Somatic activating mutations in <i>PIK3CA</i> cause generalized lymphatic anomaly

DOI PDF 被引用文献4件
  • 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
  • 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
  • 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
  • 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
  • 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
  • Noor Khurana
    Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 3
  • Devon Hominick
    Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 3
  • María Beato
    Department of Pathology, Hospital Universitario La Paz, Madrid, Spain 4
  • Isabel Colmenero
    Department of Pathology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain 5
  • 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
  • Juan M. Torres Canizalez
    Unit of Immunology, Hospital Universitario La Paz, Madrid, Spain 6
  • Rebeca Rodríguez Pena
    Unit of Immunology, Hospital Universitario La Paz, Madrid, Spain 6
  • 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
  • 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
  • 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
  • Cristina Villaverde
    Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain 8
  • Ana Bustamante
    Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain 8
  • Carmen Ayuso
    Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain 8
  • Pablo Lapunzina
    Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain 8
  • Juan C. Lopez-Gutierrez
    Vascular Anomalies Center, Plastic Surgery, Hospital Universitario La Paz, Madrid, Spain 11
  • Michael T. Dellinger
    Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 3
  • 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

説明

<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>

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