title: Somatic PIK3CA mutations as a driver of sporadic venous malformations.
abstract: Venous malformations (VM) are vascular malformations characterized by enlarged and distorted blood vessel channels. VM grow over time and cause substantial morbidity because of disfigurement, bleeding, and pain, representing a clinical challenge in the absence of effective treatments (Nguyenet al, 2014; Uebelhoeret al, 2012). Somatic mutations may act as drivers of these lesions, as suggested by the identification of TEK mutations in a proportion of VM (Limayeet al, 2009). We report that activating PIK3CA mutations gives rise to sporadic VM in mice, which closely resemble the histology of the human disease. Furthermore, we identified mutations in PIK3CA and related genes of the PI3K (phosphatidylinositol 3-kinase)/AKT pathway in about 30% of human VM that lack TEK alterations. PIK3CA mutations promote downstream signaling and proliferation in endothelial cells and impair normal vasculogenesis in embryonic development. We successfully treated VM in mouse models using pharmacological inhibitors of PI3Kα administered either systemically or topically. This study elucidates the etiology of a proportion of VM and proposes a therapeutic approach for this disease.
authors.affiliation: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Pau
authors.initials: P
authors.lastname: Castel
authors.affiliation: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Carmona
authors.affiliation: Developmental Biology Program, Sloan Kettering Institute, New York, NY 10065, USA.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Grego-Bessa
authors.affiliation: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Genomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Agnès
authors.initials: A
authors.lastname: Viale
authors.affiliation: Developmental Biology Program, Sloan Kettering Institute, New York, NY 10065, USA.
authors.forename: Kathryn V
authors.initials: KV
authors.lastname: Anderson
authors.affiliation: Department of Pathology, Hospital de la Santa Creu i Sant Pau, 167 Sant Antoni M. Claret, Barcelona 08025, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bague
authors.affiliation: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.affiliation: Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain.
authors.forename: Eulàlia
authors.initials: E
authors.lastname: Baselga
authors.affiliation: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. baselgaj@mskcc.org.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D004622:Embryo, Mammalian / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012867:Skin / Q000098:blood supply / Q000473:pathology; D013116:Spinal Cord / Q000098:blood supply / Q000473:pathology; D054079:Vascular Malformations / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*
chemical_list: D047428:Protein Kinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C546639:Pik3ca protein, mouse; C045073:Cre recombinase; D019426:Integrases