title: MYCN gene overrepresentation detected in primary neuroblastoma tumour cells without amplification.
abstract: Neuroblastoma is the most frequent solid extracranial neoplasm of childhood, with a median age of presentation of under 2 years. This tumour is highly malignant in patients older than 12 months of age with metastatic disease. Clinical studies have confirmed that amplification of the MYCN proto-oncogene is one of the best prognostic indicators of poor outcome. Approximately 30% of neuroblastoma tumours present MYCN amplification at diagnosis. Far less is known about the incidence and consequences of overrepresentation of the gene due to duplication or rearrangement of the chromosome arm in which the gene is situated. This study has analysed 110 neuroblastomas by FISH and has detected a gain of 1-3 copies per cell of MYCN in 8% of MYCN-non-amplified tumours. In these primary tumours, cells gained small numbers of additional MYCN genes by two mechanisms: formation of an isochromosome 2p, or an unbalanced translocation involving the short arm of chromosome 2 (with MYCN) and various partner chromosomes. Quantitative RT-PCR showed three- to seven-fold elevated MYCN expression in three tumours. Although the follow-up time to date is still short, clinical outcome suggests that low-level overexpression of the MYCN gene does not enhance tumour aggressiveness and rapidity of disease progression, as is often seen in neuroblastoma with MYCN amplification. It is hypothesized that the small elevation in MYCN expression could alter the regulation of apoptosis, as has been shown in experimental models.
authors.affiliation: Laboratoire de Génomique Cellulaire des Cancers, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 1599, Institut Gustave Roussy, Villejuif, France. avalent@igr.fr
authors.forename: Alexander
authors.initials: A
authors.lastname: Valent
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Le Roux
authors.forename: Michel
authors.initials: M
authors.lastname: Barrois
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Terrier-Lacombe
authors.forename: Dominique
authors.initials: D
authors.lastname: Valteau-Couanet
authors.forename: Bernadette
authors.initials: B
authors.lastname: Léon
authors.forename: Barbara
authors.initials: B
authors.lastname: Spengler
authors.forename: Gilbert
authors.initials: G
authors.lastname: Lenoir
authors.forename: Jean
authors.initials: J
authors.lastname: Bénard
authors.forename: Alain
authors.initials: A
authors.lastname: Bernheim
mesh_terms: D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D000071447:N-Myc Proto-Oncogene Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D011003:Ploidies; D016133:Polymerase Chain Reaction / Q000379:methods; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D015854:Up-Regulation
chemical_list: C000715470:MAS1 protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D012334:RNA, Neoplasm