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.

Genotype‐phenotype correlations in multiple lesions of familial cerebral cavernous malformations concerning phosphatidylinositol 3‐kinase catalytic subunit alpha mutations

“…In familiar cases, CCM germline mutations occur earlier than somatic PIK3CA mutations, nevertheless, CCM mutations may be a secondary event following the mutation of PI3K pathway genes in sporadic cases. [3][4][5] Two subgroups' lesions harboured different genotypes and related phenotypes, which implies an underlying molecular mechanism within them. Recent studies indicated that PIK3CA mutation was associated with haemorrhagic events in CCMs.…”

“…Jie Wang 1,2 Jihong Tang 3,4 Yingxi Yang 4 Yuming Jiao 1,2 Ran Huo 1,2 Hongyuan Xu 1,2 Shaozhi Zhao 1,2 Yingfan Sun 1,2 Qiheng He 1,2 Qifeng Yu 1,2 Shuo Wang 1,2 Jizong Zhao 1,2 Jiguang Wang 3,4,5 Yong Cao…”

Plasma water T2detects age-stratified differences in cardiometabolic health among familial CCM patients with Hispanic CCM1 mutation

“…Although further research and validation is needed, plasma water T 2 shows potential for addressing that need. 1 F, female; M, male 2 H, Hispanic; NH, non-Hispanic 3 median (interquartile range), full range 4 individuals carrying the same Baca familial CCM1 hemizygous mutation 5 individuals with no known CCM mutation and poor cardiometabolic health (T 2 ≤700.1 msec) 6 individuals with no known CCM mutation and good cardiometabolic health (T 2 >700.1 msec) 7 individuals with no known CCM mutation; combination of unhealthy and healthy groups…”

“…CCMs are characterized by two distinct features, each associated with both common and unique causative genetic mutation landscapes. These features encompass familial CCMs (fCCMs), which are inherited, and sporadic CCMs (sCCMs), which arise de novo [2,4,5]. The focus of this study is on a single "common Hispanic" fCCM1 mutation due to its inheritable nature and traceable genetic lineage route.…”

Plasma water T2 detects age-stratified differences in cardiometabolic health among familial CCM patients with Hispanic CCM1 mutation

“…CCMs are characterized by two distinct features, each associated with both common and unique causative genetic mutation landscapes. These features encompass familial CCMs (fCCMs), which are inherited, and sporadic CCMs (sCCMs), which arise de novo (Zhang 2011 ;Zhang et al 2022; Zhang et al 2023). The focus of this study is on a single "common Hispanic" fCCM1 mutation due to its inheritable nature and traceable genetic lineage route.…”