Recurrent PTPRB and PLCG1 mutations in angiosarcoma

S. Behjati, P.S. Tarpey, H. Sheldon, I. Martincorena, P. Van Loo, G. Gundem, D.C. Wedge, M. Ramakrishna, S.L. Cooke, N. Pillay, H.K.M. Vollan, E. Papaemmanuil, H. Koss, T.D. Bunney, C. Hardy, O.R. Joseph, S. Martin, L. Mudie, A. Butler, J.W. TeagueM. Patil, G. Steers, Y. Cao, C. Gumbs, D. Ingram, A.J. Lazar, L. Little, H. Mahadeshwar, A. Protopopov, G.A. Al Sannaa, S. Seth, X. Song, J. Tang, J. Zhang, V. Ravi, K.E. Torres, B. Khatri, D. Halai, I. Roxanis, D. Baumhoer, R. Tirabosco, M.F. Amary, C. Boshoff, U. McDermott, M. Katan, M.R. Stratton, P.A. Futreal, A.M. Flanagan, A. Harris, P.J. Campbell

Research output: Contribution to journalArticlepeer-review

Abstract

Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionizing radiation or chronic lymphoedema1. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signaling genes, as a key driver of angiosarcoma1. 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.
Original languageEnglish
Pages (from-to)376-379
Number of pages4
JournalNature Genetics
Volume46
Issue number4
DOIs
Publication statusPublished - 16 Mar 2014

Keywords

  • Analysis of Variance
  • Base Sequence
  • Exome
  • Hemangiosarcoma
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Neovascularization, Pathologic
  • Phospholipase C gamma
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3
  • RNA Interference
  • Sequence Analysis, RNA
  • Vascular Endothelial Growth Factor A

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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