title: MYCN-status in neuroblastoma: characteristics of tumours showing amplification, gain, and non-amplification.
abstract: While the role of MYCN-amplification (MNA) for risk assessment in neuroblastoma is undisputed, the phenomenon of gene copy excess below the amplification threshold is rarely described. To discuss biological characteristics and the clinical impact of the so-called MYCN-gain versus amplified or non-amplified cases, we investigated the MYCN status of 659 patients uniformly analysed by fluorescence in situ hybridisation. The number of MYCN-amplified tumours in our cohort was 18% (116/659); an additional 38 tumours (6%) displayed MYCN-gain. Both alterations were associated with an advanced stage disease, an increased patient age and further chromosomal alterations. Most of the amplified neuroblastomas displayed 1p aberrations, whereas MYCN-gain tumours correlated with 11q alterations. In contrast to the amplified cases, tumours with gain displayed no increased MYCN RNA levels. MNA versus non-amplification discriminated between good and poor outcomes, independent of stage, age and the degree of amplification. However, patients with amplified tumours showed a significantly better outcome when this was combined with non-stage 4 disease and age <1 year versus stage 4 and age < 1 year. Although MYCN-gain was associated with poor event-free-survival (EFS) in stages 1-3, 4S (P=0.005), this might be related to associated genetic aberrations and not to the MYCN-gain itself. A survival difference between neuroblastomas with gain and single copy MYCN could not be delineated. In conclusion, MNA predicts a poor outcome for neuroblastoma patients of all stages and age. MYCN-gain is also a characteristic feature of advanced stage tumours and older patients, but is not associated with higher MYCN expression and appears not to be discriminative in predicting patient outcome.
authors.affiliation: University of Cologne, Children's Hospital, Paediatric Oncology, Joseph-Stelzmann-Str. 9, Köln 50924, Germany. ruediger.spitz@medizin.uni-koeln.de
authors.forename: Ruediger
authors.initials: R
authors.lastname: Spitz
authors.forename: B
authors.initials: B
authors.lastname: Hero
authors.forename: M
authors.initials: M
authors.lastname: Skowron
authors.forename: K
authors.initials: K
authors.lastname: Ernestus
authors.forename: F
authors.initials: F
authors.lastname: Berthold
mesh_terms: D015139:Blotting, Southern; D002675:Child, Preschool; D018572:Disease-Free Survival; D005784:Gene Amplification / Q000235:genetics*; D016259:Genes, myc; D006801:Humans; D007223:Infant; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009447:Neuroblastoma / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018709:Statistics, Nonparametric