Methylation-associated PHOX2B gene silencing is a rare event in human neuroblastoma.

Neuroblastoma (NB), an embryonic tumour originating from neural crest cells, is one of the most common solid tumours in childhood. Although NB is characterised by numerous recurrent, large-scale chromosome rearrangements, the genes targeted by these imbalances have remained elusive. We recently identified the paired-like homeobox 2B (PHOX2B, MIM 603851) gene as disease-causing in dysautonomic disorders including Congenital Central Hypoventilation Syndrome (CCHS), Hirschsprung disease (HSCR) and NB in various combinations. Most patients with NB due to a germline heterozygous PHOX2B gene mutation are familial and/or syndromic. PHOX2B, at chromosome 4p12, does not lie in a commonly rearranged locus in NB. To evaluate the role of PHOX2B in sporadic, isolated NB, we analysed 13 NB cell lines and 45 tumours for expression, mutations of coding and promoter sequences, loss of heterozygosity (LOH), or aberrant hypermethylation of PHOX2B (13 cell lines and 18 tumours). We didn't identify any mutation but LOH in about 10% of the cases and aberrant CpG dinucleotide methylation of the 500 bp PHOX2B promoter region in 4/31 tumours and cell lines (12.9%). Altogether, both germinal and somatic anomalies at the PHOX2B locus are found in NB.