title: Functional MYCN signature predicts outcome of neuroblastoma irrespective of MYCN amplification.
abstract: Neuroblastoma is a pediatric tumor of the sympathetic nervous system. MYCN (V-myc myelocytomatosis viral-related oncogene, neuroblastoma derived [avian]) is amplified in 20% of neuroblastomas, and these tumors carry a poor prognosis. However, tumors without MYCN amplification also may have a poor outcome. Here, we identified downstream targets of MYCN by shRNA-mediated silencing MYCN in neuroblastoma cells. From these targets, 157 genes showed an expression profile correlating with MYCN mRNA levels in NB88, a series of 88 neuroblastoma tumors, and therefore represent in vivo relevant MYCN pathway genes. This 157-gene signature identified very poor prognosis tumors in NB88 and independent neuroblastoma cohorts and was more powerful than MYCN amplification or MYCN expression alone. Remarkably, this signature also identified poor outcome of a group of tumors without MYCN amplification. Most of these tumors have low MYCN mRNA levels but high nuclear MYCN protein levels, suggesting stabilization of MYCN at the protein level. One tumor has an MYC amplification and high MYC expression. Chip-on-chip analyses showed that most genes in this signature are directly regulated by MYCN. MYCN induces genes functioning in cell cycle and DNA repair while repressing neuronal differentiation genes. The functional MYCN-157 signature recognizes classical neuroblastoma with MYCN amplification, as well as a newly identified group marked by MYCN protein stabilization.
authors.affiliation: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. l.j.valentijn@amc.uva.nl
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Valentijn
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.forename: Franciska
authors.initials: F
authors.lastname: Haneveld
authors.forename: Rachida Ait
authors.initials: RA
authors.lastname: Aissa
authors.forename: Peter
authors.initials: P
authors.lastname: van Sluis
authors.forename: Marloes E C
authors.initials: ME
authors.lastname: Broekmans
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Molenaar
authors.forename: Johan
authors.initials: J
authors.lastname: van Nes
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D016000:Cluster Analysis; D004260:DNA Repair / Q000235:genetics; D005784:Gene Amplification / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D009474:Neurons / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D016896:Treatment Outcome; D015854:Up-Regulation / Q000235:genetics
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins