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.