Somatic <i>PIK3CA</i> Mutations in Sporadic Cerebral Cavernous Malformations.

Abstract

Cerebral cavernous malformations (CCMs) are common sporadic and inherited vascular malformations of the central nervous system. Although familial CCMs are linked to loss-of-function mutations in <i>KRIT1</i> (<i>CCM1</i>), <i>CCM2</i>, or <i>PDCD10</i> (<i>CCM3</i>), the genetic cause of sporadic CCMs, representing 80% of cases, remains incompletely understood. We developed two mouse models harboring mutations identified in human meningiomas with the use of the prostaglandin D2 synthase (PGDS) promoter. We performed targeted DNA sequencing of surgically resected CCMs from patients and confirmed our findings by droplet digital polymerase-chain-reaction analysis. We found that in mice expressing one of two common genetic drivers of meningioma - <i>Pik3ca</i> ^H1047R or <i>AKT1</i> ^E17K - in PGDS-positive cells, a spectrum of typical CCMs develops (in 22% and 11% of the mice, respectively) instead of meningiomas, which prompted us to analyze tissue samples from sporadic CCMs from 88 patients. We detected somatic activating <i>PIK3CA</i> and <i>AKT1</i> mutations in 39% and 1%, respectively, of lesion tissue from the patients. Only 10% of lesions harbored mutations in the <i>CCM</i> genes. We analyzed lesions induced by the activating mutations <i>Pik3ca</i> ^H1074R and <i>AKT1</i> ^E17K in mice and identified the PGDS-expressing pericyte as the probable cell of origin. In tissue samples from sporadic CCMs, mutations in <i>PIK3CA</i> were represented to a greater extent than mutations in any other gene. The contribution of somatic mutations in the genes that cause familial CCMs was comparatively small. (Funded by the Fondation ARC pour la Recherche contre le Cancer and others.).