title: Recurrent PTPRB and PLCG1 mutations in angiosarcoma.
abstract: Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionizing radiation or chronic lymphoedema. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signaling genes, as a key driver of angiosarcoma. Here we employed whole-genome, whole-exome and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harbored predominantly truncating mutations in 10 of 39 tumors (26%). PLCG1, a signal transducer of tyrosine kinases, encoded a recurrent, likely activating p.Arg707Gln missense variant in 3 of 34 cases (9%). Overall, 15 of 39 tumors (38%) harbored at least one driver mutation in angiogenesis signaling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signaling in angiosarcoma.
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.|Department of Paediatrics, University of Cambridge, Hills Road, Cambridge, CB2 2XY, UK.
authors.forename: Sam
authors.initials: S
authors.lastname: Behjati
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Tarpey
authors.affiliation: The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Sheldon
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Inigo
authors.initials: I
authors.lastname: Martincorena
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.|Human Genome Laboratory, Department of Human Genetics, VIB and KU Leuven, B-3000 Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Van Loo
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Gunes
authors.initials: G
authors.lastname: Gundem
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Wedge
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Manasa
authors.initials: M
authors.lastname: Ramakrishna
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Susanna L
authors.initials: SL
authors.lastname: Cooke
authors.affiliation: Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK.|University College London Cancer Institute, Huntley Street, London, WC1E 6BT, UK.
authors.forename: Nischalan
authors.initials: N
authors.lastname: Pillay
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.|Department of Oncology, Oslo University Hospital, N-0310 Oslo, Norway.|The K.G. Jebsen Center for Breast Cancer Research, University of Oslo, N-0424 Oslo, Norway.
authors.forename: Hans Kristian M
authors.initials: HKM
authors.lastname: Vollan
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Elli
authors.initials: E
authors.lastname: Papaemmanuil
authors.affiliation: Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK.|Division of Molecular Structure, MRC-National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Hans
authors.initials: H
authors.lastname: Koss
authors.affiliation: Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK.
authors.forename: Tom D
authors.initials: TD
authors.lastname: Bunney
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Hardy
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Olivia R
authors.initials: OR
authors.lastname: Joseph
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Sancha
authors.initials: S
authors.lastname: Martin
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Mudie
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Butler
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Jon W
authors.initials: JW
authors.lastname: Teague
authors.affiliation: Department of Pathology, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
authors.forename: Meena
authors.initials: M
authors.lastname: Patil
authors.affiliation: Department of Pathology, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Steers
authors.affiliation: M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.affiliation: M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Gumbs
authors.affiliation: M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA.
authors.forename: Davis
authors.initials: D
authors.lastname: Ingram
authors.affiliation: M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA.
authors.forename: Latasha
authors.initials: L
authors.lastname: Little
authors.affiliation: M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA.
authors.forename: Harshad
authors.initials: H
authors.lastname: Mahadeshwar
authors.affiliation: M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA.
authors.forename: Alexei
authors.initials: A
authors.lastname: Protopopov
authors.affiliation: M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA.
authors.forename: Ghadah A
authors.initials: GA
authors.lastname: Al Sannaa
authors.affiliation: M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA.
authors.forename: Sahil
authors.initials: S
authors.lastname: Seth
authors.affiliation: M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA.
authors.forename: Xingzhi
authors.initials: X
authors.lastname: Song
authors.affiliation: M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA.
authors.forename: Jiabin
authors.initials: J
authors.lastname: Tang
authors.affiliation: M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA.
authors.forename: Vinod
authors.initials: V
authors.lastname: Ravi
authors.affiliation: M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA.
authors.forename: Keila E
authors.initials: KE
authors.lastname: Torres
authors.affiliation: Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK.
authors.forename: Bhavisha
authors.initials: B
authors.lastname: Khatri
authors.affiliation: Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK.
authors.forename: Dina
authors.initials: D
authors.lastname: Halai
authors.affiliation: Department of Pathology, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Roxanis
authors.affiliation: Bone Tumour Reference Centre, Institute of Pathology, University Hospital Basel, Basel, Institute for Applied Cancer Science, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Baumhoer
authors.affiliation: Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK.
authors.forename: Roberto
authors.initials: R
authors.lastname: Tirabosco
authors.affiliation: Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK.
authors.forename: M Fernanda
authors.initials: MF
authors.lastname: Amary
authors.affiliation: University College London Cancer Institute, Huntley Street, London, WC1E 6BT, UK.|Pfizer Oncology, 10555 Science Center Dr, La Jolla, CA, 92121.
authors.forename: Chris
authors.initials: C
authors.lastname: Boshoff
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.affiliation: Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK.
authors.forename: Matilda
authors.initials: M
authors.lastname: Katan
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.|M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA.
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.affiliation: Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK.|University College London Cancer Institute, Huntley Street, London, WC1E 6BT, UK.
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Flanagan
authors.affiliation: The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.|Department of Pathology, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Harris
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.|Department of Haematology, Addenbrooke's Hospital, Cambridge, UK.|Department of Haematology, University of Cambridge, Hills Road, Cambridge, CB2 2XY, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
mesh_terms: D000704:Analysis of Variance; D001483:Base Sequence; D059472:Exome / Q000235:genetics; D006394:Hemangiosarcoma / Q000188:drug therapy* / Q000235:genetics*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics; D051966:Phospholipase C gamma / Q000235:genetics*; D034622:RNA Interference; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000235:genetics*; D017423:Sequence Analysis, RNA; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C516886:PTPRB protein, human; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; C522157:PLCG1 protein, human; D051966:Phospholipase C gamma