Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development

J Pathol. 2006 Jan;208(1):17-25. doi: 10.1002/path.1882.


The naevoid basal cell carcinoma syndrome (NBCCS) is caused by mutations in the hedgehog receptor PTCH gene. It is characterized by developmental defects and a predisposition to the development of certain tumours, such as basal cell carcinoma, medulloblastoma and meningioma, and potentially fetal rhabdomyomas and embryonal rhabdomyosarcomas. This study aimed to analyse PTCH status in an NBCCS patient with fetal rhabdomyoma and to investigate whether deregulation of hedgehog signalling, as shown by altered expression of hedgehog pathway components and/or genetic imbalances, is a general finding in sporadic rhabdomyomas and rhabdomyosarcomas. The NBCCS patient had a novel PTCH germ-line mutation, 1370insT, and developed a fetal rhabdomyoma that harboured a 30 bp in-frame deletion in the second allele resulting in homozygous inactivation of PTCH. Sporadic rhabdomyomas and rhabdomyosarcomas showed overexpression of PTCH (43/43) and GLI1 (41/43) mRNA, as determined by in situ hybridization, indicating ongoing active hedgehog signalling. Immunohistochemical staining revealed a subgroup of fetal rhabdomyomas and embryonal rhabdomyosarcomas (12/34) lacking PTCH immunoreactivity. Four of nine informative fetal rhabdomyomas and embryonal rhabdomyosarcomas showed loss of heterozygosity (LOH) in the PTCH region with two of these (one fetal rhabdomyoma and one embryonal rhabdomyosarcoma) also showing LOH in the SUFU region. These findings suggest that haploinsufficiency for the two tumour suppressor genes PTCH and SUFU, which are both active in the same signalling pathway, may be important for tumour development. Based on our results we propose that the pathogenesis of rhabdomyoblastic tumours, particularly fetal rhabdomyomas and embryonal rhabdomyosarcomas, involves deregulation of the hedgehog signalling pathway.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Carcinoma, Basal Cell / genetics
  • Child
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Genes, Neoplasm / genetics
  • Humans
  • Immunohistochemistry / methods
  • In Situ Hybridization
  • Infant
  • Loss of Heterozygosity / genetics
  • Male
  • Middle Aged
  • Mutation / genetics
  • Neoplasm Proteins / genetics
  • Patched Receptors
  • Patched-1 Receptor
  • RNA, Messenger / genetics
  • RNA, Neoplasm / genetics
  • Receptors, Cell Surface / genetics*
  • Repressor Proteins / genetics*
  • Rhabdomyoma / genetics*
  • Rhabdomyosarcoma / genetics*
  • Rhabdomyosarcoma, Embryonal / genetics
  • Signal Transduction / genetics*
  • Submandibular Gland Neoplasms


  • Neoplasm Proteins
  • PTCH protein, human
  • Patched Receptors
  • Patched-1 Receptor
  • RNA, Messenger
  • RNA, Neoplasm
  • Receptors, Cell Surface
  • Repressor Proteins
  • SUFU protein, human