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snoRNPs Regulate Telomerase Activity in Neuroblastoma and Are Associated with Poor Prognosis.

von Stedingk, Kristoffer LU ; Koster, Jan ; Piqueras, Marta ; Noguera, Rosa ; Navarro, Samuel ; Påhlman, Sven LU ; Versteeg, Rogier ; Øra, Ingrid LU ; Gisselsson Nord, David LU and Lindgren, David LU , et al. (2013) In Translational Oncology 6(4). p.447-457
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Translational Oncology
volume
6
issue
4
pages
11 pages
publisher
Neoplasia Press
external identifiers
  • wos:000328361500008
  • pmid:23908688
  • scopus:84881040690
ISSN
1936-5233
DOI
10.1593/tlo.13112
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Molecular Tumour Biology (013017540), Molecular Medicine (013031200), Division of Clinical Genetics (013022003), Paediatrics (Lund) (013002000)
id
63a2f30b-9c39-4f59-971c-b147481bf24e (old id 4006252)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23908688?dopt=Abstract
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3730020/
date added to LUP
2016-04-01 10:24:09
date last changed
2020-09-16 01:17:27
@article{63a2f30b-9c39-4f59-971c-b147481bf24e,
  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.},
  author       = {von Stedingk, Kristoffer and Koster, Jan and Piqueras, Marta and Noguera, Rosa and Navarro, Samuel and Påhlman, Sven and Versteeg, Rogier and Øra, Ingrid and Gisselsson Nord, David and Lindgren, David and Axelson, Håkan},
  issn         = {1936-5233},
  language     = {eng},
  number       = {4},
  pages        = {447--457},
  publisher    = {Neoplasia Press},
  series       = {Translational Oncology},
  title        = {snoRNPs Regulate Telomerase Activity in Neuroblastoma and Are Associated with Poor Prognosis.},
  url          = {http://dx.doi.org/10.1593/tlo.13112},
  doi          = {10.1593/tlo.13112},
  volume       = {6},
  year         = {2013},
}