Recurrent mutations in PTPRB and PLCG1 were identified in angiosarcomas.

  • Major finding: Recurrent mutations in PTPRB and PLCG1 were identified in angiosarcomas.

  • Clinical relevance: Loss-of-function mutations in PTPRB may confer sensitivity to antiangiogenic agents.

  • Impact: Loss-of-function PTPRB and gain-of-function PLCG1 mutations may be drivers of secondary angiocarcinoma.

Angiosarcoma is a rare, aggressive soft-tissue sarcoma that arises in the vascular endothelium either spontaneously or as a result of ionizing radiation or lymphedema. Behjati and colleagues used whole-genome sequencing to characterize the genetic features of primary and secondary angiosarcoma and identified mutations affecting protein tyrosine phosphatase receptor type B (PTPRB) in 2 of 3 angiosarcomas initially sequenced. Additional whole-exome sequencing of 36 angiosarcomas revealed 14 PTPRB mutations in 10 (26%) tumors. Of note, PTPRB mutations were specific to secondary angiosarcomas, occurring in 10 out of 22 (45%) samples, and were not found in other vascular cancers. Most mutations were nonsense or missense mutations predicted to disrupt PTPRB function. PTPRB is exclusively expressed in the vascular endothelium and negatively regulates angiogenesis by inhibiting VEGF receptor 2 (VEGFR2). Silencing PTPRB to recapitulate loss of function in human endothelial cells resulted in morphologic changes characteristic of angiogenesis that could be reversed with the VEGFR2 inhibitors sunitinib and vatalanib. Mutations in the phospholipase C gamma 1 (PLCG1) gene were also identified in 3 of the tumors with PTPRB mutations (an overall frequency of 9%). PLCG1 is known to activate VEGF signaling and promote angiogenesis, and the R707Q identified in all 3 samples is predicted to increase PLCG1 activity. In further targeted screening, the authors found that 15 of 39 (38%) angiosarcomas harbored at least one mutation in an angiogenesis-related gene, further pointing to a role of aberrant angiogenic signaling in angiosarcoma, but 4 tumors had mutations in multiple angiogenesis-related genes, indicating that therapeutically targeting only one pathway may prove ineffective. Although further research is necessary to determine whether specific angiosarcoma mutations confer sensitivity to antiangiogenic therapies, these results provide evidence that PTPRB and PLCG1 mutations are driving events in a subset of secondary angiosarcomas.

Behjati S, Tarpey PS, Sheldon H, Martincorena I, Van Loo P, Gundem G, et al. Recurrent PTPRB and PLCG1 mutations in angiosarcoma. Nat Genet 2014 Mar 16 [Epub ahead of print].