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1.  snoRNPs Regulate Telomerase Activity in Neuroblastoma and Are Associated with Poor Prognosis12 
Translational Oncology  2013;6(4):447-457.
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.
PMCID: PMC3730020  PMID: 23908688
2.  Genetic Instability and Intratumoral Heterogeneity in Neuroblastoma with MYCN Amplification Plus 11q Deletion 
PLoS ONE  2013;8(1):e53740.
Background/Aim
Genetic analysis in neuroblastoma has identified the profound influence of MYCN amplification and 11q deletion in patients’ prognosis. These two features of high-risk neuroblastoma usually occur as mutually exclusive genetic markers, although in rare cases both are present in the same tumor. The purpose of this study was to characterize the genetic profile of these uncommon neuroblastomas harboring both these high-risk features.
Methods
We selected 18 neuroblastomas with MNA plus 11q loss detected by FISH. Chromosomal aberrations were analyzed using Multiplex Ligation-dependent Probe Amplification and Single Nucleotide Polymorphism array techniques.
Results and Conclusion
This group of tumors has approximately the same high frequency of aberrations as found earlier for 11q deleted tumors. In some cases, DNA instability generates genetic heterogeneity, and must be taken into account in routine genetic diagnosis.
doi:10.1371/journal.pone.0053740
PMCID: PMC3544899  PMID: 23341988
3.  Outcome Prediction of Children with Neuroblastoma using a Multigene Expression Signature, a Retrospective SIOPEN/COG/GPOH Study 
The lancet oncology  2009;10(7):663-671.
BACKGROUND
More accurate prognostic assessment of patients with neuroblastoma is required to improve the choice of risk-related therapy. The aim of this study is to develop and validate a gene expression signature for improved outcome prediction.
METHODS
Fifty-nine genes were carefully selected based on an innovative data-mining strategy and profiled in the largest neuroblastoma patient series (n=579) to date using RT-qPCR starting from only 20 ng of RNA. A multigene expression signature was built using 30 training samples, tested on 313 test samples and subsequently validated in a blind study on an independent set of 236 additional tumours.
FINDINGS
The signature accurately classifies patients with respect to overall and progression-free survival (p<0·0001). The signature has a performance, sensitivity, and specificity of 85·4% (95%CI: 77·7–93·2), 84·4% (95%CI: 66·5–94·1), and 86·5% (95%CI: 81·1–90·6), respectively to predict patient outcome. Multivariate analysis indicates that the signature is a significant independent predictor after controlling for currently used riskfactors. Patients with high molecular risk have a higher risk to die from disease and for relapse/progression than patients with low molecular risk (odds ratio of 19·32 (95%CI: 6·50–57·43) and 3·96 (95%CI: 1·97–7·97) for OS and PFS, respectively). Patients with increased risk for adverse outcome can also be identified within the current treatment groups demonstrating the potential of this signature for improved clinical management. These results were confirmed in the validation study in which the signature was also independently statistically significant in a model adjusted for MYCN status, age, INSS stage, ploidy, INPC grade of differentiation, and MKI. The high patient/gene ratio (579/59) underlies the observed statistical power and robustness.
INTERPRETATION
A 59-gene expression signature predicts outcome of neuroblastoma patients with high accuracy. The signature is an independent risk predictor, identifying patients with increased risk in the current clinical risk groups. The applied method and signature is suitable for routine lab testing and ready for evaluation in prospective studies.
FUNDING
The Belgian Foundation Against Cancer, found of public interest (project SCIE2006-25), the Children Cancer Fund Ghent, the Belgian Society of Paediatric Haematology and Oncology, the Belgian Kid’s Fund and the Fondation Nuovo-Soldati (JV), the Fund for Scientific Research Flanders (KDP, JH), the Fund for Scientific Research Flanders (grant number: G•0198•08), the Institute for the Promotion of Innovation by Science and Technology in Flanders, Strategisch basisonderzoek (IWT-SBO 60848), the Fondation Fournier Majoie pour l’Innovation, the Instituto Carlos III,RD 06/0020/0102 Spain, the Italian Neuroblastoma Foundation, the European Community under the FP6 (project: STREP: EET-pipeline, number: 037260), and the Belgian program of Interuniversity Poles of Attraction, initiated by the Belgian State, Prime Minister's Office, Science Policy Programming.
doi:10.1016/S1470-2045(09)70154-8
PMCID: PMC3045079  PMID: 19515614
4.  Tissue microarrays: applications in study of p16 and p53 alterations in Ewing's cell lines 
Diagnostic Pathology  2008;3(Suppl 1):S27.
Background
Tissue microarrays (TMAs) are used to study genomics and proteomics in several tumour tissue samples. Cell lines (CC) are of great importance in the study of the genetic changes in tumours, and some reveal several aspects of tumour oncogenesis. There are few published reports on Ewing's tumours with TMAs including original tumours (OT) and corresponding CC.
Methods
We have performed four TMAs, from 3 OT and the corresponding CC of successive in vivo and in vitro tumour passages. Xenotransplant CC in nude mice from OT (XT/OT) was made. Subsequently multiple XT were performed and in vitro XT cell line (CC/XT) was obtained. In vivo re-inoculation of CC/XT (XT/CC) was planned. TMAs with the successive tumour passages that grew in nude mice (XT/OT and XT/CC) were analyzed by morphologic pattern (Hematoxilin/eosin), immunohistochemical staining (CD99, FLI1, p16, p53, ki-67), fluorescent in situ hybridization-FISH-(EWSR1 break apart, p16 and p53 status) and gene fusion types.
Results
Heterogeneous results of the p16, p53 and ki67 in OT, XT/OT, CC/XT and XT/CC were observed. The three cell lines revealed EWS/FLI1 rearrangements. p16 gene was deleted only in one case. The deletion was detected by FISH and confirmed by PCR assays. A p53 alteration was found in the second case with monosomy and subsequently polysomic status of chromosome 17 during the evolution of CC. The PCR study revealed p53 mutation. The third case showed hypermethylation in the promoter of p16. The growth of the tumour in nude mice was more accelerated when the inoculation was performed from the CC/XT, increasing progressively over the passages. The third case did not reveal tumour growth in nude mice after the re-inoculation of CC/XT.
Conclusion
The study of several cores from original tumours and successive tumour passages in TMAs facilitated the analysis of the genetic alteration and protein expression in Ewing's tumours.
doi:10.1186/1746-1596-3-S1-S27
PMCID: PMC2500108  PMID: 18673516

Results 1-4 (4)