title: Segmental chromosome aberrations converge on overexpression of mitotic spindle regulatory genes in high-risk neuroblastoma.
abstract: Integration of genome-wide profiles of DNA copy number alterations (CNAs) and gene expression variations (GEVs) could provide combined power to the identification of driver genes and gene networks in tumors. Here we merge matched genome and transcriptome microarray analyses from neuroblastoma samples to derive correlation patterns of CNAs and GEVs, irrespective of their genomic location. Neuroblastoma correlation patterns are strongly asymmetrical, being on average 10 CNAs linked to 1 GEV, and show the widespread prevalence of long range covariance. Functional enrichment and network analysis of the genes covarying with CNAs consistently point to a major cell function, the regulation of mitotic spindle assembly. Moreover, elevated expression of 14 key genes promoting this function is strongly associated to high-risk neuroblastomas with 1p loss and MYCN amplification in a set of 410 tumor samples (P < 0.00001). Independent CNA/GEV profiling on neuroblastoma cell lines shows that increased levels of expression of these genes are linked to 1p loss. By this approach, we reveal a convergence of clustered neuroblastoma CNAs toward increased expression of a group of prognostic and functionally cooperating genes. We therefore propose gain of function of the spindle assembly machinery as a lesion potentially offering new targets for therapy of high-risk neuroblastoma.
authors.affiliation: Laboratory of Translational Genomics, Centre for Integrative Biology and Department of Information Engineering and Computer Science, University of Trento, 38122 Trento, Italy.
authors.forename: Wen Fong
authors.initials: WF
authors.lastname: Ooi
authors.forename: Angela
authors.initials: A
authors.lastname: Re
authors.forename: Viktoryia
authors.initials: V
authors.lastname: Sidarovich
authors.forename: Valentina
authors.initials: V
authors.lastname: Canella
authors.forename: Natalia
authors.initials: N
authors.lastname: Arseni
authors.forename: Valentina
authors.initials: V
authors.lastname: Adami
authors.forename: Giulia
authors.initials: G
authors.lastname: Guarguaglini
authors.forename: Maria
authors.initials: M
authors.lastname: Giubettini
authors.forename: Paola
authors.initials: P
authors.lastname: Scaruffi
authors.forename: Sara
authors.initials: S
authors.lastname: Stigliani
authors.forename: Patrizia
authors.initials: P
authors.lastname: Lavia
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Tonini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Quattrone
mesh_terms: D002869:Chromosome Aberrations; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D008941:Spindle Apparatus / Q000235:genetics* / Q000378:metabolism
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins