Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations
Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations
复制标题
散发性脑和脊髓海绵状畸形中的体细胞MAP3K3和PIK3CA突变
DOI：
10.1093/brain/awab117
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发表时间：
2021-03-17
期刊：
影响因子：
14.5
通讯作者：
Wang, Yibo
中科院分区：
文献类型：
--
作者：
Hong, Tao;Xiao, Xiao;Wang, Yibo
影响中枢神经系统的海绵状畸形约占总人口的0.16-0.4%。大多数(85%)的海绵状畸形是散发性的，但散发性海绵状畸形的遗传背景仍然是个谜。对81例患者进行全外显子测序，发现73例(90.1%)患者携带MAP3K3和PIK3CA两个基因的体细胞错义变异。突变谱与病变大小(P=0.001)、解剖分布(P<；0.001)、磁共振征象(P=0.004)和出血事件(P=0.006)相关。PIK3CA基因突变是临床出血事件的显著预测因素(P=0.003，优势比=11.252，95%可信区间=2.275~55.648)。内皮细胞群体的丰富与较高的体细胞突变丰度相关。MAP3K3突变的过表达干扰了体外血管内皮细胞模型和体内斑马鱼胚胎的血管生成。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群之间的不同转录特征，并经病理染色证实。MAP3K3突变携带者明显的细胞凋亡和PIK3CA突变携带者GDF15和SERPINA5的过度表达与其表型有关。我们发现在大多数(90.1%)散发性海绵状血管畸形中激活MAP3K3和PIK3CA体细胞突变，并且PIK3CA突变可以增加明显出血的风险。我们的数据提供了对基因组景观的洞察，提出了一种机制解释，并强调了对散发性海绵状畸形进行分子分类的可能性。
Cavernous malformations affecting the CNS occur in similar to 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.