Somatic PIK3CA mutations as a driver of sporadic venous malformations
Por:
Castel, P, Carmona, FJ, Grego-Bessa, J, Berger, MF, Viale, A, Anderson, KV, Bague, S, Scaltriti, M, Antonescu, CR, Baselga, E, Baselga, J
Publicada:
30 mar 2016
Resumen:
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 (Nguyen et al., 2014; Uebelhoer et al., 2012). Somatic mutations may act as drivers of these lesions, as suggested by the identification of TEK mutations in a proportion of VM(Limaye et 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 PI3K alpha administered either systemically or topically. This study elucidates the etiology of a proportion of VM and proposes a therapeutic approach for this disease.
Filiaciones:
Castel, P:
Mem Sloan Kettering Canc Ctr, HOPP, 1275 York Ave, New York, NY 10065 USA
Carmona, FJ:
Mem Sloan Kettering Canc Ctr, HOPP, 1275 York Ave, New York, NY 10065 USA
Grego-Bessa, J:
Sloan Kettering Inst, Dev Biol Program, New York, NY 10065 USA
Berger, MF:
Mem Sloan Kettering Canc Ctr, HOPP, 1275 York Ave, New York, NY 10065 USA
Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA
Viale, A:
Mem Sloan Kettering Canc Ctr, Genom Core Lab, New York, NY 10065 USA
Anderson, KV:
Sloan Kettering Inst, Dev Biol Program, New York, NY 10065 USA
Bague, S:
Hosp Santa Creu & Sant Pau, Dept Pathol, 167 St Antoni M Claret, Barcelona 08025, Spain
Scaltriti, M:
Mem Sloan Kettering Canc Ctr, HOPP, 1275 York Ave, New York, NY 10065 USA
Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA
Antonescu, CR:
Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA
Baselga, E:
Hosp Santa Creu & Sant Pau, Dept Dermatol, Barcelona 08025, Spain
Baselga, J:
Mem Sloan Kettering Canc Ctr, HOPP, 1275 York Ave, New York, NY 10065 USA
Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA
Green Accepted, Bronze
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