Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma.
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.
Walter
Jeffrey W
JW
Department of Genetics, Duke University Medical Center, Durham, NC 27710, USA.
North
Paula E
PE
Waner
Milton
M
Mizeracki
Adam
A
Blei
Francine
F
Walker
John W T
JW
Reinisch
John F
JF
Marchuk
Douglas A
DA
D002999:Clone Cells; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D006391:Hemangioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D039942:Neuropilin-1; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017978:Receptors, Growth Factor / Q000235:genetics*; D040262:Receptors, Vascular Endothelial Growth Factor; D040321:Vascular Endothelial Growth Factor Receptor-3
D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D017978:Receptors, Growth Factor; D039942:Neuropilin-1; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040321:Vascular Endothelial Growth Factor Receptor-3