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Recurrent PTPRB and PLCG1 mutations in angiosarcoma

2014; Nature Portfolio; Volume: 46; Issue: 4 Linguagem: Inglês

10.1038/ng.2921

1546-1718

Sam Behjati, Patrick Tarpey, Helen Sheldon, Iñigo Martincorena, Peter Van Loo, Gunes Gundem, David C. Wedge, Manasa Ramakrishna, Susanna L. Cooke, Nischalan Pillay, Hans Kristian Moen Vollan, Elli Papaemmanuil, Hans Koss, Tom D. Bunney, Claire Hardy, Olivia Joseph, Sancha Martin, Laura Mudie, Adam P. Butler, Jon W. Teague, Meena Patil, Graham Steers, Yu Cao, Curtis Gumbs, Davis R. Ingram, Alexander J. Lazar, Latasha Little, Harshad S. Mahadeshwar, Alexei Protopopov, Ghadah 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, Maria Fernanda Amary, Chris Boshoff, Ultan McDermott, Matilda Katan, Michael R. Stratton, P. Andrew Futreal, Adrienne M. Flanagan, Adrian L. Harris, Peter J. Campbell,

Protist diversity and phylogeny

Peter Campbell and colleagues identify PLCG1 and PTPRB as new driver genes for angiosarcoma through whole-exome sequencing of tumor samples. They find somatic PTPRB mutations in 10 of 39 cases and PLCG1 mutations in 3 of 34 cases, along with mutations in known cancer-related genes. 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.