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Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations.

Authors :
Hong, Tao
Xiao, Xiao
Ren, Jian
Cui, Bing
Zong, Yuru
Zou, Jian
Kou, Zqi
Jiang, Nan
Meng, Guolu
Zeng, Gao
Shan, Yongzhi
Wu, Hao
Chen, Zan
Liang, Jiantao
Xiao, Xinru
Tang, Jie
Wei, Yukui
Ye, Ming
Sun, Liyong
Li, Guilin
Source :
Brain: A Journal of Neurology. Sep2021, Vol. 144 Issue 9, p2648-2658. 11p.
Publication Year :
2021

Abstract

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00068950
Volume :
144
Issue :
9
Database :
Academic Search Index
Journal :
Brain: A Journal of Neurology
Publication Type :
Academic Journal
Accession number :
153798248
Full Text :
https://doi.org/10.1093/brain/awab117