Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.
Department of Paediatrics, University of Cambridge, Hills Road, Cambridge, CB2 2XY, UK.
Nat Genet. 2014 Apr;46(4):376-379. doi: 10.1038/ng.2921. Epub 2014 Mar 16.
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.
血管肉瘤是一种侵袭性恶性肿瘤，可自发或继发于电离辐射或慢性淋巴水肿。先前的研究已经确定了异常的血管生成，包括血管生成信号基因的偶尔体细胞突变，是血管肉瘤的一个关键驱动因素。在这里，我们采用全基因组、全外显子组和靶向测序来研究原发性和继发性血管肉瘤的体细胞变化。我们鉴定了两个与血管生成密切相关的基因 PTPRB 和 PLCG1 的复发性突变。内皮磷酸酶 PTPRB 是血管生长因子酪氨酸激酶的负调节剂，在 39 个肿瘤中的 10 个（26%）中主要存在截断突变。PLCGl，一种酪氨酸激酶的信号转导物，在 34 个病例中的 3 个（9%）中编码了一种复发性的、可能激活的 p.Arg707Gln 错义变体。总的来说，在 39 个肿瘤中有 15 个（38%）至少携带一个血管生成信号基因的驱动突变。我们的发现为目前针对血管肉瘤中血管生成信号的靶向治疗提供了信息和支持。
