Cancer Letters

Cancer Letters

Volume 228, Issues 1–2, 18 October 2005, Pages 51-58
Cancer Letters

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

https://doi.org/10.1016/j.canlet.2005.01.055Get rights and content

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.

Section snippets

Hereditary and syndromic neuroblastomas

Hereditary neuroblastoma accounts for less than 5% of all neuroblastic tumours. Rare neuroblastoma families have been described and fit an autosomal dominant trait of inheritance with incomplete penetrance. Nevertheless, no predisposition gene has been identified so far. The high recurrence of loss of heterozygosity for chromosome 1p36 and 11q23 has supported the existence of putative tumour suppressor genes within these regions [1], [2], but markers at these loci do not segregate with

Paired-like homeodomain proteins in the cascade pathway of neurogenesis

Neuroblastomas occur in the sympatho-adrenal lineage, which are neural-crest cells derived structures. The malignant cells, therefore, arise from the unique progenitor of two closely related contingents of cells, sympathoblasts and chromaffin cells, both of which are derived from neural crests. In those latter, neurogenesis and commitment in the adrenergic lineage require a cascade of genes, implying a network variably organised from cell type to cell type, but constantly centred on the

PHOX2B in children neurocristopathies

Amiel and colleagues described the pattern of expression of PHOX2B in human embryos, encompassing locus coeruleus and cranial motoneurons, paravertebral sympathetic ganglia, carotid body (where chemoreceptors are localised for the adaptation of respiration to hypercarbia), and enteric ganglia [18]. Assuming the critical role of PHOX2B in neural-crest-derived structures, they carried out a mutation screening of PHOX2B gene in a set of 29 patients suffering from CCHS. In this first report,

Syndromic and familial neuroblastic tumours with PHOX2B mutations

In the first family case, stage 3 neuroblastoma was diagnosed in a 6-year-old boy, second child of non-consanguineous parents. Surgery and chemotherapy were conducted, but the tumour experienced multiple recurrences. In the father, biopsy of a suspect cervical node revealed a carcinoma from undetermined origin; tomodensitometry, performed in order to explore this carcinoma, incidentally detected an adrenal mass. Surgery and histopathology lead to the diagnosis of a well-differentiated

Oncologic signification of PHOX2B mutations

PHOX2B mutations are the first predisposition germline mutations identified in neuroblastoma. In both families, neuroblastic tumours occur in association with HSCR, either in the proband or in relatives harbouring the mutation. The penetrance of HSCR and of neuroblastic tumours is incomplete, since three mutation carriers from the two families are asymptomatic. However, the totally asymptomatic tumour in the father and the eldest son from the first family must be kept in mind, illustrating that

Conclusion

PHOX2B is the first identified gene predisposing to neuroblastic tumours. However, it may account only for a small proportion of hereditary neuroblastoma, and mutations mainly occur in a wider context of neurocristopathies. Other candidate genes should therefore still be considered. Among them, a particular attention would be paid to genes involved in sympatho-adrenal lineage development. The precise oncogenic role of PHOX2B mutations is still on debate. Dominant negative effect,

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