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J Exp Med. 2019 Feb 4;216(2):407-418. doi: 10.1084/jem.20181353. Epub 2018 Dec 27.

Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly.

Author information

1
Vascular Malformations Section, Institute of Medical and Molecular Genetics, Institute of Medical and Molecular Genetics-Instituto de Investigación PAZ, Hospital Universitario La Paz, Madrid, Spain.
2
Bioinformatics Section, Institute of Medical and Molecular Genetics, Institute of Medical and Molecular Genetics-Instituto de Investigación PAZ, Hospital Universitario La Paz, Madrid, Spain.
3
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX.
4
Department of Pathology, Hospital Universitario La Paz, Madrid, Spain.
5
Department of Pathology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
6
Unit of Immunology, Hospital Universitario La Paz, Madrid, Spain.
7
Structural and Functional Genomics Section, Institute of Medical and Molecular Genetics, Institute of Medical and Molecular Genetics-Instituto de Investigación PAZ, Hospital Universitario La Paz, Madrid, Spain.
8
Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.
9
Department of Genetics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz Universidad Autónoma de Madrid, Madrid, Spain.
10
Clinical Genetics Section, Institute of Medical and Molecular Genetics, Institute of Medical and Molecular Genetics-Instituto de Investigación PAZ, Hospital Universitario La Paz, Madrid, Spain.
11
Vascular Anomalies Center, Plastic Surgery, Hospital Universitario La Paz, Madrid, Spain.
12
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX michael.dellinger@utsouthwestern.edu.
13
Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX.
14
Vascular Malformations Section, Institute of Medical and Molecular Genetics, Institute of Medical and Molecular Genetics-Instituto de Investigación PAZ, Hospital Universitario La Paz, Madrid, Spain vmartinezglez@salud.madrid.org.

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.

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