Somatic PIK3CA and PTEN mutations with endothelial PI3K/AKT/mTOR activation in RAS-negative brain arteriovenous malformations.

Somatic mutations affecting endothelial signaling pathways have emerged as important contributors to brain arteriovenous malformations (bAVMs). Although activating mutations in the RAS/MAPK pathway have been frequently reported, alternative molecular mechanisms remain incompletely understood. We describe 2 autopsy-confirmed bAVMs harboring somatic PIK3CA mutations, including one case with a concurrent PTEN alteration. Histologically, both lesions demonstrated typical bAVM architecture without unusual structural features. Immunohistochemical analysis revealed lesion-restricted activation of the PI3K/AKT/mTOR pathway in endothelial cells; adjacent normal vessels were negative. In contrast, ERK phosphorylation was focal and limited; targeted sequencing did not identify pathogenic RAS/MAPK mutations. These findings suggest dominant PI3K pathway activation with secondary or limited MAPK engagement. Variant allele frequencies were interpreted cautiously owing to whole-genome amplification from autopsy-derived tissue. In one case, prior Gamma Knife radiosurgery was considered to have contributed to the findings but histological features of radiation-associated vascular injury were not observed. Together, these findings support molecular heterogeneity in bAVMs and suggest that PIK3CA-driven PI3K pathway activation may contribute to vascular remodeling in RAS-negative lesions. Correlation of molecular alterations with pathway-specific endothelial activation highlights the value of integrated genetic and pathological assessment in bAVMs.