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.
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We thank M. Taylor and R. 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 the Oxford University Hospitals NHS Trust, the University of Texas MD Anderson Cancer Center Sarcoma Program and the London Sarcoma Service. This work was supported by funding from the Wellcome Trust (grant reference 077012/Z/05/Z). The material was obtained from the Royal National Orthopaedic Hospital Musculoskeletal Research Program and Biobank and from the Oxford Radcliffe Biobank. Support was provided to A.M.F. by the National Institute for Health Research, the University College London Hospital Biomedical Research Centre and the Cancer Research UK University College London Experimental Cancer Medicine Centre. Support was provided to A.H. by Cancer Research UK, the 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). H.K.M.V. is supported by the Norwegian Radium Hospital's Foundation. S.B. is funded through the Wellcome Trust PhD Programme for Clinicians. P.A.F. is supported by the Cancer Prevention Research Institute of Texas and the Welch Foundation.
Integrated supplementary information
Clinical features of cases included in this study with likely driver mutations.
Coding mutations in 11 angiosarcomas subjected to whole-genome or whole-exome sequencing.
Substitutions and indels identified in three angiosarcoma genomes.
Rearrangements identified in three angiosarcoma genomes.
Amplification and homozygous deletions identified in three angiosarcoma genomes.
Cancer genes screened by targeted sequencing.
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Hepatology Research (2019)