Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, China International Neuroscience Institute, Beijing, China.
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Brain. 2021 Oct 22;144(9):2648-2658. doi: 10.1093/brain/awab117.
Cavernous malformations affecting the CNS occur in ∼0.16-0.4% of the general population. The majority (85%) of cavernous malformations are in a sporadic form, but the genetic background of sporadic cavernous malformations remains enigmatic. Of the 81 patients, 73 (90.1%) patients were detected carrying somatic missense variants in two genes: MAP3K3 and PIK3CA by whole-exome sequencing. The mutation spectrum correlated with lesion size (P = 0.001), anatomical distribution (P < 0.001), MRI appearance (P = 0.004) and haemorrhage events (P = 0.006). PIK3CA mutation was a significant predictor of overt haemorrhage events (P = 0.003, odds ratio = 11.252, 95% confidence interval = 2.275-55.648). Enrichment of endothelial cell population was associated with a higher fractional abundance of the somatic mutations. Overexpression of the MAP3K3 mutation perturbed angiogenesis of endothelial cell models in vitro and zebrafish embryos in vivo. Distinct transcriptional signatures between different genetic subgroups of sporadic cavernous malformations were identified by single cell RNA sequencing and verified by pathological staining. Significant apoptosis in MAP3K3 mutation carriers and overexpression of GDF15 and SERPINA5 in PIK3CA mutation carriers contributed to their phenotype. We identified activating MAP3K3 and PIK3CA somatic mutations in the majority (90.1%) of sporadic cavernous malformations and PIK3CA mutations could confer a higher risk for overt haemorrhage. Our data provide insights into genomic landscapes, propose a mechanistic explanation and underscore the possibility of a molecular classification for sporadic cavernous malformations.
影响中枢神经系统的海绵状血管畸形在普通人群中的发生率为 0.16-0.4%。大多数（85%）海绵状血管畸形为散发性，但散发性海绵状血管畸形的遗传背景仍不清楚。在 81 名患者中，通过全外显子组测序，73 名（90.1%）患者检测到携带两个基因的体细胞错义变异：MAP3K3 和 PIK3CA。突变谱与病变大小（P=0.001）、解剖分布（P<0.001）、MRI 表现（P=0.004）和出血事件（P=0.006）相关。PIK3CA 突变是显性出血事件的显著预测因子（P=0.003，优势比=11.252，95%置信区间=2.275-55.648）。内皮细胞群体的富集与体细胞突变的分数丰度较高相关。MAP3K3 突变的过表达扰乱了内皮细胞模型的体外血管生成和斑马鱼胚胎的体内血管生成。通过单细胞 RNA 测序鉴定了散发性海绵状血管畸形不同遗传亚组之间的独特转录特征，并通过病理染色进行了验证。MAP3K3 突变携带者中存在显著的细胞凋亡，PIK3CA 突变携带者中 GDF15 和 SERPINA5 的过表达导致其表型。我们在大多数（90.1%）散发性海绵状血管畸形中发现了激活的 MAP3K3 和 PIK3CA 体细胞突变，PIK3CA 突变可能会增加显性出血的风险。我们的数据提供了对基因组景观的深入了解，提出了一种机制解释，并强调了对散发性海绵状血管畸形进行分子分类的可能性。
