title: Activating PIK3CA alleles and lymphangiogenic phenotype of lymphatic endothelial cells isolated from lymphatic malformations.
abstract: Lymphatic malformations (LMs) are developmental anomalies of the lymphatic system associated with the dysmorphogenesis of vascular channels lined by lymphatic endothelial cells (LECs). Seeking to identify intrinsic defects in affected LECs, cells were isolated from malformation tissue or fluid on the basis of CD31 and podoplanin (PDPN) expression. LECs from five unrelated LM lesions were characterized, including cells derived from one patient previously diagnosed with CLOVES. CLOVES-related LECs carried a known, activating mutation in PIK3CA (p.H1047L), confirmed by direct sequencing. Activating PIK3CA mutations (p.E542K and p.E545A) were identified in lesion-derived cells from the other four patients, also by direct sequencing. The five LM-LEC cultures shared a lymphangiogenic phenotype distinguished by PI3K/AKT activation, enhanced sprouting efficiency, elevated VEGF-C expression and COX2 expression, shorter doubling times and reduced expression of angiopoietin 2 and CXCR4. Nine additional LM-LEC populations and 12 of 15 archived LM tissue samples were shown to bear common PIK3CA variants by allele-specific PCR. The activation of a central growth/survival pathway (PI3K/AKT) represents a feasible target for the non-invasive treatment of LMs bearing in mind that background genetics may individualize lesions and influence treatments.
authors.affiliation: Hemangioma and Vascular Malformation Center, Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital and Medical Center, MLC 2023, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA, Division of Otolaryngology, Head and Neck Surgery, Cincinnati Children's Hospital and Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Osborn
authors.affiliation: Hemangioma and Vascular Malformation Center, Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital and Medical Center, MLC 2023, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Dickie
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital and Medical Center, MLC 4006, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA and.
authors.forename: Derek E
authors.initials: DE
authors.lastname: Neilson
authors.affiliation: Hemangioma and Vascular Malformation Center, Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital and Medical Center, MLC 2023, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Glaser
authors.affiliation: Hemangioma and Vascular Malformation Center, Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital and Medical Center, MLC 2023, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
authors.forename: Kaari A
authors.initials: KA
authors.lastname: Lynch
authors.affiliation: Department of Pathology, Cincinnati Children's Hospital and Medical Center, MLC 1035, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Hemangioma and Vascular Malformation Center, Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital and Medical Center, MLC 2023, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA, belinda.dickie@cchmc.org.
authors.forename: Belinda Hsi
authors.initials: BH
authors.lastname: Dickie
mesh_terms: D000293:Adolescent; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D042583:Lymphangiogenesis / Q000235:genetics*; D044148:Lymphatic Abnormalities / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D008297:Male; D009154:Mutation; D009287:Naphthyridines / Q000494:pharmacology; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction; D015533:Transcriptional Activation; D055815:Young Adult
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D009287:Naphthyridines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C576806:SAR131675; C484760:PIK3CA protein, human