GSE195732
Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations
Purpose: Cerebral cavernous malformations (CCMs) are hemorrhagic neurovascular malformations that may lead to stroke, seizures and other clinical sequelae. Recent studies have shown that somatic mutations in MAP3K3 and PIK3CA also contribute to CCM pathogenesis; however, it remains unclear how these mutations contribute to sporadic versus familial cases. In our previous research, we've shown that co-occurring MAP3K3 and PIK3CA mutations are present within the same clonal population of cells. The overall goal of this study was to identify PIK3CA mutations in CCM-associated developmental venous anomalies (DVA). We also analyzed the plasma miRNome of patients with (1) DVA without associated CCM, as well as (2) DVA with an associated CCM) to identify circulating miRNAs that might serve as biomarkers reflecting PIK3CA activity. Methods: We collected and sequenced the plasma miRNome of 12 individuals with a sporadic CCM associated with a DVA (CCM + DVA), 6 individuals with a DVA without a CCM (DVA only), and 7 healthy controls. Results: We found that the identical PIK3CA mutation is found in endothelial cells of both the DVA and its associated CCM, but that an activating MAP3K3 mutation appears only in the CCM. The analyses miR-134-5p was downregulated in the groups of patients with only a DVA only group (when compared to healthy controls). This miRNA has been shown to target PIK3CA. In addition, miR-182-5p, was upregulated and targets MAP3K3; while let-7c-5p was downregulated and targets both PIK3CA and MAP3K3 in the group of patients with CCM and an associated DVA (when compared to DVA only). Conclusions: These results support a mechanism where DVA develop as the result of a PIK3CA mutation, creating a region of the brain vasculature that functions as a genetic primer for CCM development following acquisition of an additional somatic mutation. Overall design: Sequencing and analyses of the differential of the human plasma miRNome in 3 cohort of patients with (1) a DVA with an associated CCM, (2) only a DVA, and (3) healthy controls.