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-Gutierrez & 2 others Michael T Dellinger, Victor Martinez-Glez

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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
JournalThe Journal of experimental medicine
Volume216
Issue number2
DOIs
StatePublished - Feb 4 2019

Fingerprint

Sirolimus
Mutation
Phosphatidylinositol 3-Kinases
Hyperplasia
Blood Vessels
Pain
Therapeutics

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Rodriguez-Laguna, L., Agra, N., Ibañez, K., Oliva-Molina, G., Gordo, G., Khurana, N., ... Martinez-Glez, V. (2019). Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly. The Journal of experimental medicine, 216(2), 407-418. https://doi.org/10.1084/jem.20181353

Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly. / Rodriguez-Laguna, Lara; Agra, Noelia; Ibañez, Kristina; Oliva-Molina, Gloria; Gordo, Gema; Khurana, Noor; Hominick, Devon; Beato, María; Colmenero, Isabel; Herranz, Gonzalo; Torres Canizalez, Juan M.; Rodríguez Pena, Rebeca; Vallespín, Elena; Martín-Arenas, Rubén; Del Pozo, Ángela; Villaverde, Cristina; Bustamante, Ana; Ayuso, Carmen; Lapunzina, Pablo; Lopez-Gutierrez, Juan C.; Dellinger, Michael T; Martinez-Glez, Victor.

In: The Journal of experimental medicine, Vol. 216, No. 2, 04.02.2019, p. 407-418.

Research output: Contribution to journalArticle

Rodriguez-Laguna, L, Agra, N, Ibañez, K, Oliva-Molina, G, Gordo, G, Khurana, N, Hominick, D, Beato, M, Colmenero, I, Herranz, G, Torres Canizalez, JM, Rodríguez Pena, R, Vallespín, E, Martín-Arenas, R, Del Pozo, Á, Villaverde, C, Bustamante, A, Ayuso, C, Lapunzina, P, Lopez-Gutierrez, JC, Dellinger, MT & Martinez-Glez, V 2019, 'Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly', The Journal of experimental medicine, vol. 216, no. 2, pp. 407-418. https://doi.org/10.1084/jem.20181353
Rodriguez-Laguna L, Agra N, Ibañez K, Oliva-Molina G, Gordo G, Khurana N et al. Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly. The Journal of experimental medicine. 2019 Feb 4;216(2):407-418. https://doi.org/10.1084/jem.20181353
Rodriguez-Laguna, Lara ; Agra, Noelia ; Ibañez, Kristina ; Oliva-Molina, Gloria ; Gordo, Gema ; Khurana, Noor ; Hominick, Devon ; Beato, María ; Colmenero, Isabel ; Herranz, Gonzalo ; Torres Canizalez, Juan M. ; Rodríguez Pena, Rebeca ; Vallespín, Elena ; Martín-Arenas, Rubén ; Del Pozo, Ángela ; Villaverde, Cristina ; Bustamante, Ana ; Ayuso, Carmen ; Lapunzina, Pablo ; Lopez-Gutierrez, Juan C. ; Dellinger, Michael T ; Martinez-Glez, Victor. / Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly. In: The Journal of experimental medicine. 2019 ; Vol. 216, No. 2. pp. 407-418.
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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 - Rodríguez Pena, Rebeca

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

PY - 2019/2/4

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