Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma.
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.
Bourdeaut
Franck
F
Laboratoire de Pathologie Moléculaire des Cancers, INSERM U-509, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France. franck.bourdeaut@curie.fr
Trochet
Delphine
D
Janoueix-Lerosey
Isabelle
I
Ribeiro
Agnès
A
Deville
Anne
A
Coz
Carole
C
Michiels
Jean-François
JF
Lyonnet
Stanislas
S
Amiel
Jeanne
J
Delattre
Olivier
O
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*
D018398:Homeodomain Proteins; C109220:NBPhox protein; D014157:Transcription Factors