TY - JOUR
T1 - Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly
AU - Rodriguez‑Laguna, Lara
AU - Agra, Noelia
AU - Ibañez, Kristina
AU - Oliva‑Molina, Gloria
AU - Gordo, Gema
AU - Khurana, Noor
AU - Hominick, Devon
AU - Beato, María
AU - Colmenero, Isabel
AU - Herranz, Gonzalo
AU - Torres Canizalez, Juan M.
AU - Pena, Rebeca Rodríguez
AU - Vallespín, Elena
AU - Martín‑Arenas, Rubén
AU - Del Pozo, Ángela
AU - Villaverde, Cristina
AU - Bustamante, Ana
AU - Ayuso, Carmen
AU - Lapunzina, Pablo
AU - Lopez‑Gutierrez, Juan C.
AU - Dellinger, Michael T.
AU - Martinez‑Glez, Victor
N1 - Publisher Copyright:
© 2018 Rodriguez‑Laguna et al.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - Generalized lymphatic anomaly (GLA) is a vascular disorder characterized by diffuse or multifocal lymphatic malformations (LMs). The etiology of GLA is poorly understood. We identified four distinct somatic PIK3CA variants (Glu542Lys, Gln546Lys, His1047Arg, and His1047Leu) in tissue samples from five out of nine patients with GLA. These same PIK3CA variants occur in PIK3CA-related overgrowth spectrum and cause hyperactivation of the PI3K–AKT–mTOR pathway. We found that the mTOR inhibitor, rapamycin, prevented lymphatic hyperplasia and dysfunction in mice that expressed an active form of PIK3CA (His1047Arg) in their lymphatics. We also found that rapamycin reduced pain in patients with GLA. In conclusion, we report that somatic activating PIK3CA mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of this disabling and deadly disease.
AB - Generalized lymphatic anomaly (GLA) is a vascular disorder characterized by diffuse or multifocal lymphatic malformations (LMs). The etiology of GLA is poorly understood. We identified four distinct somatic PIK3CA variants (Glu542Lys, Gln546Lys, His1047Arg, and His1047Leu) in tissue samples from five out of nine patients with GLA. These same PIK3CA variants occur in PIK3CA-related overgrowth spectrum and cause hyperactivation of the PI3K–AKT–mTOR pathway. We found that the mTOR inhibitor, rapamycin, prevented lymphatic hyperplasia and dysfunction in mice that expressed an active form of PIK3CA (His1047Arg) in their lymphatics. We also found that rapamycin reduced pain in patients with GLA. In conclusion, we report that somatic activating PIK3CA mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of this disabling and deadly disease.
UR - http://www.scopus.com/inward/record.url?scp=85061054997&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061054997&partnerID=8YFLogxK
U2 - 10.1084/jem.20181353
DO - 10.1084/jem.20181353
M3 - Article
C2 - 30591517
AN - SCOPUS:85061054997
SN - 0022-1007
VL - 216
SP - 407
EP - 418
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 2
ER -