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. Author manuscript; available in PMC: 2022 Jun 25.
Published in final edited form as: Circ Res. 2021 Jun 24;129(1):195–215. doi: 10.1161/CIRCRESAHA.121.318174

Figure 1. Somatic mutations driving CCM progression.

Figure 1.

In familial CCM (top), lesion formation is initiated by a somatic mutation in a CCM gene resulting in biallelic loss of function which may occur multiple times resulting in the formation of multiple quiescent CCMs. A subset of these CCMs acquire a somatic gain of function mutation in PIK3CA which fuels lesion growth. Sporadic CCM formation (bottom) requires either two somatic CCM mutations to occur in the same cell resulting in biallelic loss of function or a single gain of function somatic mutation in MAP3K3. A CCM at this stage may or may not acquire a somatic gain of function in PIK3CA which would fuel lesion growth. The order in which the mutations occur is not yet known. This figure shows the CCM/MAP3K3 mutations as occurring first, however the PIK3CA mutation may occur first in some or all cases.