SnoRNPs Regulate Telomerase Activity in Neuroblastoma and Are Associated with Poor Prognosis

Overview

Journal Transl Oncol

Specialty Oncology

Date 2013 Aug 3

PMID 23908688

Citations 13

Authors

Kristoffer von Stedingk

Jan Koster

Marta Piqueras

Rosa Noguera

Samuel Navarro

Sven Pahlman

Rogier Versteeg

Ingrid Ora

David Gisselsson

David Lindgren

Hakan Axelson

Affiliations

Soon will be listed here.

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.

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References

Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A . Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002; 3(7):RESEARCH0034. PMC: 126239. DOI: 10.1186/gb-2002-3-7-research0034. View

Wei J, Greer B, Westermann F, Steinberg S, Son C, Chen Q . Prediction of clinical outcome using gene expression profiling and artificial neural networks for patients with neuroblastoma. Cancer Res. 2004; 64(19):6883-91. PMC: 1298184. DOI: 10.1158/0008-5472.CAN-04-0695. View

Xu D, POPOV N, Hou M, Wang Q, Bjorkholm M, Gruber A . Switch from Myc/Max to Mad1/Max binding and decrease in histone acetylation at the telomerase reverse transcriptase promoter during differentiation of HL60 cells. Proc Natl Acad Sci U S A. 2001; 98(7):3826-31. PMC: 31137. DOI: 10.1073/pnas.071043198. View

Podlevsky J, Chen J . It all comes together at the ends: telomerase structure, function, and biogenesis. Mutat Res. 2011; 730(1-2):3-11. PMC: 4420735. DOI: 10.1016/j.mrfmmm.2011.11.002. View

Guiducci C, Cerone M, Bacchetti S . Expression of mutant telomerase in immortal telomerase-negative human cells results in cell cycle deregulation, nuclear and chromosomal abnormalities and rapid loss of viability. Oncogene. 2001; 20(6):714-25. DOI: 10.1038/sj.onc.1204145. View

Brodeur G . Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 2003; 3(3):203-16. DOI: 10.1038/nrc1014. View

Ohali A, Avigad S, Ash S, Goshen Y, Luria D, Feinmesser M . Telomere length is a prognostic factor in neuroblastoma. Cancer. 2006; 107(6):1391-9. DOI: 10.1002/cncr.22132. View

Oberthuer A, Berthold F, Warnat P, Hero B, Kahlert Y, Spitz R . Customized oligonucleotide microarray gene expression-based classification of neuroblastoma patients outperforms current clinical risk stratification. J Clin Oncol. 2006; 24(31):5070-8. DOI: 10.1200/JCO.2006.06.1879. View

Hakin-Smith V, Jellinek D, Levy D, Carroll T, Teo M, Timperley W . Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme. Lancet. 2003; 361(9360):836-8. DOI: 10.1016/s0140-6736(03)12681-5. View

10.

Savage S, Bertuch A . The genetics and clinical manifestations of telomere biology disorders. Genet Med. 2010; 12(12):753-64. PMC: 3825100. DOI: 10.1097/GIM.0b013e3181f415b5. View

11.

Ulaner G . Telomere maintenance in clinical medicine. Am J Med. 2004; 117(4):262-9. DOI: 10.1016/j.amjmed.2004.02.048. View

12.

Maris J . Recent advances in neuroblastoma. N Engl J Med. 2010; 362(23):2202-11. PMC: 3306838. DOI: 10.1056/NEJMra0804577. View

13.

Hoareau-Aveilla C, Bonoli M, Caizergues-Ferrer M, Henry Y . hNaf1 is required for accumulation of human box H/ACA snoRNPs, scaRNPs, and telomerase. RNA. 2006; 12(5):832-40. PMC: 1440901. DOI: 10.1261/rna.2344106. View

14.

Asgharzadeh S, Pique-Regi R, Sposto R, Wang H, Yang Y, Shimada H . Prognostic significance of gene expression profiles of metastatic neuroblastomas lacking MYCN gene amplification. J Natl Cancer Inst. 2006; 98(17):1193-203. DOI: 10.1093/jnci/djj330. View

15.

Oberthuer A, Hero B, Berthold F, Juraeva D, Faldum A, Kahlert Y . Prognostic impact of gene expression-based classification for neuroblastoma. J Clin Oncol. 2010; 28(21):3506-15. DOI: 10.1200/JCO.2009.27.3367. View

16.

Vermeulen J, De Preter K, Naranjo A, Vercruysse L, Van Roy N, Hellemans J . Predicting outcomes for children with neuroblastoma using a multigene-expression signature: a retrospective SIOPEN/COG/GPOH study. Lancet Oncol. 2009; 10(7):663-71. PMC: 3045079. DOI: 10.1016/S1470-2045(09)70154-8. View

17.

Kiss T, Fayet-Lebaron E, Jady B . Box H/ACA small ribonucleoproteins. Mol Cell. 2010; 37(5):597-606. DOI: 10.1016/j.molcel.2010.01.032. View

18.

Janoueix-Lerosey I, Schleiermacher G, Michels E, Mosseri V, Ribeiro A, Lequin D . Overall genomic pattern is a predictor of outcome in neuroblastoma. J Clin Oncol. 2009; 27(7):1026-33. DOI: 10.1200/JCO.2008.16.0630. View

19.

Sieron P, Hader C, Hatina J, Engers R, Wlazlinski A, Muller M . DKC1 overexpression associated with prostate cancer progression. Br J Cancer. 2009; 101(8):1410-6. PMC: 2768451. DOI: 10.1038/sj.bjc.6605299. View

20.

Montanaro L, Brigotti M, Clohessy J, Barbieri S, Ceccarelli C, Santini D . Dyskerin expression influences the level of ribosomal RNA pseudo-uridylation and telomerase RNA component in human breast cancer. J Pathol. 2006; 210(1):10-8. DOI: 10.1002/path.2023. View