title: Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma.
abstract: Hereditary predisposition to neuroblastoma accounts for less than 5% of neuroblastomas and is probably heterogeneous. Recently, a predisposition gene has been mapped to 16p12-p13, but has not yet been identified. Occurrence of neuroblastoma in association with congenital central hypoventilation and Hirschsprung's disease suggests that genes, involved in the development of neural-crest-derived cells, may be altered in these conditions. The recent identification of PHOX2B as the major disease-causing gene in congenital central hypoventilation prompted us to test it as a candidate gene in familial neuroblastoma. We report a family with three first-degree relatives with neuroblastic tumours (namely two ganglioneuromas and one neuroblastoma) in one branch and two siblings with Hirschsprung's disease in another branch. A constitutional R100L PHOX2B mutation was identified in all three patients affected with tumours. We also report a germline PHOX2B mutation in one patient treated for Hirschsprung's disease who subsequently developed a multifocal neuroblastoma in infancy. Both mutations disrupt the homeodomain of the PHOX2B protein. No loss of heterozygosity at the PHOX2B locus was observed in the tumour, suggesting that haplo-insufficiency, gain of function or dominant negative effects may account for the oncogenic effects of these mutations. These observations identify PHOX2B as the first predisposing gene to hereditary neuroblastic tumours.
authors.affiliation: Laboratoire de Pathologie Moléculaire des Cancers, INSERM U-509, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France. franck.bourdeaut@curie.fr
authors.forename: Franck
authors.initials: F
authors.lastname: Bourdeaut
authors.forename: Delphine
authors.initials: D
authors.lastname: Trochet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Janoueix-Lerosey
authors.forename: Agnès
authors.initials: A
authors.lastname: Ribeiro
authors.forename: Anne
authors.initials: A
authors.lastname: Deville
authors.forename: Carole
authors.initials: C
authors.lastname: Coz
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Michiels
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
mesh_terms: D000328:Adult; D002648:Child; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C109220:NBPhox protein; D014157:Transcription Factors