal, with a 2-year survival rate of only 10% to 30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in the brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet-derived growth factor receptor α (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs. To determine whether PDGFRA is also targeted by more subtle mutations missed by copy number analysis, we sequenced all PDGFRA coding exons from a cohort of pediatric HGGs. Somatic-activating mutations were identified in 14.4% (13 of 90) of nonbrainstem pediatric HGGs and 4.7% (2 of 43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. Forty percent of tumors with mutation showed concurrent amplification, whereas 60% carried heterozygous mutations. Six different mutations impacting different domains all resulted in ligand-independent receptor activation that was blocked by small molecule inhibitors of PDGFR. Expression of mutants in p53-null primary mouse astrocytes conferred a proliferative advantage in vitro and generated HGGs in vivo with complete penetrance when implanted into brain. The gene expression signatures of these murine HGGs reflected the spectrum of human diffuse HGGs. PDGFRA intragenic deletion of exons 8 and 9 were previously shown in adult HGG, but were not detected in 83 nonbrainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFRα in childhood HGG. The outcome for children with high-grade gliomas (HGG) remains dismal, with a 2-year survival rate of only 10% to 30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in the brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet-derived growth factor receptor α (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs. To determine whether PDGFRA is also targeted by more subtle mutations missed by copy number analysis, we sequenced all PDGFRA coding exons from a cohort of pediatric HGGs. Somatic-activating mutations were identified in 14.4% (13 of 90) of nonbrainstem pediatric HGGs and 4.7% (2 of 43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. Forty percent of tumors with mutation showed concurrent amplification, whereas 60% carried heterozygous mutations. Six different mutations impacting different domains all resulted in ligand-independent receptor activation that was blocked by small molecule inhibitors of PDGFR. Expression of mutants in p53-null primary mouse astrocytes conferred a proliferative advantage in vitro and generated HGGs in vivo with complete penetrance when implanted into brain. The gene expression signatures of these murine HGGs reflected the spectrum of human diffuse HGGs. PDGFRA intragenic deletion of exons 8 and 9 were previously shown in adult HGG, but were not detected in 83 nonbrainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFRα in childhood HGG.
Author	Diaz, Alexander K Paugh, Barbara S Carvalho, Diana Jones, Chris Baker, Suzanne J Onar-Thomas, Arzu Broniscer, Alberto Qu, Chunxu Zhang, Jinghui Endersby, Raelene Zhang, Junyuan Ellison, David W Bax, Dorine A Wetmore, Cynthia Reis, Rui M Zhu, Xiaoyan
Author_xml	– sequence: 1 givenname: Barbara S surname: Paugh fullname: Paugh, Barbara S organization: Authors' Affiliations: Departments of Developmental Neurobiology, Computational Biology, Biostatistics, Oncology, and Pathology, St. Jude Children's Research Hospital; Interdisciplinary Biomedical Science Program, University of Tennessee Health Sciences Center, Memphis, Tennessee; Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, Australia; Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom; and Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil – sequence: 2 givenname: Xiaoyan surname: Zhu fullname: Zhu, Xiaoyan – sequence: 3 givenname: Chunxu surname: Qu fullname: Qu, Chunxu – sequence: 4 givenname: Raelene surname: Endersby fullname: Endersby, Raelene – sequence: 5 givenname: Alexander K surname: Diaz fullname: Diaz, Alexander K – sequence: 6 givenname: Junyuan surname: Zhang fullname: Zhang, Junyuan – sequence: 7 givenname: Dorine A surname: Bax fullname: Bax, Dorine A – sequence: 8 givenname: Diana surname: Carvalho fullname: Carvalho, Diana – sequence: 9 givenname: Rui M surname: Reis fullname: Reis, Rui M – sequence: 10 givenname: Arzu surname: Onar-Thomas fullname: Onar-Thomas, Arzu – sequence: 11 givenname: Alberto surname: Broniscer fullname: Broniscer, Alberto – sequence: 12 givenname: Cynthia surname: Wetmore fullname: Wetmore, Cynthia – sequence: 13 givenname: Jinghui surname: Zhang fullname: Zhang, Jinghui – sequence: 14 givenname: Chris surname: Jones fullname: Jones, Chris – sequence: 15 givenname: David W surname: Ellison fullname: Ellison, David W – sequence: 16 givenname: Suzanne J surname: Baker fullname: Baker, Suzanne J
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/23970477$$D View this record in MEDLINE/PubMed
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Snippet	The outcome for children with high-grade gliomas (HGG) remains dismal, with a 2-year survival rate of only 10% to 30%. Diffuse intrinsic pontine glioma (DIPG)...
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SubjectTerms	Adolescent Animals Brain Neoplasms - genetics Brain Neoplasms - pathology Child Child, Preschool Gene Expression Profiling Genome-Wide Association Study Glioma - genetics Glioma - pathology Humans Mice Mutation Receptor, Platelet-Derived Growth Factor alpha - genetics Receptor, Platelet-Derived Growth Factor alpha - metabolism
Title	Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas
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