Developmental venous anomalies are a genetic primer for cerebral cavernous malformations

Cerebral cavernous malformations (CCM) are a neurovascular anomaly that may occur sporadically, or be inherited due to autosomal dominant mutations in KRIT1, CCM2, or PDCD10. Individual lesions are caused by somatic mutations which have been identified in KRIT1, CCM2, PDCD10, MAP3K3, and PIK3CA. However, the interactions between mutations, and their relative contributions to sporadic versus familial cases remain unclear. We show that mutations in KRIT1, CCM2, PDCD10, and MAP3K3 are mutually exclusive, but may co-occur with mutations in PIK3CA. We also find that MAP3K3 mutations may cause sporadic, but not familial CCM. Furthermore, we find identical PIK3CA mutations in CCMs and adjacent developmental venous anomalies (DVA), a common vascular malformation frequently found in the vicinity of sporadic CCMs. However, somatic mutations in MAP3K3 are found only in the CCM. This suggests that sporadic CCMs are derived from cells of the DVA which have acquired an additional mutation in MAP3K3.