PIK3CA and cerebral cavernous malformation: However, given the well-established role of PTEN as a negative regulator of the PI3K/Akt signaling pathway, the very recent discovery that activating mutations in genes involved in such pathway are implicated in CCM disease pathogenesis [14,15,16,44] leaves open the intriguing possibility that PTEN mutations may indeed contribute to CCM disease, thus raising the necessity for further investigation.