Somatic activating mutations in <i>PIK3CA</i> cause generalized lymphatic anomaly
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- Lara Rodriguez-Laguna
- 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 1
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- Noelia Agra
- 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 1
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- Kristina Ibañez
- Bioinformatics Section, Institute of Medical and Molecular Genetics, Institute of Medical and Molecular Genetics–Instituto de Investigación PAZ, Hospital Universitario La Paz, Madrid, Spain 2
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- Gloria Oliva-Molina
- 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 1
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- Gema Gordo
- 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 1
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- Noor Khurana
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 3
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- Devon Hominick
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 3
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- María Beato
- Department of Pathology, Hospital Universitario La Paz, Madrid, Spain 4
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- Isabel Colmenero
- Department of Pathology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain 5
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- Gonzalo Herranz
- 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 1
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- Juan M. Torres Canizalez
- Unit of Immunology, Hospital Universitario La Paz, Madrid, Spain 6
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- Rebeca Rodríguez Pena
- Unit of Immunology, Hospital Universitario La Paz, Madrid, Spain 6
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- Elena Vallespín
- 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 7
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- Rubén Martín-Arenas
- 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 7
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- Ángela del Pozo
- Bioinformatics Section, Institute of Medical and Molecular Genetics, Institute of Medical and Molecular Genetics–Instituto de Investigación PAZ, Hospital Universitario La Paz, Madrid, Spain 2
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- Cristina Villaverde
- Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain 8
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- Ana Bustamante
- Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain 8
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- Carmen Ayuso
- Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain 8
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- Pablo Lapunzina
- Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain 8
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- Juan C. Lopez-Gutierrez
- Vascular Anomalies Center, Plastic Surgery, Hospital Universitario La Paz, Madrid, Spain 11
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- Michael T. Dellinger
- Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 3
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- Victor Martinez-Glez
- 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 1
Description
<jats:p>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.</jats:p>
Journal
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- Journal of Experimental Medicine
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Journal of Experimental Medicine 216 (2), 407-418, 2018-12-27
Rockefeller University Press
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Details 詳細情報について
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- CRID
- 1360855568933775744
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- ISSN
- 15409538
- 00221007
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- Data Source
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- Crossref