Segmental chromosome aberrations converge on overexpression of mitotic spindle regulatory genes in high-risk neuroblastoma

Wen Fong Ooi, Angela Re, Viktoryia Sidarovich, Valentina Canella, Natalia Arseni, Valentina Adami, Giulia Guarguaglini, Maria Giubettini, Paola Scaruffi, Sara Stigliani, Patrizia Lavia, Gian Paolo Tonini, Alessandro Quattrone

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)545-556
Number of pages12
JournalGenes Chromosomes and Cancer
Volume51
Issue number6
DOIs
Publication statusPublished - Jun 2012

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

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