Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma
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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,
References (29)
- et al.
Molecular genetic analysis of familial neuroblastoma
Eur. J. Cancer
(1997) - et al.
Defects in sensory and autonomic ganglia and absence of locus coeruleus in mice deficient for the homeobox gene Phox2a
Neuron
(1997) - et al.
Mammalian achaete–scute homolog 1 is required for the early development of olfactory and autonomic neurons
Cell
(1993) - et al.
Germline PHOX2B mutation in hereditary neuroblastoma
Am. J. Hum. Genet.
(2004) Achaete–scute homolog-1 and Notch in lung neuroendocrine development and cancer
Cancer Lett.
(2004)- et al.
Novel regions of chromosomal loss in familial neuroblastoma by comparative genomic hybridization
Genes Chromosomes Cancer
(1997) - et al.
Identification and high-resolution mapping of a constitutional 11q deletion in an infant with multifocal neuroblastoma
Lancet Oncol.
(2001) - et al.
Familial predisposition to neuroblastoma does not map to chromosome band 1p36
Cancer Res.
(1996) - et al.
Evidence for a hereditary neuroblastoma predisposition locus at chromosome 16p12-13
Cancer Res.
(2002) - et al.
Weak linkage at 4p16 to predisposition for human neuroblastoma
Oncogene
(2002)
Neuroblastoma in a transgenic mouse carrying a metallothionein/ret fusion gene
Br. J. Cancer
The importance of having your SOX on: role of SOX10 in the development of neural crest-derived melanocytes and glia
Oncogene
Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2
Nat. Genet.
The homeobox gene Phox2b is essential for the development of autonomic neural crest derivatives
Nature
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2018, EBioMedicineCitation Excerpt :Familial neuroblastoma is rare, with approximately 1–2% of all neuroblastoma cases. The genetic etiology of familial neuroblastoma is relatively elucidated, that is the highly mutations in PHOX2B (Mosse et al., 2004; Bourdeaut et al., 2005) or ALK gene (Devoto et al., 2011). However, the genetic events predisposing individuals to sporadic neuroblastoma, the most common neuroblastoma, remains unclear.
Congenital central hypoventilation syndrome: An overview of etiopathogenesis, associated pathologies, clinical presentation, and management
2018, Autonomic Neuroscience: Basic and ClinicalCitation Excerpt :Frameshift, missense, and nonsense mutations are occasionally found but are considered to be less frequent in comparison to alanine expansions. Cases have been reported in which PHO2XB mutations have occurred in patients who do not present with CCHS, but rather exhibit a tumor of neural crest origin such as neuroblastomas, ganglioneuromas, and ganglioeuroblastomas (Bygarski et al., 2013; Alvord and Shaw, 1989; Benailly et al., 2003; Bourdeaut et al., 2005). About 15–20% of CCHS cases have also been linked to HSCR.
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