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Review
. 2005 Oct 18;228(1-2):51-8.
doi: 10.1016/j.canlet.2005.01.055.

Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma

Franck Bourdeaut  1 , Delphine Trochet, Isabelle Janoueix-Lerosey, Agnès Ribeiro, Anne Deville, Carole Coz, Jean-François Michiels, Stanislas Lyonnet, Jeanne Amiel, Olivier Delattre
Affiliations
Review

Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma

Franck Bourdeaut et al. Cancer Lett. .

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.

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