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. 2011 Oct 25;105(9):1352-61.
doi: 10.1038/bjc.2011.388. Epub 2011 Oct 4.

Expression of miR-487b and miR-410 encoded by 14q32.31 locus is a prognostic marker in neuroblastoma

C-H Gattolliat  1 , L Thomas, S A Ciafrè, G Meurice, G Le Teuff, B Job, C Richon, V Combaret, P Dessen, D Valteau-Couanet, E May, P Busson, S Douc-Rasy, J Bénard
Affiliations

Expression of miR-487b and miR-410 encoded by 14q32.31 locus is a prognostic marker in neuroblastoma

C-H Gattolliat et al. Br J Cancer. .

Abstract

Background: Combination of age at diagnosis, stage and MYCN amplification stratifies neuroblastoma into low-risk and high-risk. We aimed to establish whether a microRNA (miRNA) signature could be associated with prognosis in both groups.

Methods: Microarray expression profiling of human miRNAs and quantitative reverse-transcriptase PCR of selected miRNAs were performed on a preliminary cohort of 13 patients. Results were validated on an independent cohort of 214 patients. The relationship between miRNA expression and the overall or disease-free survival was analysed on the total cohort of 227 patients using the log-rank test and the multivariable Cox proportional hazard model.

Results: A total of 15 of 17 miRNAs that discriminated high-risk from low-risk neuroblastoma belonged to the imprinted human 14q32.31 miRNA cluster and two, miR-487b and miR-410, were significantly downregulated in the high-risk group. Multivariable analyses showed miR-487b expression as associated with overall survival and disease-free survival in the whole cohort, independently of clinical covariates. Moreover, miR-487b and miR-410 expression was significantly associated with disease-free survival of the non-MYCN-amplified favourable neuroblastoma: localised (stage 1, 2 and 3) and stage 4 of infant <18 months.

Conclusion: Expression of miR-487b and miR-410 shows predictive value beyond the classical high-/low-risk stratification and is a biomarker of relapse in favourable neuroblastoma.

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Figures

Figure 1
Figure 1
Patients characteristics and tumour clustering using miRNA expression profiling. (A) Clinical main characteristics of patients from the preliminary cohort. INSS: International Neuroblastoma Staging System. Present status February 2011: A, Alive; DoD, dead of disease. (B) Unsupervised hierarchical clustering. The unsupervised cluster was built by computing a distance matrix (Euclidian distance) between all arrays using the dist() function of R. The distance matrix was then clustered according to ‘ward’ method available in hclust() function of R. The high-risk neuroblastomas are indicated in orange and the low-risk neuroblastomas in blue.
Figure 2
Figure 2
Summary heat map showing the clustering based on 14q32.31 miRNA cluster. Data are represented as two dendrograms. The vertical dendrogram indicates patient sample with closest miRNA expression patterns. The horizontal dendrogram indicates miRNA with closest expression pattern across all patient samples. The Euclidian distance has been used as distance metric, and the clustering is using the ‘ward’ method to gather miRNAs or patient samples together. The heat map colours range from orange (high intensity values) to blue (low intensity values). The miRNAs used for the clustering strongly discriminate the high-risk from the low-risk neuroblastoma. See also Table 1 and Supplementary Table 3.
Figure 3
Figure 3
Scatter plots showing the statistical analysis of miR-487b, miR-410 and miR-409-3p expression levels in tissue samples of validation test. (A) Validation set tumours (n=214) stratified in two groups, low-risk (blue, n=142) vs high-risk (red, n=72). (B) Analysis of the whole cohort (n=227) stratified according to age, stage and MYCN-amplification status (1: n=1192: n=173: n=114: n=495:n=31). Two-tailed Student t-test indicates significance between the two subgroups. Black bars inside the plots indicate the mean value of miRNA expression levels.
Figure 4
Figure 4
Kaplan–Meier curves for overall and disease-free survival of the whole neuroblastoma cohort (n=226) for miR-487b and miR-410 expression. The miRNA expression levels were converted into discrete variables by discriminating the samples into two classes (high and low), under or over the cutoffs.
Figure 5
Figure 5
Kaplan–Meier curves for overall and disease-free survival of (A) non-MYCN-amplified localised neuroblastoma (n=119) and (B) non-MYCN-amplified stage 4S and 4 neuroblastoma of age <18 months (n=28) for miR-487b and miR-410 expression. The miRNA expression levels were converted into discrete variables into high and low classes, under or over the cutoffs. No relapse was observed in patients on (B).
See this image and copyright information in PMC

References

    1. Ambros IM, Benard J, Boavida M, Bown N, Caron H, Combaret V, Couturier J, Darnfors C, Delattre O, Freeman-Edward J, Gambini C, Gross N, Hattinger CM, Luegmayr A, Lunec J, Martinsson T, Mazzocco K, Navarro S, Noguera R, O′Neill S, Potschger U, Rumpler S, Speleman F, Tonini GP, Valent A, van Roy N, Amann G, De Bernardi B, Kogner P, Ladenstein R, Michon J, Pearson AD, Ambros PF (2003) Quality assessment of genetic markers used for therapy stratification. J Clin Oncol 21: 2077–2084 - PubMed
    1. Ambros IM, Brunner B, Aigner G, Bedwell C, Beiske K, Benard J, Bown N, Combaret V, Couturier J, Defferrari R, Gross N, Jeison M, Lunec J, Marques B, Martinsson T, Mazzocco K, Noguera R, Schleiermacher G, Speleman F, Stallings R, Tonini GP, Tweddle DA, Valent A, Vicha A, Roy NV, Villamon E, Ziegler A, Preuner S, Drobics M, Ladenstein R, Amann G, Schuit RJ, Potschger U, Ambros PF (2011) A multilocus technique for risk evaluation of patients with neuroblastoma. Clin Cancer Res 17: 792–804 - PubMed
    1. Benard J, Raguenez G, Kauffmann A, Valent A, Ripoche H, Joulin V, Job B, Danglot G, Cantais S, Robert T, Terrier-Lacombe MJ, Chassevent A, Koscielny S, Fischer M, Berthold F, Lipinski M, Tursz T, Dessen P, Lazar V, Valteau-Couanet D (2008) MYCN-non-amplified metastatic neuroblastoma with good prognosis and spontaneous regression: a molecular portrait of stage 4S. Mol Oncol 2: 261–271 - PMC - PubMed
    1. Bettan-Renaud L, Bayle C, Teyssier JR, Benard J (1989) Stability of phenotypic and genotypic traits during the establishment of a human neuroblastoma cell line, IGR-N-835. Int J Cancer 44: 460–466 - PubMed
    1. Bray I, Bryan K, Prenter S, Buckley PG, Foley NH, Murphy DM, Alcock L, Mestdagh P, Vandesompele J, Speleman F, London WB, McGrady PW, Higgins DG, O′Meara A, O′Sullivan M, Stallings RL (2009) Widespread dysregulation of miRNAs by MYCN amplification and chromosomal imbalances in neuroblastoma: association of miRNA expression with survival. PLoS ONE 4: e7850. - PMC - PubMed

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