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A Patient-Derived Xenograft Model for Venous Malformation
Published on: June 15, 2020
Somatic Activating PIK3CA Mutations Cause Venous Malformation
Nisha Limaye1, Jaakko Kangas2, Antonella Mendola1
1Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
Abstract:
Somatic mutations in TEK, the gene encoding endothelial cell tyrosine kinase receptor TIE2, cause more than half of sporadically occurring unifocal venous malformations (VMs). Here, we report that somatic mutations in PIK3CA, the gene encoding the catalytic p110α subunit of PI3K, cause 54% (27 out of 50) of VMs with no detected TEK mutation. The hotspot mutations c.1624G>A, c.1633G>A, and c.3140A>G (p.Glu542Lys, p.Glu545Lys, and p.His1047Arg), frequent in PIK3CA-associated cancers, overgrowth syndromes, and lymphatic malformation (LM), account for >92% of individuals who carry mutations. Like VM-causative mutations in TEK, the PIK3CA mutations cause chronic activation of AKT, dysregulation of certain important angiogenic factors, and abnormal endothelial cell morphology when expressed in human umbilical vein endothelial cells (HUVECs). The p110α-specific inhibitor BYL719 restores all abnormal phenotypes tested, in PIK3CA- as well as TEK-mutant HUVECs, demonstrating that they operate via the same pathogenic pathways. Nevertheless, significant genotype-phenotype correlations in lesion localization and histology are observed between individuals with mutations in PIK3CA versus TEK, pointing to gene-specific effects.
Insights
Somatic mutations in PIK3CA are a significant cause of venous malformations (VMs), activating AKT and leading to abnormal cell growth. A specific inhibitor shows promise in restoring normal cell function in both PIK3CA- and TEK-mutant VMs.
Area of Science:
- Genetics
- Molecular Biology
- Vascular Biology
Background:
- Somatic mutations in TEK (TIE2) are a known cause of sporadic venous malformations (VMs).
- The genetic underpinnings of VMs without TEK mutations require further elucidation.
Purpose of the Study:
- To identify the genetic cause of VMs in patients lacking TEK mutations.
- To characterize the functional consequences of identified mutations in VMs.
- To explore potential therapeutic targets for VM treatment.
Main Methods:
- Somatic mutation analysis of the PIK3CA gene in VM patient samples.
- Expression of mutant PIK3CA in human umbilical vein endothelial cells (HUVECs).
- Assessment of AKT activation, angiogenic factor dysregulation, and endothelial cell morphology.
- Inhibition studies using a PIK3CA-specific inhibitor (BYL719).
Main Results:
- Somatic PIK3CA mutations were identified in 54% of VMs without TEK mutations.
- Hotspot PIK3CA mutations (p.Glu542Lys, p.Glu545Lys, p.His1047Arg) were prevalent.
- PIK3CA mutations led to chronic AKT activation and abnormal endothelial cell phenotypes.
- BYL719 treatment rescued abnormal phenotypes in both PIK3CA- and TEK-mutant HUVECs.
- Genotype-phenotype correlations were observed between PIK3CA and TEK mutations.
Conclusions:
- PIK3CA mutations are a major driver of sporadic venous malformations.
- PIK3CA and TEK mutations converge on common pathogenic pathways involving AKT.
- Targeted inhibition of PIK3CA offers a potential therapeutic strategy for VMs.
- Gene-specific effects contribute to variations in VM presentation.
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