Identification of genetic causes and molecular mechanisms in lymphatic anomalies
(2021)
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- Abstract
- This thesis focuses on unifocal lymphatic malformations (LMs), Gorham-Stout disease (GSD), and lymphatic-related fetal hydrops (LRFH). In a first study, we identified a somatic PIK3CA mutation in 75.5% of LM patients, indicating that PI3K-pathway inhibitors could be used to treat the majority of LMs. Hotspot mutations were more frequent in common and combined LMs compared to syndromes. We also discovered an activating somatic mutation in KRAS in one GSD patient. We showed that activated KRAS signaling in LECs impairs development of lymphatic valves and stimulates development of lymphatics in bone. Trametinib was able to prevent the loss of valves. Finally, we found that EPHB4 kinase-dead variants in LRFH accumulate on cell surface compared to wild-type, whereas CM-AVM2-causing variants are reduced. Altogether, these data increased our knowledge on the genetic and molecular mechanisms underlying lymphatic endothelial-related diseases and allow to envision efficient drug-based therapy.
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Citations
Homayun Sepehr, N. (2021). Identification of genetic causes and molecular mechanisms in lymphatic anomalies. https://hdl.handle.net/2078.5/108455