title: Mutations in Hedgehog pathway genes in fetal rhabdomyomas.
abstract: Ligand-independent, constitutive activation of Hedgehog signalling in mice expressing a mutant, activated SmoM2 allele 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 fluorescence in situ hybridization testing for PTCH1. Our studies identified functionally relevant aberrations at the PTCH1 locus in three of five FRM tumours surveyed, including a PTCH1 frameshift mutation in one tumour and homozygous deletions of PTCH1 in two tumours. These data suggest that activated Hedgehog signalling contributes to the biology of human FRM.
authors.affiliation: Howard Hughes Medical Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute, Cambridge, MA, USA. simone.hettmer@childrens.harvard.edu
authors.forename: Simone
authors.initials: S
authors.lastname: Hettmer
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Teot
authors.forename: Paul
authors.initials: P
authors.lastname: van Hummelen
authors.forename: Laura
authors.initials: L
authors.lastname: MacConaill
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Claudia
authors.initials: C
authors.lastname: Dall'Osso
authors.forename: Junhao
authors.initials: J
authors.lastname: Mao
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gruber
authors.forename: Holcombe E
authors.initials: HE
authors.lastname: Grier
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez-Galindo
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Fletcher
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
mesh_terms: D000818:Animals; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D004195:Disease Models, Animal; D016368:Frameshift Mutation; D017353:Gene Deletion; D015870:Gene Expression; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019042:Muscle Neoplasms / Q000235:genetics* / Q000473:pathology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D012207:Rhabdomyoma / Q000235:genetics* / Q000473:pathology
chemical_list: D004273:DNA, Neoplasm; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface
keywords: PTCH1; fetal rhabdomyoma; hedgehog signalling