Familial CCM Genes Might Not Be Main Drivers for Pathogenesis of Sporadic CCMs-Genetic Similarity between Cancers and Vascular Malformations

Abstract

Cerebral cavernous malformations (CCMs) are abnormally dilated intracranial capillaries that form cerebrovascular lesions with a high risk of hemorrhagic stroke. Recently, several somatic "activating" gain-of-function (GOF) point mutations in PIK3CA (phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit p110α) were discovered as a dominant mutation in the lesions of sporadic forms of cerebral cavernous malformation (sCCM), raising the possibility that CCMs, like other types of vascular malformations, fall in the PIK3CA-related overgrowth spectrum (PROS). However, this possibility has been challenged with different interpretations. In this review, we will continue our efforts to expound the phenomenon of the coexistence of gain-of-function (GOF) point mutations in the PIK3CA gene and loss-of-function (LOF) mutations in CCM genes in the CCM lesions of sCCM and try to delineate the relationship between mutagenic events with CCM lesions in a temporospatial manner. Since GOF PIK3CA point mutations have been well studied in reproductive cancers, especially breast cancer as a driver oncogene, we will perform a comparative meta-analysis for GOF PIK3CA point mutations in an attempt to demonstrate the genetic similarities shared by both cancers and vascular anomalies.

Keywords: CCM signaling complex (CSC); Cerebral cavernous malformations (CCMs); PIK3CA-related overgrowth spectrum (PROS); developmental venous anomalies (DVAs); familial CCM (fCCM); gain-of-function (GOF); phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit p110α (PIK3CA); sporadic CCM (sCCM); tumor driver mutations; tumor passenger mutations; vascular malformations (VMs); venous malformations (VeMs).

Figure 1

Oncogrid analysis of simple somatic mutations in known breast cancer oncogenes and key genes within the CmPn signaling network. Known driver oncogenes (red colored) and key components (black colored) of the CmPn signaling network from 200 breast cancer lesions in Genomic Data Commons (GDC) and The Cancer Genome Atlas (TCGA). Utilizing the GDC data portal from the National Cancer Institute (NCI), the distribution of simple somatic mutations (SSM) for breast cancer lesions for common breast cancer driver genes, along with SSM counted in all key CmPn players were assessed. SSM, represented with green dots, are somatic mutations that include single base substitutions, small deletions, and insertions (≤200 bp).

Figure 2

Oncogrid analysis of simple somatic mutations in known reproductive cancer oncogenes and key genes within the CmPn signaling network. Known driver oncogenes (red colored) and key components (black colored) of the CmPn signaling network from 200 breast cancer lesions in Genomic Data Commons (GDC) and The Cancer Genome Atlas (TCGA). Utilizing the GDC data portal from the National Cancer Institute (NCI), the distribution of simple somatic mutations (SSM) for reproductive cancer lesions for common cancer driver genes, along with SSM counted in all key CmPn players were assessed. SSM, represented with green dots, are somatic mutations that include single base substitutions, small deletions, and insertions (≤200 bp).