Institute of Cancer Research, London, UK.
Institut Gustav Roussy, Villejuif, France.
Nat Genet. 2014 May;46(5):457-461. doi: 10.1038/ng.2925. Epub 2014 Apr 6.
Diffuse intrinsic pontine gliomas (DIPGs) are highly infiltrative malignant glial neoplasms of the ventral pons that, due to their location within the brain, are unsuitable for surgical resection and consequently have a universally dismal clinical outcome. The median survival time is 9-12 months, with neither chemotherapeutic nor targeted agents showing substantial survival benefit in clinical trials in children with these tumors. We report the identification of recurrent activating mutations in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, in 21% of DIPG samples. Strikingly, these somatic mutations (encoding p.Arg206His, p.Arg258Gly, p.Gly328Glu, p.Gly328Val, p.Gly328Trp and p.Gly356Asp substitutions) have not been reported previously in cancer but are identical to mutations found in the germ line of individuals with the congenital childhood developmental disorder fibrodysplasia ossificans progressiva (FOP) and have been shown to constitutively activate the BMP-TGF-β signaling pathway. These mutations represent new targets for therapeutic intervention in this otherwise incurable disease.
弥漫性内在脑桥神经胶质瘤（DIPG）是一种高度浸润性的桥脑恶性神经胶质瘤，由于其位于脑内，不适合手术切除，因此临床预后普遍较差。中位生存时间为 9-12 个月，在针对这些肿瘤的儿童临床试验中，无论是化疗药物还是靶向药物均未显示出显著的生存获益。我们报告了在 21%的 DIPG 样本中发现了 ACVR1 基因的反复激活突变，该基因编码 I 型激活素受体丝氨酸/苏氨酸激酶。值得注意的是，这些体细胞突变（编码 p.Arg206His、p.Arg258Gly、p.Gly328Glu、p.Gly328Val、p.Gly328Trp 和 p.Gly356Asp 取代）以前在癌症中没有报道过，但与在先天性儿童发育障碍纤维发育不良性骨化性进展（FOP）的个体的种系中发现的突变相同，并且已经证明它们可使 BMP-TGF-β 信号通路持续激活。这些突变代表了针对这种无法治愈的疾病的新的治疗干预靶点。
