Mutations in Hedgehog pathway genes in fetal rhabdomyomas

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Ligand-independent, constitutive activation of Hedgehog signalling in mice expressing a mutant, activatedSmoM2allele results in the development of multifocal, highly differentiated tumours that express myogenic markers (including desmin, actin, MyoD and myogenin). The histopathology of these tumours, commonly classified as rhabdomyosarcomas, more closely resembles human fetal rhabdomyoma (FRM), a benign tumour that can be difficult to distinguish from highly differentiated rhabdomyosarcomas. We evaluated the spectrum of Hedgehog (HH) pathway gene mutations in a cohort of human FRM tumours by targeted Illumina sequencing and fluorescencein situhybridization testing forPTCH1. Our studies identified functionally relevant aberrations at thePTCH1locus in three of five FRM tumours surveyed, including aPTCH1frameshift mutation in one tumour and homozygous deletions ofPTCH1in two tumours. These data suggest that activated Hedgehog signalling contributes to the biology of human FRM. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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