PDF(Pubmed)
Abstract：
Extra-axial cavernous hemangiomas (ECHs) are complex vascular lesions mainly found in the spine and cavernous sinus. Their removal poses significant risk due to their vascularity and diffuse nature, and their genetic underpinnings remain incompletely understood. Our approach involved genetic analyses on 31 tissue samples of ECHs employing whole-exome sequencing and targeted deep sequencing. We explored downstream signaling pathways, gene expression changes, and resultant phenotypic shifts induced by these mutations, both in vitro and in vivo. In our cohort, 77.4% of samples had somatic missense variants in GNA14, GNAQ, or GJA4. Transcriptomic analysis highlighted significant pathway upregulation, with the GNAQ c.626A>G (p.Gln209Arg) mutation elevating PI3K-AKT-mTOR and angiogenesis-related pathways, while GNA14 c.614A>T (p.Gln205Leu) mutation led to MAPK and angiogenesis-related pathway upregulation. Using a mouse xenograft model, we observed enlarged vessels from these mutations. Additionally, we initiated rapamycin treatment in a 14-year-old individual harboring the GNAQ c.626A>G (p.Gln209Arg) variant, resulting in gradual regression of cutaneous cavernous hemangiomas and improved motor strength, with minimal side effects. Understanding these mutations and their pathways provides a foundation for developing therapies for ECHs resistant to current therapies. Indeed, the administration of rapamycin in an individual within this study highlights the promise of targeted treatments in treating these complex lesions.
摘要：
轴外海绵状血管瘤（ECHs）是复杂的血管病变，主要见于脊柱和海绵窦。由于它们的血管分布和弥漫性，它们的移除会带来很大的风险，和他们的基因基础仍然没有完全理解。我们的方法涉及使用全外显子组测序和靶向深度测序对31个ECH组织样品进行遗传分析。我们探索了下游信号通路，基因表达变化，这些突变诱导的表型转变，在体外和体内。在我们的队列中，77.4%的样本在GNA14、GNAQ、或者GJA4.转录组分析强调了显著的途径上调，与GNAQc.626A>G（p。Gln209Arg）突变升高PI3K-AKT-mTOR和血管生成相关途径，而GNA14c.614A>T(p.Gln205Leu)突变导致MAPK和血管生成相关通路上调。使用小鼠异种移植模型，我们从这些突变中观察到增大的血管。此外,我们在一名14岁的患者中开始了雷帕霉素治疗，该患者患有GNAQc.626A>G（p。Gln209Arg)变体,导致皮肤海绵状血管瘤逐渐消退并改善运动强度，副作用最小。了解这些突变及其途径为开发对当前疗法具有抗性的ECHs疗法奠定了基础。的确,在这项研究中，在个体中使用雷帕霉素强调了靶向治疗这些复杂病变的前景。
