Comprehensive phenotypic and genomic characterization of venous malformations
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Updated: Jul 2, 2025
A Patient-Derived Xenograft Model for Venous Malformation
Published on: June 15, 2020
Katsutoshi Hirose1, Yumiko Hori2, Michio Ozeki3
1Department of Oral and Maxillofacial Pathology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Abstract:
Venous malformations (VMs) are the most common vascular malformations. TEK and PIK3CA are the causal genes of VMs, and may be involved in the PI3K/AKT pathway. However, the downstream mechanisms underlying the TEK or PIK3CA mutations in VMs are not completely understood. This study aimed to identify a possible association between genetic mutations and clinicopathological features. A retrospective clinical, pathological, and genetic study of 114 patients with VMs was performed. TEK, PIK3CA, and combined TEK/PIK3CA mutations were identified in 49 (43%), 13 (11.4%), and 2 (1.75%) patients, respectively. TEK-mutant VMs more commonly occurred in younger patients than TEK and PIK3CA mutation-negative VMs (other-mutant VMs), and showed more frequent skin involvement and no lymphocytic aggregates. No significant differences were observed in sex, location of occurrence, malformed vessel size, vessel density, or thickness of the vascular smooth muscle among the VM genotypes. Immunohistochemical analysis revealed that the expression levels of phosphorylated AKT (p-AKT) were higher in the TEK-mutant VMs than those in PIK3CA-mutant and other-mutant VMs. The expression levels of p-mTOR and its downstream effectors were higher in all the VM genotypes than those in normal vessels. Spatial transcriptomics revealed that the genes involved in "blood vessel development", "positive regulation of cell migration", and "extracellular matrix organization" were up-regulated in a TEK-mutant VM. Significant genotype-phenotype correlations in clinical and pathological features were observed among the VM genotypes, indicating gene-specific effects. Detailed analysis of gene-specific effects in VMs may offer insights into the underlying molecular pathways and implications for targeted therapies.
Insights
Genetic mutations in TEK and PIK3CA are linked to venous malformations (VMs). TEK mutations in VMs are associated with younger patients and skin involvement, impacting the PI3K/AKT pathway for potential targeted therapies.
Area of Science:
- Vascular Biology
- Genetics
- Pathology
Background:
- Venous malformations (VMs) are common vascular anomalies.
- TEK and PIK3CA genes are implicated in VM development, potentially through the PI3K/AKT pathway.
- Downstream mechanisms of TEK/PIK3CA mutations in VMs require further elucidation.
Purpose of the Study:
- To investigate the association between genetic mutations (TEK, PIK3CA) and clinicopathological features in VMs.
- To explore the downstream molecular effects of these mutations.
- To identify genotype-specific patterns in VM development.
Main Methods:
- Retrospective study of 114 VM patients.
- Genetic analysis for TEK and PIK3CA mutations.
- Immunohistochemistry for p-AKT and p-mTOR.
- Spatial transcriptomics for gene expression analysis.
Main Results:
- TEK mutations (43%) were more frequent than PIK3CA mutations (11.4%).
- TEK-mutant VMs occurred in younger patients, showed more skin involvement, and lacked lymphocytic aggregates.
- Increased p-AKT in TEK-mutant VMs; elevated p-mTOR in all VM genotypes.
- Upregulation of 'blood vessel development' and 'cell migration' genes in TEK-mutant VMs.
- Significant genotype-phenotype correlations were observed.
Conclusions:
- TEK and PIK3CA mutations exhibit distinct clinicopathological features and molecular signaling in VMs.
- Gene-specific effects influence VM development and presentation.
- Findings provide insights into VM pathogenesis and potential targeted therapeutic strategies.
