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Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly
Lara Rodriguez-Laguna1, Noelia Agra1, Kristina Ibañez2
1Vascular Malformations Section, Institute of Medical and Molecular Genetics, Institute of Medical and Molecular Genetics-Instituto de Investigación PAZ, Hospital Universitario La Paz, Madrid, Spain.
The Journal of Experimental Medicine
|December 29, 2018
Summary
Somatic PIK3CA mutations cause generalized lymphatic anomaly (GLA). The mTOR inhibitor rapamycin shows promise in treating this vascular disorder, reducing lymphatic malformations and pain in patients.
Area of Science:
- Vascular Biology
- Molecular Genetics
- Pharmacology
Background:
- Generalized lymphatic anomaly (GLA) is a rare vascular disorder involving lymphatic malformations (LMs).
- The underlying genetic causes of GLA have remained largely unknown.
- The PI3K-AKT-mTOR pathway is crucial in cell growth and proliferation.
Purpose of the Study:
- To investigate the genetic basis of GLA.
- To explore the therapeutic potential of mTOR inhibitors in GLA.
Main Methods:
- Somatic PIK3CA variants were identified in patient tissue samples using genetic sequencing.
- A mouse model with lymphatic-specific PIK3CA activation was utilized.
- The efficacy of rapamycin was assessed in both preclinical models and human patients.
Main Results:
- Four distinct somatic PIK3CA variants were found in 5 of 9 GLA patients.
- These variants are known to activate the PI3K-AKT-mTOR pathway.
- Rapamycin treatment reduced lymphatic hyperplasia and dysfunction in mice and alleviated pain in GLA patients.
Conclusions:
- Somatic activating PIK3CA mutations are a causative factor in GLA.
- Rapamycin demonstrates preclinical and clinical efficacy for GLA treatment.
- Targeting the PI3K-AKT-mTOR pathway with rapamycin offers a potential therapeutic strategy for GLA.
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