title: snoRNPs Regulate Telomerase Activity in Neuroblastoma and Are Associated with Poor Prognosis.
abstract: Amplification of the MYCN oncogene is strongly associated with poor prognosis in neuroblastoma (NB). In addition to MYCN amplification, many studies have focused on identifying patients with a poor prognosis based on gene expression profiling. The majority of prognostic signatures today are comprised of large gene lists limiting their clinical application. In addition, although of prognostic significance, most of these signatures fail to identify cellular processes that can explain their relation to prognosis. Here, we determined prognostically predictive genes in a data set containing 251 NBs. Gene Ontology analysis was performed on significant genes with a positive hazard ratio to search for cellular processes associated with poor prognosis. An enrichment in ribonucleoproteins (RNPs) was found. Genes involved in the stabilization and formation of the central small nucleolar RNP (snoRNP) complex were scrutinized using a backward conditional Cox regression resulting in an snoRNP signature consisting of three genes: DKC1, NHP2, and GAR1. The snoRNP signature significantly and independently predicted prognosis when compared to the established clinical risk factors. Association of snoRNP protein expression and prognosis was confirmed using tissue micro-arrays. Knockdown of snoRNP expression in NB cell lines resulted in reduced telomerase activity and an increase in anaphase bridge frequency. In addition, in patient material, expression of the snoRNP complex was significantly associated with telomerase activity, occurrence of segmental aberrations, and expression-based measurements of chromosomal instability. Together, these results underscore the prognostic value of snoRNP complex expression in NB and suggest a role for snoRNPs in telomere maintenance and genomic stability.
authors.affiliation: Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: von Stedingk
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.forename: Marta
authors.initials: M
authors.lastname: Piqueras
authors.forename: Rosa
authors.initials: R
authors.lastname: Noguera
authors.forename: Samuel
authors.initials: S
authors.lastname: Navarro
authors.forename: Sven
authors.initials: S
authors.lastname: Påhlman
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
authors.forename: Ingrid
authors.initials: I
authors.lastname: Ora
authors.forename: David
authors.initials: D
authors.lastname: Gisselsson
authors.forename: David
authors.initials: D
authors.lastname: Lindgren
authors.forename: Håkan
authors.initials: H
authors.lastname: Axelson
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