Recurrent PTPRB and PLCG1 mutations in angiosarcoma

Sam Behjati, Patrick S Tarpey, Helen Sheldon, Inigo Martincorena, Peter Van Loo, Gunes Gundem, David C Wedge, Manasa Ramakrishna, Susanna L Cooke, Nischalan Pillay, Hans Kristian M Vollan, Elli Papaemmanuil, Hans Koss, Tom D Bunney, Claire Hardy, Olivia R Joseph, Sancha Martin, Laura Mudie, Adam Butler, Jon W Teague, Meena Patil, Graham Steers, Yu Cao, Curtis Gumbs, Davis Ingram, Alexander J Lazar, Latasha Little, Harshad Mahadeshwar, Alexei Protopopov, Ghadah A Al Sannaa, Sahil Seth, Xingzhi Song, Jiabin Tang, Jianhua Zhang, Vinod Ravi, Keila E Torres, Bhavisha Khatri, Dina Halai, Ioannis Roxanis, Daniel Baumhoer, Roberto Tirabosco, M Fernanda Amary, Chris Boshoff, Ultan McDermott, Matilda Katan, Michael R Stratton, P Andrew Futreal, Adrienne M Flanagan, Adrian Harris, Peter J Campbell

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.