Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma

Authors

  • Jeffrey W. Walter,

    1. Department of Genetics, Duke University Medical Center, Durham, North Carolina
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  • Paula E. North,

    1. Department of Pathology, University of Arkansas for Medical Sciences, and Arkansas Children's Hospital, Little Rock, Arkansas
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  • Milton Waner,

    1. Department of Head and Neck Surgery and Otolaryngology, University of Arkansas for Medical Sciences, and Arkansas Children's Hospital, Little Rock, Arkansas
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  • Adam Mizeracki,

    1. Department of Pathology, University of Arkansas for Medical Sciences, and Arkansas Children's Hospital, Little Rock, Arkansas
    2. Department of Head and Neck Surgery and Otolaryngology, University of Arkansas for Medical Sciences, and Arkansas Children's Hospital, Little Rock, Arkansas
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  • Francine Blei,

    1. Department of Pediatrics, New York University Medical Center, New York, New York
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  • John W. T. Walker,

    1. Cleft/Craniofacial Center, Division of Plastic Surgery, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California
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  • John F. Reinisch,

    1. Cleft/Craniofacial Center, Division of Plastic Surgery, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California
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  • Douglas A. Marchuk

    Corresponding author
    1. Department of Genetics, Duke University Medical Center, Durham, North Carolina
    • Department of Genetics, Box 3175, Duke University Medical Center, Durham, NC 27710
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Abstract

Juvenile hemangiomas are the most common tumors of infancy, occurring in as many as 10% of all births. These benign vascular lesions enlarge rapidly during the first year of life by hyperplasia of endothelial cells and attendant pericytes and then spontaneously involute over a period of years, leaving loose fibrofatty tissue. Several hypotheses have been put forth concerning hemangiogenesis, including the possibility that the tumor is the result of somatic mutation in one or more components of critical vascular growth-regulatory pathways. To test this hypothesis, we obtained 15 proliferative-phase hemangiomas after surgical resection and dissected them to enrich for the lesional (endothelial and pericytic) components of each specimen. To determine whether hemangiomas represent a clonal expansion from a single progenitor cell, we assayed X-inactivation patterns for each lesion by using the polymorphic X-linked human androgen receptor gene. Twelve of 14 informative hemangiomas showed a significant degree of allelic loss after methylation-based and transcription-based polymerase chain reaction clonality assays, suggesting a nonrandom X-inactivation pattern and, thus, a monoclonal origin. We then sequenced genes encoding the receptors of the vascular endothelial growth factors (VEGFs) as candidates for potential somatic mutation. Mutations were found in two of the 15 hemangioma specimens: a missense mutation (P1147S) in the kinase domain of the VEGFR2 (FLK1/KDR) gene in one specimen and a missense mutation (P954S) in the kinase insert of the VEGFR3 (FLT4) gene in another specimen. In each case, the mutation was detected in tumor tissue but not in adjacent normal tissue. These results suggest that one potential mechanism involved in hemangioma formation is the alteration of the VEGF signaling pathway in endothelial and/or pericytic cells. © 2002 Wiley-Liss, Inc.

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