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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Recurrent <italic>PTPRB</italic> and <italic>PLCG1</italic> mutations in angiosarcoma</title><author><name sortKey="Behjati, Sam" sort="Behjati, Sam" uniqKey="Behjati S" first="Sam" last="Behjati">Sam Behjati</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Department of Paediatrics, University of Cambridge, Hills Road, Cambridge, CB2 2XY, UK</nlm:aff></affiliation></author><author><name sortKey="Tarpey, Patrick S" sort="Tarpey, Patrick S" uniqKey="Tarpey P" first="Patrick S" last="Tarpey">Patrick S. Tarpey</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Sheldon, Helen" sort="Sheldon, Helen" uniqKey="Sheldon H" first="Helen" last="Sheldon">Helen Sheldon</name><affiliation><nlm:aff id="A3">The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK</nlm:aff></affiliation></author><author><name sortKey="Martincorena, Inigo" sort="Martincorena, Inigo" uniqKey="Martincorena I" first="Inigo" last="Martincorena">Inigo Martincorena</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Van Loo, Peter" sort="Van Loo, Peter" uniqKey="Van Loo P" first="Peter" last="Van Loo">Peter Van Loo</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Human Genome Laboratory, Department of Human Genetics, VIB and KU Leuven, B-3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Gundem, Gunes" sort="Gundem, Gunes" uniqKey="Gundem G" first="Gunes" last="Gundem">Gunes Gundem</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Wedge, David C" sort="Wedge, David C" uniqKey="Wedge D" first="David C" last="Wedge">David C. Wedge</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Ramakrishna, Manasa" sort="Ramakrishna, Manasa" uniqKey="Ramakrishna M" first="Manasa" last="Ramakrishna">Manasa Ramakrishna</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Cooke, Susanna L" sort="Cooke, Susanna L" uniqKey="Cooke S" first="Susanna L" last="Cooke">Susanna L. Cooke</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Pillay, Nischalan" sort="Pillay, Nischalan" uniqKey="Pillay N" first="Nischalan" last="Pillay">Nischalan Pillay</name><affiliation><nlm:aff id="A5">Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A6">University College London Cancer Institute, Huntley Street, London, WC1E 6BT, UK</nlm:aff></affiliation></author><author><name sortKey="Vollan, Hans Kristian M" sort="Vollan, Hans Kristian M" uniqKey="Vollan H" first="Hans Kristian M" last="Vollan">Hans Kristian M. Vollan</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A7">Department of Oncology, Oslo University Hospital, N-0310 Oslo, Norway</nlm:aff></affiliation><affiliation><nlm:aff id="A8">The K.G. Jebsen Center for Breast Cancer Research, University of Oslo, N-0424 Oslo, Norway</nlm:aff></affiliation></author><author><name sortKey="Papaemmanuil, Elli" sort="Papaemmanuil, Elli" uniqKey="Papaemmanuil E" first="Elli" last="Papaemmanuil">Elli Papaemmanuil</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Koss, Hans" sort="Koss, Hans" uniqKey="Koss H" first="Hans" last="Koss">Hans Koss</name><affiliation><nlm:aff id="A9">Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A10">Division of Molecular Structure, MRC-National Institute for Medical Research, Mill Hill, London NW7 1AA, UK</nlm:aff></affiliation></author><author><name sortKey="Bunney, Tom D" sort="Bunney, Tom D" uniqKey="Bunney T" first="Tom D" last="Bunney">Tom D. Bunney</name><affiliation><nlm:aff id="A9">Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK</nlm:aff></affiliation></author><author><name sortKey="Hardy, Claire" sort="Hardy, Claire" uniqKey="Hardy C" first="Claire" last="Hardy">Claire Hardy</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Joseph, Olivia R" sort="Joseph, Olivia R" uniqKey="Joseph O" first="Olivia R" last="Joseph">Olivia R. Joseph</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Martin, Sancha" sort="Martin, Sancha" uniqKey="Martin S" first="Sancha" last="Martin">Sancha Martin</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Mudie, Laura" sort="Mudie, Laura" uniqKey="Mudie L" first="Laura" last="Mudie">Laura Mudie</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Butler, Adam" sort="Butler, Adam" uniqKey="Butler A" first="Adam" last="Butler">Adam Butler</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Teague, Jon W" sort="Teague, Jon W" uniqKey="Teague J" first="Jon W" last="Teague">Jon W. Teague</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Patil, Meena" sort="Patil, Meena" uniqKey="Patil M" first="Meena" last="Patil">Meena Patil</name><affiliation><nlm:aff id="A11">Department of Pathology, John Radcliffe Hospital, Oxford, OX3 9DS, UK</nlm:aff></affiliation></author><author><name sortKey="Steers, Graham" sort="Steers, Graham" uniqKey="Steers G" first="Graham" last="Steers">Graham Steers</name><affiliation><nlm:aff id="A11">Department of Pathology, John Radcliffe Hospital, Oxford, OX3 9DS, UK</nlm:aff></affiliation></author><author><name sortKey="Cao, Yu" sort="Cao, Yu" uniqKey="Cao Y" first="Yu" last="Cao">Yu Cao</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Gumbs, Curtis" sort="Gumbs, Curtis" uniqKey="Gumbs C" first="Curtis" last="Gumbs">Curtis Gumbs</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Ingram, Davis" sort="Ingram, Davis" uniqKey="Ingram D" first="Davis" last="Ingram">Davis Ingram</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Lazar, Alexander J" sort="Lazar, Alexander J" uniqKey="Lazar A" first="Alexander J" last="Lazar">Alexander J. Lazar</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Little, Latasha" sort="Little, Latasha" uniqKey="Little L" first="Latasha" last="Little">Latasha Little</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Mahadeshwar, Harshad" sort="Mahadeshwar, Harshad" uniqKey="Mahadeshwar H" first="Harshad" last="Mahadeshwar">Harshad Mahadeshwar</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Protopopov, Alexei" sort="Protopopov, Alexei" uniqKey="Protopopov A" first="Alexei" last="Protopopov">Alexei Protopopov</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Al Sannaa, Ghadah A" sort="Al Sannaa, Ghadah A" uniqKey="Al Sannaa G" first="Ghadah A" last="Al Sannaa">Ghadah A. Al Sannaa</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Seth, Sahil" sort="Seth, Sahil" uniqKey="Seth S" first="Sahil" last="Seth">Sahil Seth</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Song, Xingzhi" sort="Song, Xingzhi" uniqKey="Song X" first="Xingzhi" last="Song">Xingzhi Song</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Tang, Jiabin" sort="Tang, Jiabin" uniqKey="Tang J" first="Jiabin" last="Tang">Jiabin Tang</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Zhang, Jianhua" sort="Zhang, Jianhua" uniqKey="Zhang J" first="Jianhua" last="Zhang">Jianhua Zhang</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Ravi, Vinod" sort="Ravi, Vinod" uniqKey="Ravi V" first="Vinod" last="Ravi">Vinod Ravi</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Torres, Keila E" sort="Torres, Keila E" uniqKey="Torres K" first="Keila E" last="Torres">Keila E. Torres</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Khatri, Bhavisha" sort="Khatri, Bhavisha" uniqKey="Khatri B" first="Bhavisha" last="Khatri">Bhavisha Khatri</name><affiliation><nlm:aff id="A5">Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK</nlm:aff></affiliation></author><author><name sortKey="Halai, Dina" sort="Halai, Dina" uniqKey="Halai D" first="Dina" last="Halai">Dina Halai</name><affiliation><nlm:aff id="A5">Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK</nlm:aff></affiliation></author><author><name sortKey="Roxanis, Ioannis" sort="Roxanis, Ioannis" uniqKey="Roxanis I" first="Ioannis" last="Roxanis">Ioannis Roxanis</name><affiliation><nlm:aff id="A11">Department of Pathology, John Radcliffe Hospital, Oxford, OX3 9DS, UK</nlm:aff></affiliation></author><author><name sortKey="Baumhoer, Daniel" sort="Baumhoer, Daniel" uniqKey="Baumhoer D" first="Daniel" last="Baumhoer">Daniel Baumhoer</name><affiliation><nlm:aff id="A13">Bone Tumour Reference Centre, Institute of Pathology, University Hospital Basel, Basel, Institute for Applied Cancer Science, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Tirabosco, Roberto" sort="Tirabosco, Roberto" uniqKey="Tirabosco R" first="Roberto" last="Tirabosco">Roberto Tirabosco</name><affiliation><nlm:aff id="A5">Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK</nlm:aff></affiliation></author><author><name sortKey="Amary, M Fernanda" sort="Amary, M Fernanda" uniqKey="Amary M" first="M Fernanda" last="Amary">M Fernanda Amary</name><affiliation><nlm:aff id="A5">Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK</nlm:aff></affiliation></author><author><name sortKey="Boshoff, Chris" sort="Boshoff, Chris" uniqKey="Boshoff C" first="Chris" last="Boshoff">Chris Boshoff</name><affiliation><nlm:aff id="A6">University College London Cancer Institute, Huntley Street, London, WC1E 6BT, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A14">Pfizer Oncology, 10555 Science Center Dr, La Jolla, CA, 92121</nlm:aff></affiliation></author><author><name sortKey="Mcdermott, Ultan" sort="Mcdermott, Ultan" uniqKey="Mcdermott U" first="Ultan" last="Mcdermott">Ultan Mcdermott</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Katan, Matilda" sort="Katan, Matilda" uniqKey="Katan M" first="Matilda" last="Katan">Matilda Katan</name><affiliation><nlm:aff id="A9">Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK</nlm:aff></affiliation></author><author><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R" last="Stratton">Michael R. Stratton</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Futreal, P Andrew" sort="Futreal, P Andrew" uniqKey="Futreal P" first="P Andrew" last="Futreal">P Andrew Futreal</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Flanagan, Adrienne M" sort="Flanagan, Adrienne M" uniqKey="Flanagan A" first="Adrienne M" last="Flanagan">Adrienne M. Flanagan</name><affiliation><nlm:aff id="A5">Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A6">University College London Cancer Institute, Huntley Street, London, WC1E 6BT, UK</nlm:aff></affiliation></author><author><name sortKey="Harris, Adrian" sort="Harris, Adrian" uniqKey="Harris A" first="Adrian" last="Harris">Adrian Harris</name><affiliation><nlm:aff id="A3">The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A11">Department of Pathology, John Radcliffe Hospital, Oxford, OX3 9DS, UK</nlm:aff></affiliation></author><author><name sortKey="Campbell, Peter J" sort="Campbell, Peter J" uniqKey="Campbell P" first="Peter J" last="Campbell">Peter J. Campbell</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A15">Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A16">Department of Haematology, University of Cambridge, Hills Road, Cambridge, CB2 2XY, UK</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24633157</idno><idno type="pmc">4032873</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032873</idno><idno type="RBID">PMC:4032873</idno><idno type="doi">10.1038/ng.2921</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">004709</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">004709</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Recurrent <italic>PTPRB</italic> and <italic>PLCG1</italic> mutations in angiosarcoma</title><author><name sortKey="Behjati, Sam" sort="Behjati, Sam" uniqKey="Behjati S" first="Sam" last="Behjati">Sam Behjati</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Department of Paediatrics, University of Cambridge, Hills Road, Cambridge, CB2 2XY, UK</nlm:aff></affiliation></author><author><name sortKey="Tarpey, Patrick S" sort="Tarpey, Patrick S" uniqKey="Tarpey P" first="Patrick S" last="Tarpey">Patrick S. Tarpey</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Sheldon, Helen" sort="Sheldon, Helen" uniqKey="Sheldon H" first="Helen" last="Sheldon">Helen Sheldon</name><affiliation><nlm:aff id="A3">The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK</nlm:aff></affiliation></author><author><name sortKey="Martincorena, Inigo" sort="Martincorena, Inigo" uniqKey="Martincorena I" first="Inigo" last="Martincorena">Inigo Martincorena</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Van Loo, Peter" sort="Van Loo, Peter" uniqKey="Van Loo P" first="Peter" last="Van Loo">Peter Van Loo</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Human Genome Laboratory, Department of Human Genetics, VIB and KU Leuven, B-3000 Leuven, Belgium</nlm:aff></affiliation></author><author><name sortKey="Gundem, Gunes" sort="Gundem, Gunes" uniqKey="Gundem G" first="Gunes" last="Gundem">Gunes Gundem</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Wedge, David C" sort="Wedge, David C" uniqKey="Wedge D" first="David C" last="Wedge">David C. Wedge</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Ramakrishna, Manasa" sort="Ramakrishna, Manasa" uniqKey="Ramakrishna M" first="Manasa" last="Ramakrishna">Manasa Ramakrishna</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Cooke, Susanna L" sort="Cooke, Susanna L" uniqKey="Cooke S" first="Susanna L" last="Cooke">Susanna L. Cooke</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Pillay, Nischalan" sort="Pillay, Nischalan" uniqKey="Pillay N" first="Nischalan" last="Pillay">Nischalan Pillay</name><affiliation><nlm:aff id="A5">Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A6">University College London Cancer Institute, Huntley Street, London, WC1E 6BT, UK</nlm:aff></affiliation></author><author><name sortKey="Vollan, Hans Kristian M" sort="Vollan, Hans Kristian M" uniqKey="Vollan H" first="Hans Kristian M" last="Vollan">Hans Kristian M. Vollan</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A7">Department of Oncology, Oslo University Hospital, N-0310 Oslo, Norway</nlm:aff></affiliation><affiliation><nlm:aff id="A8">The K.G. Jebsen Center for Breast Cancer Research, University of Oslo, N-0424 Oslo, Norway</nlm:aff></affiliation></author><author><name sortKey="Papaemmanuil, Elli" sort="Papaemmanuil, Elli" uniqKey="Papaemmanuil E" first="Elli" last="Papaemmanuil">Elli Papaemmanuil</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Koss, Hans" sort="Koss, Hans" uniqKey="Koss H" first="Hans" last="Koss">Hans Koss</name><affiliation><nlm:aff id="A9">Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A10">Division of Molecular Structure, MRC-National Institute for Medical Research, Mill Hill, London NW7 1AA, UK</nlm:aff></affiliation></author><author><name sortKey="Bunney, Tom D" sort="Bunney, Tom D" uniqKey="Bunney T" first="Tom D" last="Bunney">Tom D. Bunney</name><affiliation><nlm:aff id="A9">Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK</nlm:aff></affiliation></author><author><name sortKey="Hardy, Claire" sort="Hardy, Claire" uniqKey="Hardy C" first="Claire" last="Hardy">Claire Hardy</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Joseph, Olivia R" sort="Joseph, Olivia R" uniqKey="Joseph O" first="Olivia R" last="Joseph">Olivia R. Joseph</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Martin, Sancha" sort="Martin, Sancha" uniqKey="Martin S" first="Sancha" last="Martin">Sancha Martin</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Mudie, Laura" sort="Mudie, Laura" uniqKey="Mudie L" first="Laura" last="Mudie">Laura Mudie</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Butler, Adam" sort="Butler, Adam" uniqKey="Butler A" first="Adam" last="Butler">Adam Butler</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Teague, Jon W" sort="Teague, Jon W" uniqKey="Teague J" first="Jon W" last="Teague">Jon W. Teague</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Patil, Meena" sort="Patil, Meena" uniqKey="Patil M" first="Meena" last="Patil">Meena Patil</name><affiliation><nlm:aff id="A11">Department of Pathology, John Radcliffe Hospital, Oxford, OX3 9DS, UK</nlm:aff></affiliation></author><author><name sortKey="Steers, Graham" sort="Steers, Graham" uniqKey="Steers G" first="Graham" last="Steers">Graham Steers</name><affiliation><nlm:aff id="A11">Department of Pathology, John Radcliffe Hospital, Oxford, OX3 9DS, UK</nlm:aff></affiliation></author><author><name sortKey="Cao, Yu" sort="Cao, Yu" uniqKey="Cao Y" first="Yu" last="Cao">Yu Cao</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Gumbs, Curtis" sort="Gumbs, Curtis" uniqKey="Gumbs C" first="Curtis" last="Gumbs">Curtis Gumbs</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Ingram, Davis" sort="Ingram, Davis" uniqKey="Ingram D" first="Davis" last="Ingram">Davis Ingram</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Lazar, Alexander J" sort="Lazar, Alexander J" uniqKey="Lazar A" first="Alexander J" last="Lazar">Alexander J. Lazar</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Little, Latasha" sort="Little, Latasha" uniqKey="Little L" first="Latasha" last="Little">Latasha Little</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Mahadeshwar, Harshad" sort="Mahadeshwar, Harshad" uniqKey="Mahadeshwar H" first="Harshad" last="Mahadeshwar">Harshad Mahadeshwar</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Protopopov, Alexei" sort="Protopopov, Alexei" uniqKey="Protopopov A" first="Alexei" last="Protopopov">Alexei Protopopov</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Al Sannaa, Ghadah A" sort="Al Sannaa, Ghadah A" uniqKey="Al Sannaa G" first="Ghadah A" last="Al Sannaa">Ghadah A. Al Sannaa</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Seth, Sahil" sort="Seth, Sahil" uniqKey="Seth S" first="Sahil" last="Seth">Sahil Seth</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Song, Xingzhi" sort="Song, Xingzhi" uniqKey="Song X" first="Xingzhi" last="Song">Xingzhi Song</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Tang, Jiabin" sort="Tang, Jiabin" uniqKey="Tang J" first="Jiabin" last="Tang">Jiabin Tang</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Zhang, Jianhua" sort="Zhang, Jianhua" uniqKey="Zhang J" first="Jianhua" last="Zhang">Jianhua Zhang</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Ravi, Vinod" sort="Ravi, Vinod" uniqKey="Ravi V" first="Vinod" last="Ravi">Vinod Ravi</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Torres, Keila E" sort="Torres, Keila E" uniqKey="Torres K" first="Keila E" last="Torres">Keila E. Torres</name><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Khatri, Bhavisha" sort="Khatri, Bhavisha" uniqKey="Khatri B" first="Bhavisha" last="Khatri">Bhavisha Khatri</name><affiliation><nlm:aff id="A5">Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK</nlm:aff></affiliation></author><author><name sortKey="Halai, Dina" sort="Halai, Dina" uniqKey="Halai D" first="Dina" last="Halai">Dina Halai</name><affiliation><nlm:aff id="A5">Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK</nlm:aff></affiliation></author><author><name sortKey="Roxanis, Ioannis" sort="Roxanis, Ioannis" uniqKey="Roxanis I" first="Ioannis" last="Roxanis">Ioannis Roxanis</name><affiliation><nlm:aff id="A11">Department of Pathology, John Radcliffe Hospital, Oxford, OX3 9DS, UK</nlm:aff></affiliation></author><author><name sortKey="Baumhoer, Daniel" sort="Baumhoer, Daniel" uniqKey="Baumhoer D" first="Daniel" last="Baumhoer">Daniel Baumhoer</name><affiliation><nlm:aff id="A13">Bone Tumour Reference Centre, Institute of Pathology, University Hospital Basel, Basel, Institute for Applied Cancer Science, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Tirabosco, Roberto" sort="Tirabosco, Roberto" uniqKey="Tirabosco R" first="Roberto" last="Tirabosco">Roberto Tirabosco</name><affiliation><nlm:aff id="A5">Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK</nlm:aff></affiliation></author><author><name sortKey="Amary, M Fernanda" sort="Amary, M Fernanda" uniqKey="Amary M" first="M Fernanda" last="Amary">M Fernanda Amary</name><affiliation><nlm:aff id="A5">Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK</nlm:aff></affiliation></author><author><name sortKey="Boshoff, Chris" sort="Boshoff, Chris" uniqKey="Boshoff C" first="Chris" last="Boshoff">Chris Boshoff</name><affiliation><nlm:aff id="A6">University College London Cancer Institute, Huntley Street, London, WC1E 6BT, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A14">Pfizer Oncology, 10555 Science Center Dr, La Jolla, CA, 92121</nlm:aff></affiliation></author><author><name sortKey="Mcdermott, Ultan" sort="Mcdermott, Ultan" uniqKey="Mcdermott U" first="Ultan" last="Mcdermott">Ultan Mcdermott</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Katan, Matilda" sort="Katan, Matilda" uniqKey="Katan M" first="Matilda" last="Katan">Matilda Katan</name><affiliation><nlm:aff id="A9">Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK</nlm:aff></affiliation></author><author><name sortKey="Stratton, Michael R" sort="Stratton, Michael R" uniqKey="Stratton M" first="Michael R" last="Stratton">Michael R. Stratton</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation></author><author><name sortKey="Futreal, P Andrew" sort="Futreal, P Andrew" uniqKey="Futreal P" first="P Andrew" last="Futreal">P Andrew Futreal</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A12">M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</nlm:aff></affiliation></author><author><name sortKey="Flanagan, Adrienne M" sort="Flanagan, Adrienne M" uniqKey="Flanagan A" first="Adrienne M" last="Flanagan">Adrienne M. Flanagan</name><affiliation><nlm:aff id="A5">Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A6">University College London Cancer Institute, Huntley Street, London, WC1E 6BT, UK</nlm:aff></affiliation></author><author><name sortKey="Harris, Adrian" sort="Harris, Adrian" uniqKey="Harris A" first="Adrian" last="Harris">Adrian Harris</name><affiliation><nlm:aff id="A3">The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A11">Department of Pathology, John Radcliffe Hospital, Oxford, OX3 9DS, UK</nlm:aff></affiliation></author><author><name sortKey="Campbell, Peter J" sort="Campbell, Peter J" uniqKey="Campbell P" first="Peter J" last="Campbell">Peter J. Campbell</name><affiliation><nlm:aff id="A1">Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A15">Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK</nlm:aff></affiliation><affiliation><nlm:aff id="A16">Department of Haematology, University of Cambridge, Hills Road, Cambridge, CB2 2XY, UK</nlm:aff></affiliation></author></analytic><series><title level="j">Nature genetics</title><idno type="ISSN">1061-4036</idno><idno type="eISSN">1546-1718</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P3">Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionising radiation or chronic lymphoedema<sup><xref rid="R1" ref-type="bibr">1</xref></sup>. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signalling genes, as a key driver of angiosarcoma<sup><xref rid="R1" ref-type="bibr">1</xref></sup>. Here, we employed whole genome, exome, and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, <italic>PTPRB</italic> and <italic>PLCG1</italic>, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harboured predominantly truncating mutations in 10/39 (26%) tumours. PLCG1, a signal transducer of tyrosine kinases, presented with a recurrent, likely activating R707Q missense variant in 3/34 cases (9%). Overall, 15/39 (38%) tumours harboured at least one driver mutation in angiogenesis signalling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signalling in angiosarcoma.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Young, Rj" uniqKey="Young R">RJ Young</name></author><author><name sortKey="Brown, Nj" uniqKey="Brown N">NJ Brown</name></author><author><name sortKey="Reed, Mw" uniqKey="Reed M">MW Reed</name></author><author><name sortKey="Hughes, D" uniqKey="Hughes D">D Hughes</name></author><author><name sortKey="Woll, Pj" uniqKey="Woll P">PJ Woll</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fachinger, G" uniqKey="Fachinger G">G Fachinger</name></author><author><name sortKey="Deutsch, U" uniqKey="Deutsch U">U Deutsch</name></author><author><name sortKey="Risau, W" uniqKey="Risau W">W Risau</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Winderlich, M" uniqKey="Winderlich M">M Winderlich</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bamford, S" uniqKey="Bamford S">S Bamford</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Guo, T" uniqKey="Guo T">T Guo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dominguez, Mg" uniqKey="Dominguez M">MG Dominguez</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Baumer, S" uniqKey="Baumer S">S Baumer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Broermann, A" uniqKey="Broermann A">A Broermann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Carra, S" uniqKey="Carra S">S Carra</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hayashi, M" uniqKey="Hayashi M">M Hayashi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, Z" uniqKey="Li Z">Z Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mellberg, S" uniqKey="Mellberg S">S Mellberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nawroth, R" uniqKey="Nawroth R">R Nawroth</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nottebaum, Af" uniqKey="Nottebaum A">AF Nottebaum</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Saharinen, P" uniqKey="Saharinen P">P Saharinen</name></author><author><name sortKey="Eklund, L" uniqKey="Eklund L">L Eklund</name></author><author><name sortKey="Pulkki, K" uniqKey="Pulkki K">K Pulkki</name></author><author><name sortKey="Bono, P" uniqKey="Bono P">P Bono</name></author><author><name sortKey="Alitalo, K" uniqKey="Alitalo K">K Alitalo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhou, Q" uniqKey="Zhou Q">Q Zhou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Everett, Kl" uniqKey="Everett K">KL Everett</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ombrello, Mj" uniqKey="Ombrello M">MJ Ombrello</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bunney, Td" uniqKey="Bunney T">TD Bunney</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Covassin, Ld" uniqKey="Covassin L">LD Covassin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lawson, Nd" uniqKey="Lawson N">ND Lawson</name></author><author><name sortKey="Mugford, Jw" uniqKey="Mugford J">JW Mugford</name></author><author><name sortKey="Diamond, Ba" uniqKey="Diamond B">BA Diamond</name></author><author><name sortKey="Weinstein, Bm" uniqKey="Weinstein B">BM Weinstein</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liao, Hj" uniqKey="Liao H">HJ Liao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Antonescu, Cr" uniqKey="Antonescu C">CR Antonescu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Behjati, S" uniqKey="Behjati S">S Behjati</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tarpey, Ps" uniqKey="Tarpey P">PS Tarpey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, H" uniqKey="Li H">H Li</name></author><author><name sortKey="Durbin, R" uniqKey="Durbin R">R Durbin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ye, K" uniqKey="Ye K">K Ye</name></author><author><name sortKey="Schulz, Mh" uniqKey="Schulz M">MH Schulz</name></author><author><name sortKey="Long, Q" uniqKey="Long Q">Q Long</name></author><author><name sortKey="Apweiler, R" uniqKey="Apweiler R">R Apweiler</name></author><author><name sortKey="Ning, Z" uniqKey="Ning Z">Z Ning</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Trapnell, C" uniqKey="Trapnell C">C Trapnell</name></author><author><name sortKey="Pachter, L" uniqKey="Pachter L">L Pachter</name></author><author><name sortKey="Salzberg, Sl" uniqKey="Salzberg S">SL Salzberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Trapnell, C" uniqKey="Trapnell C">C Trapnell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Loo, P" uniqKey="Van Loo P">P Van Loo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Greenman, C" uniqKey="Greenman C">C Greenman</name></author><author><name sortKey="Wooster, R" uniqKey="Wooster R">R Wooster</name></author><author><name sortKey="Futreal, Pa" uniqKey="Futreal P">PA Futreal</name></author><author><name sortKey="Stratton, Mr" uniqKey="Stratton M">MR Stratton</name></author><author><name sortKey="Easton, Df" uniqKey="Easton D">DF Easton</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9216904</journal-id><journal-id journal-id-type="pubmed-jr-id">2419</journal-id><journal-id journal-id-type="nlm-ta">Nat Genet</journal-id><journal-id journal-id-type="iso-abbrev">Nat. Genet.</journal-id><journal-title-group><journal-title>Nature genetics</journal-title></journal-title-group><issn pub-type="ppub">1061-4036</issn><issn pub-type="epub">1546-1718</issn></journal-meta><article-meta><article-id pub-id-type="pmid">24633157</article-id><article-id pub-id-type="pmc">4032873</article-id><article-id pub-id-type="doi">10.1038/ng.2921</article-id><article-id pub-id-type="manuscript">EMS57096</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Recurrent <italic>PTPRB</italic> and <italic>PLCG1</italic> mutations in angiosarcoma</article-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Behjati</surname><given-names>Sam</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Tarpey</surname><given-names>Patrick S</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Sheldon</surname><given-names>Helen</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Martincorena</surname><given-names>Inigo</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Van Loo</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Gundem</surname><given-names>Gunes</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Wedge</surname><given-names>David C</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ramakrishna</surname><given-names>Manasa</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Cooke</surname><given-names>Susanna L</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Pillay</surname><given-names>Nischalan</given-names></name><xref ref-type="aff" rid="A5">5</xref><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Vollan</surname><given-names>Hans Kristian M</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A7">7</xref><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Papaemmanuil</surname><given-names>Elli</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Koss</surname><given-names>Hans</given-names></name><xref ref-type="aff" rid="A9">9</xref><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Bunney</surname><given-names>Tom D</given-names></name><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Hardy</surname><given-names>Claire</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Joseph</surname><given-names>Olivia R</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Martin</surname><given-names>Sancha</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Mudie</surname><given-names>Laura</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Butler</surname><given-names>Adam</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Teague</surname><given-names>Jon W</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Patil</surname><given-names>Meena</given-names></name><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>Steers</surname><given-names>Graham</given-names></name><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>Cao</surname><given-names>Yu</given-names></name><xref ref-type="aff" rid="A12">12</xref></contrib><contrib contrib-type="author"><name><surname>Gumbs</surname><given-names>Curtis</given-names></name><xref ref-type="aff" rid="A12">12</xref></contrib><contrib contrib-type="author"><name><surname>Ingram</surname><given-names>Davis</given-names></name><xref ref-type="aff" rid="A12">12</xref></contrib><contrib contrib-type="author"><name><surname>Lazar</surname><given-names>Alexander J</given-names></name><xref 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rid="A1">1</xref><xref ref-type="aff" rid="A15">15</xref><xref ref-type="aff" rid="A16">16</xref></contrib></contrib-group><aff id="A1"><label>1</label>Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK</aff><aff id="A2"><label>2</label>Department of Paediatrics, University of Cambridge, Hills Road, Cambridge, CB2 2XY, UK</aff><aff id="A3"><label>3</label>The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK</aff><aff id="A4"><label>4</label>Human Genome Laboratory, Department of Human Genetics, VIB and KU Leuven, B-3000 Leuven, Belgium</aff><aff id="A5"><label>5</label>Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, HA7 4LP, UK</aff><aff id="A6"><label>6</label>University College London Cancer Institute, Huntley Street, London, WC1E 6BT, UK</aff><aff id="A7"><label>7</label>Department of Oncology, Oslo University Hospital, N-0310 Oslo, Norway</aff><aff id="A8"><label>8</label>The K.G. Jebsen Center for Breast Cancer Research, University of Oslo, N-0424 Oslo, Norway</aff><aff id="A9"><label>9</label>Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK</aff><aff id="A10"><label>10</label>Division of Molecular Structure, MRC-National Institute for Medical Research, Mill Hill, London NW7 1AA, UK</aff><aff id="A11"><label>11</label>Department of Pathology, John Radcliffe Hospital, Oxford, OX3 9DS, UK</aff><aff id="A12"><label>12</label>M. D. Anderson Cancer Center, The University of Texas, 1901 East Road, Houston, Texas 77054, USA</aff><aff id="A13"><label>13</label>Bone Tumour Reference Centre, Institute of Pathology, University Hospital Basel, Basel, Institute for Applied Cancer Science, Switzerland</aff><aff id="A14"><label>14</label>Pfizer Oncology, 10555 Science Center Dr, La Jolla, CA, 92121</aff><aff id="A15"><label>15</label>Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK</aff><aff id="A16"><label>16</label>Department of Haematology, University of Cambridge, Hills Road, Cambridge, CB2 2XY, UK</aff><author-notes><corresp id="CR1">Correspondence should be addressed to P.C. (<email>pc8@sanger.ac.uk</email>)</corresp><fn id="FN1"><p id="P1"><bold>Author contributions</bold></p><p id="P2">S.B. and P.S.T. performed analyses of sequencing data. H.S performed <italic>in vitro</italic> experiments. P.V.L performed copy number analysis. D.C.W. and I.M. performed statistical analyses. S.L.C. performed rearrangement analysis. G.G., N.P., M.R., H.K.M.V., and E.P contributed to data analysis. H.K., T.B., M.K. contributed structural analyses. C.H., O.J., L.M., H.M., A.P., Ji.T., L.L., Y.C., C.G. coordinated sample processing and technical investigations. Sa.M. coordinated sample acquisition. A.B., J.T., S.S., X.S, J.Z. coordinated informatics analyses. B.K., D.H., D.B., M.P., G.S., I.R., R.T., M.F.A., A.M.F., C.B., V.R., K.E.T., D.I., A.J.L, G.S. and A.H. provided samples and clinical data. P.C., M.R.S., A.H., P.A.F., U.M. and A.M.F directed the research. M.R.S., P.C., S.B. and P.S.T. wrote the manuscript, with contributions from A.H., A.M.F and P.A.F.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>14</day><month>4</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>16</day><month>3</month><year>2014</year></pub-date><pub-date pub-type="ppub"><month>4</month><year>2014</year></pub-date><pub-date pub-type="pmc-release"><day>01</day><month>10</month><year>2014</year></pub-date><volume>46</volume><issue>4</issue><fpage>376</fpage><lpage>379</lpage><pmc-comment>elocation-id from pubmed: 10.1038/ng.2921</pmc-comment>
<permissions><license><license-p>Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:<uri xlink:type="simple" xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</uri></license-p></license></permissions><abstract><p id="P3">Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionising radiation or chronic lymphoedema<sup><xref rid="R1" ref-type="bibr">1</xref></sup>. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signalling genes, as a key driver of angiosarcoma<sup><xref rid="R1" ref-type="bibr">1</xref></sup>. Here, we employed whole genome, exome, and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, <italic>PTPRB</italic> and <italic>PLCG1</italic>, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harboured predominantly truncating mutations in 10/39 (26%) tumours. PLCG1, a signal transducer of tyrosine kinases, presented with a recurrent, likely activating R707Q missense variant in 3/34 cases (9%). Overall, 15/39 (38%) tumours harboured at least one driver mutation in angiogenesis signalling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signalling in angiosarcoma.</p></abstract></article-meta></front><body><p id="P4">We performed whole genome sequencing of three angiosarcomas, along with paired normal DNA from the same patients. The somatic mutation burden of the three cases varied from 0.7–2.2 substitutions per megabase and 0.1–0.2 indels per megabase (<xref ref-type="supplementary-material" rid="SD10">Supplementary Fig. 1</xref>; <xref ref-type="supplementary-material" rid="SD4">Supplementary Table 1</xref>-<xref ref-type="supplementary-material" rid="SD8">5</xref>). Remarkably, in two of the three angiosarcomas we identified truncating mutations in the <italic>PTPRB</italic> (<italic>VE-PTP</italic>) gene, a tyrosine phosphatase specific to vascular endothelium that inhibits angiogenesis<sup><xref rid="R2" ref-type="bibr">2</xref></sup>. One tumour had a nonsense substitution (p.E1444*) and the other both a nonsense (p.C1693*) and a missense (p.Y309C) mutation.</p><p id="P5">To explore this observation further, we extended our investigation to 36 angiosarcomas which we studied by whole exome sequencing (n=8) or by targeted sequencing of 360 cancer genes (n=4; <xref ref-type="supplementary-material" rid="SD1">Supplementary Table 6</xref>) or 28 angiogenesis-related genes (n=24; <xref ref-type="supplementary-material" rid="SD9">Supplementary Table 7</xref>). The entire footprint of <italic>PTPRB</italic> was sequenced, to enable the identification of structural rearrangements in addition to coding point mutations. Angiogenesis-related genes were also sequenced in eight epithelioid haemangioendotheliomas, nine Kaposi’s sarcomas, and two haemangiomas.</p><p id="P6">In total, we identified 14 <italic>PTPRB</italic> mutations in 10/39 (26%) angiosarcomas, comprising eight nonsense, two essential splice, a frameshift insertion and three missense variants (<xref ref-type="fig" rid="F1">Fig. 1</xref>). No large deletions or rearrangements were identified, although the presence of small intragenic deletions cannot be excluded. All truncating mutations disrupt the coding sequence of <italic>PTPRB</italic> before or within the tyrosine phosphatase domain. Two of the missense mutations (Y309C and W130R) lie within the extracellular domain of <italic>PTPRB</italic>, inhibition of which has been shown to disrupt <italic>PTPRB</italic> function<sup><xref rid="R3" ref-type="bibr">3</xref></sup>. The third missense mutation, P1996L, lies within the tyrosine phosphatase domain. The <italic>in silico</italic> variant effect prediction tool, SIFT, ascribes deleterious consequences to these missense variants. No <italic>PTPRB</italic> mutations were identified in haemangioendothelioma, Kaposi sarcoma, or in haemangioma. Inactivating <italic>PTPRB</italic> mutations are also rare in other cancer types, as documented in COSMIC<sup><xref rid="R4" ref-type="bibr">4</xref></sup>, suggesting that <italic>PTPRB</italic> disruption is largely specific to angiosarcoma. Statistical analysis demonstrated that these truncating <italic>PTPRB</italic> mutations were extremely unlikely to have accumulated by chance in angisoarcoma (q = 10<sup>−9</sup>), suggesting that inactivating <italic>PTPRB</italic> mutations are driver events. Notably, all <italic>PTPRB</italic> mutations were identified in tumours that were either known to be secondary and / or have <italic>MYC</italic> amplification, a biomarker of radiation-associated secondary angiosarcoma<sup><xref rid="R5" ref-type="bibr">5</xref></sup> (p = 0.005). In this group the prevalence of <italic>PTPRB</italic> mutations was 45% (10/22 cases).</p><p id="P7">Four angiosarcomas harboured two different non-synonymous <italic>PTPRB</italic> mutations each, including at least one truncating variant in each case. In two of these cases both mutations were truncating, consistent with biallelic inactivation, suggesting that <italic>PTPRB</italic> operates as a recessive cancer gene. In six angiosarcomas there was a single heterozygous <italic>PTPRB</italic> variant, 5 truncating and one missense, without evidence of LOH. The presence of a single detectable non-synonymous mutation in 60% of tumours is not unusual for tumour suppressor genes (<xref ref-type="supplementary-material" rid="SD11">Supplementary Fig. 2</xref>). We analysed published catalogues of somatic mutation from 4,073 tumours to determine the frequency of a second mutation, including LOH, co-occurring with a truncating mutation in established suppressor genes. This analysis indicates that the pattern of mutation we observed in <italic>PTPRB</italic> is compatible with a recessive driver mechanism (<xref ref-type="supplementary-material" rid="SD11">Supplementary Fig. 2</xref>). Nevertheless, we cannot exclude the possibility that other mechanisms such as haploinsufficiency or dominant negative effects are operative.</p><p id="P8"><italic>PTPRB</italic>, a negative regulator of angiogenesis, is expressed exclusively in vascular endothelium, both during development and in adult tissues<sup><xref rid="R2" ref-type="bibr">2</xref>,<xref rid="R6" ref-type="bibr">6</xref></sup>. It inhibits VEGFR2, VE-cadherin, and angiopoietin signalling, thus acting as an integral modifier of angiogenesis<sup><xref rid="R2" ref-type="bibr">2</xref>,<xref rid="R3" ref-type="bibr">3</xref>,<xref rid="R6" ref-type="bibr">6</xref>-<xref rid="R15" ref-type="bibr">15</xref></sup>. In <italic>in vitro</italic> models of angiogenesis, PTPRB inhibition increases angiogenesis<sup><xref rid="R12" ref-type="bibr">12</xref></sup>. <italic>PTPRB</italic> null mice die <italic>in utero</italic> and display severe vascular malformations<sup><xref rid="R6" ref-type="bibr">6</xref></sup>. Although the role of <italic>PTPRB</italic> as a negative regulator of angiogenesis is well established, it is not known whether <italic>PTPRB</italic> driven angiogenesis can be inhibited through pharmacological VEGF inhibition. Consequently, we investigated the effects of knockdown of <italic>PTPRB</italic> on primary cultures of human umbilical vein endothelial cells (HUVEC). Silencing of <italic>PTPRB</italic> via siRNA induced features of angiogenesis such as spheroid sprouting after 24 hours and spindle-like morphology. In the presence of sunitinib or vatalinib, inhibitors of VEGFR2 kinase, these features were abolished (<xref ref-type="fig" rid="F2">Figure 2</xref>; <xref ref-type="supplementary-material" rid="SD2">Supplementary Figure 3</xref>). These findings in HUVEC, a model of vascular endothelium, provide a rationale for exploring whether <italic>PTPRB</italic> mutation status correlates with treatment response to anti-angiogenic agents.</p><p id="P9">To explore the contribution of other genes in angiosarcoma we analysed variant data from 15 angiosarcomas interrogated by whole genome, exome, or cancer gene sequencing (<xref ref-type="fig" rid="F3">Fig. 3</xref>). Cancer genes mutated in more than one tumour included <italic>TP53</italic> (3/15 cases; 20%), <italic>KDM6A</italic> (2/15 cases; 13%), and <italic>MYC</italic> (6/15 cases; 40%). Strikingly, we also identified a recurrent missense variant, R707Q, in <italic>PLCG1</italic>, in 3/15 cases (20%). <italic>PLCG1</italic> encodes phospholipase C gamma 1 (PLCγ1), a tyrosine kinase signal transducer within the phosphoinositide signalling pathway. Statistical analysis showed that the enrichment of R707Q mutation in angiosarcoma is highly significant (q = 0.000002). Capillary sequencing of an additional 15 cases of angiosarcoma indicated that the overall prevalence of R707Q mutations was 9% (3/34 cases). No <italic>PLCG1</italic> mutations were found in any of the other tumour types investigated here. Notably, all three <italic>PLCG1</italic> R707Q mutations co-occurred with <italic>PTPRB</italic> mutations.</p><p id="P10">The presence of a single recurrent R707Q missense variant suggests that <italic>PLCG1</italic> is activated in angiosarcoma. Arginine 707 lies within the auto-inhibitory cSH2 domain of PLCγ1<sup><xref rid="R16" ref-type="bibr">16</xref>-<xref rid="R19" ref-type="bibr">19</xref></sup> and provides structural support to this domain. <italic>In silico</italic> modelling of the mutated protein predicts that the substituted glutamine destabilises the cSH2 domain which may result in overactive PLCγ1 (<xref ref-type="supplementary-material" rid="SD3">Supplementary Fig. 4</xref>). Disruption of the auto-inhibitory cSH2 domain has been shown to cause murine and human immune disorders through constitutive activation of PLCγ enzymes<sup><xref rid="R16" ref-type="bibr">16</xref>-<xref rid="R19" ref-type="bibr">19</xref></sup>. Interestingly, forward genetic screening of zebrafish has identified <italic>PLCG1</italic> as a non-redundant regulator of arterial angiogenesis that transduces activation of VEGF signalling<sup><xref rid="R20" ref-type="bibr">20</xref>,<xref rid="R21" ref-type="bibr">21</xref></sup>, and <italic>Plcg1</italic>-deficient mice exhibit reduced vasculogenesis<sup><xref rid="R22" ref-type="bibr">22</xref></sup>. <italic>PLCG1</italic> is ubiquitously expressed in normal tissue<sup><xref rid="R17" ref-type="bibr">17</xref>,<xref rid="R19" ref-type="bibr">19</xref></sup>, and whole RNA sequencing of four angiosarcomas, including two positive for <italic>PLCG1</italic> R707Q, demonstrated <italic>PLCG1</italic> expression in each case. In the context of existing knowledge about <italic>PLCG1</italic>, our observations therefore lend support to the hypothesis that activated <italic>PLCG1</italic> drives angiosarcoma, downstream of receptor tyrosine kinases, through constitutive activation of angiogenesis signalling. The effects of <italic>PLCG1</italic> mutations on the response to therapeutics targeting tyrosine kinases will be an important future investigation.</p><p id="P11">In addition to 15 angiosarcomas screened for driver mutations, we performed a focused screen for mutations in angiogenesis-related genes (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 6</xref>) in a further 24 angiosarcomas. Considering both cohorts together, 15/39 angiosarcomas harbour at least one mutation in an angiogenesis-related gene highlighting aberrant angiogenesis as a common driver in a subset of tumours. Mutated genes included <italic>H/K/N-RAS</italic> (5/39 cases), <italic>PIK3CA</italic> (1/39 cases), and <italic>FLT4</italic> (1/39 cases). We did not find variants in <italic>VEGFR2 (KDR)</italic> that have previously been reported<sup><xref rid="R23" ref-type="bibr">23</xref></sup> (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 1</xref>). Amongst other vascular tumours we identified one Kaposi sarcoma (n=9) with a <italic>PIK3CA</italic> and one epithelioid haemangioendothelioma (n=8) with a <italic>PTEN</italic> driver mutation (<xref ref-type="supplementary-material" rid="SD4">Supplementary Table 1</xref>). Interestingly, in our series aberrant angiogenesis was most frequent amongst secondary and/or MYC-amplified angiosarcomas (12/22 cases), although this observation requires investigation in larger series. There was no evidence of mutual exclusivity of mutations in angiogenesis-related genes (<xref ref-type="fig" rid="F3">Fig. 3</xref>; <xref ref-type="supplementary-material" rid="SD4">Supplementary Table 1</xref>). In four angiosarcomas we found more than one angiogenesis-related gene mutated, indicating that targeting treatment exclusively at the tyrosine kinase level may not suffice to overcome aberrant angiogenesis.</p><p id="P12">As angiosarcoma is a rare tumour, combined efforts to curate larger patient series are required to explore further the somatic changes that underpin its pathogenesis. This study, however, provides a first comprehensive insight into the somatic variation in angiosarcoma and identifies frequent mutations in angiogenesis-related genes in a subset of tumours. The next challenge will be to functionally explore these findings in appropriate angiosarcoma models that accommodate the complexity of the driver landscape we report here. It is now indicated to determine the clinical utility of <italic>PTPRB</italic> and <italic>PLCG1</italic> as possible biomarkers of secondary disease and as novel therapeutic targets in angiosarcoma.</p><sec sec-type="methods" specific-use="web-only" id="S1"><title>Online methods</title><sec sec-type="subjects" id="S2"><title>Patient samples</title><p id="P13">Informed consent was obtained from all subjects and ethical approval obtained from Cambridgeshire 2 Research Ethics Service (reference 09/H0308/165). Collection and use of patient samples were approved by the appropriate institutional review board (IRB) of each institution.</p></sec><sec id="S3"><title>Whole genome, exome and cancer gene sequencing</title><p id="P14">DNA was extracted from 11 angiosarcomas as well as matched normal tissue derived from the same individuals. Three cases were whole genome sequenced to an average depth of at least 40× or 30× for tumour and normal DNA, respectively, as previously described<sup><xref rid="R24" ref-type="bibr">24</xref></sup>. Whole exome sequencing was performed on 8 cases as previously described<sup><xref rid="R25" ref-type="bibr">25</xref></sup>, and at least 70% of the coding sequence was covered by 30×. DNA extracted from an additional 4 tumours that did not have matched normal tissue DNA were subjected to targeted sequencing of 360 established and putative cancer gene using a custom made bait set (Agilent) for target enrichment (<xref ref-type="supplementary-material" rid="SD9">Supplementary Table 7</xref>). Paired end sequencing was performed on Illumina Hiseq 2000 or 2500 analysers. Reads were aligned to the reference human genome (NCBI37) by using BWA on default settings<sup><xref rid="R26" ref-type="bibr">26</xref></sup>. Reads which were unmapped or PCR-derived duplicates were excluded from the analysis.</p></sec><sec id="S4"><title>Variant detection</title><p id="P15">The CaVEMan (cancer variants through expectation maximization) algorithm was used to call single nucleotide substitutions<sup><xref rid="R25" ref-type="bibr">25</xref></sup>. To call insertions and deletions, we used split-read mapping implemented as a modification of the Pindel algorithm<sup><xref rid="R27" ref-type="bibr">27</xref></sup>. To call rearrangements we applied the BRASS (breakpoint via assembly) algorithm, which identifies rearrangements by grouping discordant read pairs that point to the same breakpoint event<sup><xref rid="R25" ref-type="bibr">25</xref></sup>. Post-processing filters were applied to the output to improve specificity. Mutations were annotated to Ensembl version 58.</p></sec><sec id="S5"><title>Variant validation</title><p id="P16">In whole genome samples, all coding variants as well as randomly selected mutations, in total 508/15292 (3.3%) substitutions and 342/1386 (25%) indels, were experimentally validated by whole exome sequencing or targeted capture with massively parallel sequencing<sup><xref rid="R25" ref-type="bibr">25</xref></sup>. The overall precision of the catalogue of substitutions and indels was thus determined to be at least 94%. Rearrangements were validated by defining the exact location of the breakpoint at nucleotide resolution through extraction of split reads across the breakpoint, algorithmically or previously<sup><xref rid="R25" ref-type="bibr">25</xref></sup>. Variants called in whole exome samples were confirmed by visual inspection or resequencing.</p></sec><sec id="S6"><title>Angiogenesis gene screen</title><p id="P17">43 tumours were included in this screen: 24 angiosarcomas; 9 Kaposi’s sarcomas; 8 haemangioendotheliomas; 2 haemangiomas. Genes of interest (<xref ref-type="supplementary-material" rid="SD1">Supplementary Table 6</xref>) and genotyping SNPs were enriched through targeted capture and sequenced by massively parallel sequencing, as described before<sup><xref rid="R25" ref-type="bibr">25</xref></sup>. The <italic>PLCG1</italic> R707Q mutation was screened for by capillary sequencing (primer sequences available on request).</p></sec><sec id="S7"><title>RNA sequencing and analysis</title><p id="P18">Total RNA was isolated from fresh frozen tissue of 4 angiosarcomas using trizol. Standard Illumina RNA libraries of poly-A selected RNA were sequenced on an Illumina HiSeq 2000 (paired end, 75 base pair read length). TopHat<sup><xref rid="R28" ref-type="bibr">28</xref></sup> (version 1.3.3) was used for alignment. Expression values were derived using Cufflinks<sup><xref rid="R29" ref-type="bibr">29</xref></sup> (version 1.0.2).</p></sec><sec id="S8"><title>Detection of copy number variation</title><p id="P19">Copy number data were derived from whole genome or exome reads using the ASCAT algorithm (version 2.2) and validated by SNP6.0 in 2 cases<sup><xref rid="R30" ref-type="bibr">30</xref></sup>. In the whole exome extension study, amplifications were derived by comparing the coverage in candidate genes against average coverage across the exome, after normalization using matched germline exome sequencing data. A 1.75-fold increase (corresponding to >= 5 copies in 50% tumour cells) was reported as an amplification. In the targeted extension study, amplifications were derived by comparing the coverage in candidate genes against the coverage in 96 SNPs of the same sample, both normalised against data from a panel of non-tumour samples. A fivefold increase in relative, normalised coverage in tumours was reported as an amplification. To assess LOH in <italic>PTPRB</italic>, all SNPs that lie within the footprint of the gene were interrogated and their allele fraction assessed for deviations from 0.5.</p></sec><sec id="S9"><title>Cell culture</title><p id="P20">Human Umbilical Vein Endothelial Cells (HUVEC) pooled from multiple donors were purchased from Lonza (Wokingham, UK). These were routinely cultured in Endothelial Growth Medium 2 (EGM-2) (Lonza) up to passage 7 and cultured in Endothelial Basal Medium 2 (EBM-2) (Lonza) during the experiments.</p></sec><sec id="S10"><title>RNAi transfection</title><p id="P21">Stealth siRNAs targeting <italic>PTPRB</italic> (HSS108847 and HSS108849) and the Stealth RNAi™ siRNA Negative Control Med GC Duplex #2 were purchased from Life Technologies. siRNA was transfected into HUVEC at a final concentration of 30nM using Lipofectamine RNAiMAX reagent (Life Technologies). Cells were transfected at 50% confluency in Opti-MEM reduced Serum Medium with GlutamMAX 1 (Life Technologies) and used after 24 hours.</p></sec><sec id="S11"><title>Western blotting and staining</title><p id="P22">Antibodies for western blotting were obtained from the following suppliers; anti-b-actin HRP (Sigma), anti-VEGFR2 and anti-P-VEGFR2 (Cell Signalling). Staining was performed on formalin fixed cells using anti-VE-cadherin (Cell Signalling) and Alexa Fluor 488 (Life Technologies).</p></sec><sec id="S12"><title>Hanging drop assay</title><p id="P23">HUVEC were trypsinised and resuspended in EBM2 (Lonza) containing 2% foetal calf serum (FCS) at a concentration of 2.5×10<sup>4</sup> cells/ml. Methylcellulose was added at 0.25% (w/v) and 20μl drops were seeded in non-adherent dish. After inversion of the plate, suspended cells form a single spheroid containing approximately 500 cells. Treated spheroids were incubated with 1μM Sunitinib (Cell Signaling Technology, Inc) or 100nM Vatalanib (Santa Cruz) for 1hr prior to being embedded in a fibrin gel using 2.5mg/ml fibrinogen-PBS solution (Sigma) and 0.007 units of thrombin (Sigma). Once clotting occurred, EBM-2 containing 2% FCS was added with or without 1μM Sunitinib or 100nM Vatalanib. Spheroid photographs were taken after 24 hours using an AMG Evos XL Core digital microscope (Fisher Scientific, Loughborough, UK). Sprouting area was measured using ImageJ64 software and the results were analysed using Graphad Prism version 6 (Graphpad Software).</p></sec><sec id="S13"><title>Statistical analyses</title><p id="P24">A Fisher’s exact test was used to assess the significance of the association between <italic>PTPRB</italic> mutations and subtypes of angiosarcoma.</p><p id="P25">For analysis of <italic>in vitro</italic> findings, a one-way ANOVA was performed on the data with a Sidak’s multiple comparisons test.</p><p id="P26">To determine whether the frequency of individual mutations classes was higher than expected by chance for each gene, we implemented a likelihood model as previously described<sup><xref rid="R31" ref-type="bibr">31</xref></sup>. To determine the probability of the identical <italic>PLCG1</italic> mutations having occurred by chance, we used the following approach: Using the rates of each mutation class estimated using the aforementioned method, the neutral rate of such an event assuming uniform mutation rates was determined to be 5.905e-06. The probability of seeing this site mutated three times in the coding sequence of 11 samples that were interrogated by unbiased sequencing was therefore approximately 4.57e-14 (cumulative Poisson distribution). Adjusting the p-value for the total number of sites in the exome the q-value for this mutation is 1.49e-06.</p><p id="P27">In order to analyse the frequency of two-hits in known tumour suppressor genes we downloaded publicly available catalogues of somatic mutations including copy number data from 4,073 tumours of the Tumour Cancer Gene Atlas consortium (as of November 2013). For every gene of a list of established tumour suppressors (see <xref ref-type="supplementary-material" rid="SD11">Supplementary Figure 2</xref>) we selected all those samples in which the gene had a truncating mutation (nonsense, essential splice site or out-of-frame indels) and quantified the frequency of a second mutations, i.e. truncating, loss of heterozygosity, missense, or in-frame indel, in the gene. Error bars in <xref ref-type="supplementary-material" rid="SD11">Supplementary Figure 2</xref> indicate the 95% confidence intervals of the total fraction of 2-hit samples (using a Chi-square approximation, as implemented in the function “prop.test” in R version 3.0.1).</p></sec></sec><sec sec-type="supplementary-material" id="SM"><title>Supplementary Material</title><supplementary-material content-type="local-data" id="SD1"><label>1</label><media xlink:href="NIHMS57096-supplement-1.pdf" orientation="portrait" xlink:type="simple" id="d37e1092" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD10"><label>8</label><media xlink:href="NIHMS57096-supplement-8.jpg" orientation="portrait" xlink:type="simple" id="d37e1096" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD11"><label>9</label><media xlink:href="NIHMS57096-supplement-9.jpg" orientation="portrait" xlink:type="simple" id="d37e1100" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD2"><label>10</label><media xlink:href="NIHMS57096-supplement-10.jpg" orientation="portrait" xlink:type="simple" id="d37e1104" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD3"><label>11</label><media xlink:href="NIHMS57096-supplement-11.jpg" orientation="portrait" xlink:type="simple" id="d37e1108" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD4"><label>Supplementary Table 1</label><media xlink:href="NIHMS57096-supplement-2.xlsx" orientation="portrait" xlink:type="simple" id="d37e1112" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD5"><label>Supplementary Table 2</label><media xlink:href="NIHMS57096-supplement-3.xlsx" orientation="portrait" xlink:type="simple" id="d37e1116" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD6"><label>Supplementary Table 3</label><media xlink:href="NIHMS57096-supplement-4.xlsx" orientation="portrait" xlink:type="simple" id="d37e1120" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD7"><label>Supplementary Table 4</label><media xlink:href="NIHMS57096-supplement-5.xlsx" orientation="portrait" xlink:type="simple" id="d37e1124" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD8"><label>Supplementary Table 5</label><media xlink:href="NIHMS57096-supplement-6.xlsx" orientation="portrait" xlink:type="simple" id="d37e1128" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD9"><label>Supplementary Table 7</label><media xlink:href="NIHMS57096-supplement-7.xlsx" orientation="portrait" xlink:type="simple" id="d37e1133" position="anchor"></media></supplementary-material></sec></body><back><ack id="S14"><title>Acknowledgements</title><p>This work was supported by funding from the Wellcome Trust (grant reference 077012/Z/05/Z). The material was obtained from the RNOH Musculoskeletal Research Program and Biobank and the Oxford Radcliffe Biobank. Support was provided to A.M.F. (UCL) by the National Institute for Health Research, UCLH Biomedical Research Centre, and the CRUK UCL Experimental Cancer Medicine Centre. Support was provided to A.H. by Cancer Research UK, Oxford Biomedical Research Centre and the Breast Cancer Research Foundation. P.J.C. is personally funded through a Wellcome Trust Senior Clinical Research Fellowship (grant reference WT088340MA). P.V.L. is a postdoctoral researcher of the Research Foundation - Flanders (FWO). HKMV is supported by the Norwegian Radium Hospital’s Foundation. SB is funded through the Wellcome Trust PhD Programme for Clinicians. PAF is supported by the Cancer Prevention Research Institute of Texas and the Welch Foundation. We thank Marian Taylor and Russell Leek for sample preparation. We are grateful to the patients for participating in the research and to the clinicians and support staff involved in their care, from Oxford University Hospitals NHS Trust, the University of Texas MD Anderson Cancer Center Sarcoma Programme, and the London Sarcoma Service.</p></ack><fn-group><fn id="FN2"><p id="P28"><bold>Accession codes</bold></p><p id="P29">Sequencing data have been deposited at the European Genome-Phenome Archive (EGA, <ext-link ext-link-type="uri" xlink:href="http://www.ebi.ac.uk/ega/">http://www.ebi.ac.uk/ega/</ext-link>), which is hosted by the European Bioinformatics Institute (EBI); EGAD00001000735.</p></fn><fn id="FN3"><p id="P30"><bold>Competing financial interests</bold></p><p id="P31">The authors declare no competing financial interests.</p></fn></fn-group><ref-list><title>References</title><ref id="R1"><label>1</label><element-citation publication-type="journal"><person-group 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Red: truncating mutations. Blue: missense.</p></caption><graphic xlink:href="emss-57096-f0001"></graphic></fig><fig id="F2" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Sensitivity of PTPRB-driven angiogenesis to VEGF inhibition.</p><p>A) HUVEC spheroids embedded in a fibrin gel were photographed after 24 hours of treatment (×10 magnification). B) Quantification of spheroid sprouting area. Error bars represent 1 × standard deviation. *p<0.0001.</p></caption><graphic xlink:href="emss-57096-f0002"></graphic></fig><fig id="F3" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Driver variants in angiosarcoma</p><p>Likely driver variants are indicated by coloured rectangles. Truncating variants (red) include nonsense, essential splice and frameshift indels. Missense substitutions are indicated in blue, amplifications in green and rearrangements in orange. Secondary angiosarcomas are either clinically classified as secondary or unclassified cases with <italic>MYC</italic> amplification.</p></caption><graphic xlink:href="emss-57096-f0003"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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