title: Methylation-associated PHOX2B gene silencing is a rare event in human neuroblastoma.
abstract: 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.
authors.affiliation: Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U-781, et Département de Génétique, Université René-Descartes, Faculté de Médecine, Hôpitaux de Paris, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, 75743 Paris Cedex 15, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: de Pontual
authors.forename: Delphine
authors.initials: D
authors.lastname: Trochet
authors.forename: Franck
authors.initials: F
authors.lastname: Bourdeaut
authors.forename: Sophie
authors.initials: S
authors.lastname: Thomas
authors.forename: Heather
authors.initials: H
authors.lastname: Etchevers
authors.forename: Agnes
authors.initials: A
authors.lastname: Chompret
authors.forename: Véronique
authors.initials: V
authors.lastname: Minard
authors.forename: Dominique
authors.initials: D
authors.lastname: Valteau
authors.forename: Laurence
authors.initials: L
authors.lastname: Brugieres
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Janoueix-Lerosey
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
mesh_terms: D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005787:Gene Frequency; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008745:Methylation; D009447:Neuroblastoma / Q000235:genetics*; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C109220:NBPhox protein; D014157:Transcription Factors