Developmental venous anomalies are a genetic primer for cerebral cavernous malformations

Abstract

Introductory Paragraph 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 .

Microphysiological model of PIK3CA-driven vascular malformations reveals a role of dysregulated Rac1 and mTORC1/2 in lesion formation

“…Collectively, our findings demonstrate a functional redundancy in the ERK1/2 and mTORC1 signaling pathways in regulating endothelial cell proliferation and vessel enlargement and that inhibition of cell growth through ERK1/2 or mTORC1 alone is not sufficient to rescue cytoskeletal perturbations that are regulated by mTORC2/Rac1/PAK signaling. These findings are in line with the two-hit model of CCMs, where loss of function mutations of the CCM complex that result in increased MEKK3–ERK5–Krüeppel-like factor signaling and a subsequent gain of function mutation in PIK3CA signaling synergize to promote aggressive CCM lesions ( 61 , 62 ).…”

Angioarchitecture and genetic variants of spinal cord cavernous malformations and associated DVAs — A case report

“…Subsequent work has also highlighted the importance of somatic mutation as a genetic agent [3]. A recent study has provided good insights into cerebral cavernous malformations with DVA [2]. However, spinal cord CM with associated DVA is not common, and sequencing analysis of genetic mutations has not been reported.…”

Symptomatic Developmental Venous Anomaly: State-of-the-Art Review on Genetics, Pathophysiology, and Imaging Approach to Diagnosis

“…DVAs may have a somatic activating mutation in the PIK3CA gene, leading to a gain of function, which acts as a genetic precursor to a sporadic CCM. 7 An acquired second-hit mutation in the CCM complex (KRIT1, CCM2, PDCD10) or MAP3K3 then results in the formation of a sporadic CCM, 7 supported by the observation that sporadic CCMs often develop within the venous drainage territory of the DVA. 8 On the other hand, hereditary CCMs preferentially develop via a mutation in the CCM complex (CCM1, CCM2, CCM3 gene loci) or the MAP3K3 locus, causing multiple quiescent CCMs, which may acquire an additional mutation in PIK3CA, driving lesional growth.…”

“…8 On the other hand, hereditary CCMs preferentially develop via a mutation in the CCM complex (CCM1, CCM2, CCM3 gene loci) or the MAP3K3 locus, causing multiple quiescent CCMs, which may acquire an additional mutation in PIK3CA, driving lesional growth. 7 Symptomatic DVA Symptomatic DVA is an umbrella term that encompasses a diverse range of DVA-related complications. Systematic review predominately from low-level evidence (ie, case series or casecontrol studies) showed that an astounding 61% of DVAs are asymptomatic: 23% with nonspecific clinical presentation, 6% with a focal neurologic deficit, 6% with hemorrhage, 4% with seizures, and ,1% with infarct.…”

“…9 As to the formation of CCMs in DVAs, there is a recently proposed genetic model for the formation of CCMs from a "2-hit hypothesis." 7 However, a more mechanical model for the de novo formation of a CCM around a DVA is proposed on the basis of a combination of venous congestion and venous ischemia due to poor venous outflow leading to a release of local angiogenetic factors and endothelial proliferation. Newly formed fragile vessels are prone to bleeding, creating an initial petechial hemorrhage, and repeat cycles of re-endothelialization and hemorrhage eventually lead to the classic multilobulated MR imaging appearance of a CCM.…”