Recurrent PTPRB and PLCG1 mutations in angiosarcoma

Behjati, S. et al. (2014) Recurrent PTPRB and PLCG1 mutations in angiosarcoma. Nature Genetics, 46(4), pp. 376-379. (doi: 10.1038/ng.2921) (PMID:24633157) (PMCID:PMC4032873)

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.

• Item Type: Articles
• Additional Information: 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.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cooke, Dr Susie and Martin, Ms Sancha
• Authors: Behjati, S., Tarpey, P. S., Sheldon, H., Martincorena, I., Van Loo, P., Gundem, G., Wedge, D. C., Ramakrishna, M., Cooke, S. L., Pillay, N., Vollan, H. K. M., Papaemmanuil, E., Koss, H., Bunney, T. D., Hardy, C., Joseph, O. R., Martin, S., Mudie, L., Butler, A., Teague, J. W., Patil, M., Steers, G., Cao, Y., Gumbs, C., Ingram, D., Lazar, A. J., Little, L., Mahadeshwar, H., Protopopov, A., Al Sannaa, G. A., Seth, S., Song, X., Tang, J., Zhang, J., Ravi, V., Torres, K. E., Khatri, B., Halai, D., Roxanis, I., Baumhoer, D., Tirabosco, R., Amary, M. F., Boshoff, C., McDermott, U., Katan, M., Stratton, M. R., Futreal, P. A., Flanagan, A. M., Harris, A., and Campbell, P. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Genetics
• Publisher: Nature Publishing Group
• ISSN: 1061-4036
• ISSN (Online): 1546-1718
• Published Online: 16 March 2014