Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly

Lara Rodriguez‑Laguna, Noelia Agra, Kristina Ibañez, Gloria Oliva‑Molina, Gema Gordo, Noor Khurana, Devon Hominick, María Beato, Isabel Colmenero, Gonzalo Herranz, Juan M. Torres Canizalez, Rebeca Rodríguez Pena, Elena Vallespín, Rubén Martín‑Arenas, Ángela Del Pozo, Cristina Villaverde, Ana Bustamante, Carmen Ayuso, Pablo Lapunzina, Juan C. Lopez‑GutierrezMichael T. Dellinger, Victor Martinez‑Glez

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)407-418
Number of pages12
JournalJournal of Experimental Medicine
Issue number2
StatePublished - Feb 1 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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