title: Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas.
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.
authors: 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.
authors: Barbara S
authors: BS
authors: Paugh
authors: Xiaoyan
authors: X
authors: Zhu
authors: Chunxu
authors: C
authors: Qu
authors: Raelene
authors: R
authors: Endersby
authors: Alexander K
authors: AK
authors: Diaz
authors: Junyuan
authors: J
authors: Zhang
authors: Dorine A
authors: DA
authors: Bax
authors: Diana
authors: D
authors: Carvalho
authors: Rui M
authors: RM
authors: Reis
authors: Arzu
authors: A
authors: Onar-Thomas
authors: Alberto
authors: A
authors: Broniscer
authors: Cynthia
authors: C
authors: Wetmore
authors: Jinghui
authors: J
authors: Zhang
authors: Chris
authors: C
authors: Jones
authors: David W
authors: DW
authors: Ellison
authors: Suzanne J
authors: SJ
authors: Baker
mesh_terms: D000293:Adolescent; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D009154:Mutation; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D020796:Receptor, Platelet-Derived Growth Factor alpha
references: Oncogene. 2007 Sep 20;26(43):6289-96
references: 17438529
references: Cancer Res. 1998 Dec 1;58(23):5275-9
references: 9850047
references: Cancer Res. 2011 Jun 15;71(12):4106-16
references: 21507933
references: Genes Dev. 2010 Oct 1;24(19):2205-18
references: 20889717
references: Cancer. 2009 Dec 15;115(24):5761-70
references: 19813274
references: Nature. 2009 Nov 5;462(7269):108-12
references: 19847166
references: Mol Cell Biol. 2007 Nov;27(22):7918-34
references: 17875932
references: Glia. 2011 Aug;59(8):1155-68
references: 21305617
references: J Neurosurg. 2006 Nov;105(5 Suppl):418-24
references: 17328268
references: Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):11011-6
references: 16046538
references: Science. 1998 Jan 23;279(5350):577-80
references: 9438854
references: Genes Dev. 2012 Dec 1;26(23):2561-6
references: 23152448
references: Cancer Res. 2003 Aug 1;63(15):4305-9
references: 12907595
references: Cancer Discov. 2012 May;2(5):458-71
references: 22588883
references: Biostatistics. 2007 Jan;8(1):118-27
references: 16632515
references: Clin Cancer Res. 2010 Jul 1;16(13):3368-77
references: 20570930
references: Mol Cell Biol. 1996 Dec;16(12):6926-36
references: 8943348
references: Cancer Cell. 2010 Jan 19;17(1):98-110
references: 20129251
references: Science. 2008 Sep 26;321(5897):1807-12
references: 18772396
references: J Clin Oncol. 2005 Aug 10;23(23):5357-64
references: 15928335
references: Acta Neuropathol. 2007 Aug;114(2):97-109
references: 17618441
references: Mol Cell Biol. 1991 Jul;11(7):3780-5
references: 1646396
references: Clin Cancer Res. 2012 Aug 15;18(16):4375-84
references: 22745105
references: Tohoku J Exp Med. 1992 Oct;168(2):265-9
references: 1306311
references: Mol Cell. 2004 Feb 13;13(3):341-55
references: 14967142
references: Cancer Cell. 2002 Apr;1(3):269-77
references: 12086863
references: J Child Neurol. 2008 Oct;23(10):1149-59
references: 18952581
references: J Clin Oncol. 2010 Mar 10;28(8):1337-44
references: 20142589
references: J Neurosci. 2008 Jan 2;28(1):264-78
references: 18171944
references: Blood. 1999 Jan 15;93(2):488-99
references: 9885210
references: J Clin Oncol. 2011 Oct 20;29(30):3999-4006
references: 21931021
references: Neuron. 2006 Jul 20;51(2):187-99
references: 16846854
references: Nat Genet. 2012 Jan 29;44(3):251-3
references: 22286216
references: J Clin Invest. 2011 Mar;121(3):905-17
references: 21393858
references: Oncogene. 2009 Jun 11;28(23):2266-75
references: 19421151
references: Genes Dev. 2007 Nov 1;21(21):2683-710
references: 17974913
references: Cancer Cell. 2011 Mar 8;19(3):305-16
references: 21397855
references: Cancer Cell. 2011 Jan 18;19(1):11-5
references: 21251612
references: Genes Dev. 2001 Aug 1;15(15):1913-25
references: 11485986
references: J Clin Oncol. 2010 Jun 20;28(18):3061-8
references: 20479398
references: Clin Cancer Res. 2008 May 15;14(10):2895-9
references: 18483355
references: PLoS One. 2012;7(2):e30313
references: 22389665
references: Biochim Biophys Acta. 2010 Mar;1798(3):605-15
references: 20036637
references: J Clin Oncol. 2009 Nov 1;27(31):5262-9
references: 19738123
references: Front Oncol. 2012 Dec 28;2:205
references: 23293772
references: Nature. 2008 Oct 23;455(7216):1061-8
references: 18772890
references: Am J Surg Pathol. 2004 Jul;28(7):889-94
references: 15223958
references: Nature. 2012 Jan 29;482(7384):226-31
references: 22286061
references: Cancer Cell. 2006 Mar;9(3):157-73
references: 16530701
references: J Biol Chem. 2002 Oct 11;277(41):38627-34
references: 12181311
references: J Med Chem. 2004 Dec 30;47(27):6658-61
references: 15615512
references: PLoS One. 2011;6(5):e20041
references: 21625383
references: Cancer Res. 2010 Mar 15;70(6):2548-57
references: 20197468
references: Biochim Biophys Acta. 1998 Aug 19;1378(1):F79-113
references: 9739761
references: Genes Dev. 2008 May 15;22(10):1276-312
references: 18483217