SomaticMAP3K3andPIK3CAmutations in sporadic cerebral and spinal cord cavernous malformations

Abstract

Cavernous malformations (CMs) affecting the central nervous system occur in approximately 0.16% to 0.4% of the general population. The majority (85%) of the CMs are in a sporadic form, but the genetic background of sporadic CMs remains enigmatic. Of the 81 patients, 73 (90.1%) patients were detected carrying somatic missense variants in 2 genes: MAP3K3 and PIK3CA by whole-exome sequencing (WES). 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, OR = 11.252, 95% CI = 2.275-55.648). Enrichment of endothelial cell (EC) population was associated with a higher fractional abundance of the somatic mutations. Overexpression of the MAP3K3 mutation perturbed angiogenesis of EC models in vitro and zebrafish embryos in vivo. Distinct transcriptional signatures between different genetic subgroups of sporadic CMs were identified by single-cell RNA-sequencing (scRNA-seq) 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 CMs 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 CMs.

Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

“…Of interest, let-7c-5p also targets COL1A1, a DEG within the transcriptome of human sporadic CCM lesions (see Supplementary Data). This gene is associated with PI3K/AKT signaling, platelet activation, and ECM-receptor interaction KEGG pathways 28,29 , all of which have previously been implicated in CCM disease 9,10,30,31 .…”

“…The majority of CCM and verrucous venous malformations with a mutation in MAP3K3 harbor the p.I441M variant 9,11,20 , however an alternative variant p.Y544H has also been identified in a venous malformation 23 . While ddPCR provides superior sensitivity and specificity compared to targeted sequencing, it is restricted to detecting a single mutation per assay.…”

“…Previous studies have established that CCM pathogenesis follows a genetic two-hit model where somatic mutations cause biallelic LOF in KRIT1, CCM2, or PDCD10 to initiate lesion formation [5][6][7][8] . Recent studies have found that somatic mutations in PIK3CA and MAP3K3 also contribute to CCM pathogenesis [9][10][11] . These discoveries opened new avenues for research and therapeutic development, but they also raised new questions about the roles of somatic mutations in familial versus sporadic lesions.…”

“…CCMs have long been known to follow a genetic two-hit model where lesion formation is initiated by somatic mutations resulting in biallelic loss of a CCM complex gene [5][6][7][8] . Recent studies have shown that somatic mutations in MAP3K3 and PIK3CA also contribute to CCM pathogenesis [9][10][11] ; however, it remains unclear how these mutations contribute to sporadic versus familial cases. Here we show that somatic mutations in MAP3K3 are mutually exclusive with mutations in CCM complex genes and that mutations in MAP3K3 contribute to sporadic, but not familial CCM.…”

Cerebrofacial vascular metameric syndrome is caused by somatic pathogenic variants in PIK3CA

“…DVAs have previously been associated with facial venous malformations ( Brinjikji et al 2018 ), suggesting that interval MRI screening of some patients with facial vascular malformations could be considered. Cerebral cavernous malformations associated with PIK3CA mutations are associated with a higher risk of hemorrhage ( Hong et al 2021 ), supporting future studies examining the efficacy of PI3K–RAS–MAPK pathway inhibitors in reducing CCM progression and bleeding.…”