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Circulating microRNA biomarkers for metastatic disease in neuroblastoma patients
Fjoralba Zeka, … , Pieter Mestdagh, Jo Vandesompele
Fjoralba Zeka, … , Pieter Mestdagh, Jo Vandesompele
Published December 6, 2018
Citation Information: JCI Insight. 2018;3(23):e97021. https://doi.org/10.1172/jci.insight.97021.
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Research Article Genetics Oncology

Circulating microRNA biomarkers for metastatic disease in neuroblastoma patients

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Abstract

In this study, the circulating miRNome from diagnostic neuroblastoma serum was assessed for identification of noninvasive biomarkers with potential in monitoring metastatic disease. After determining the circulating neuroblastoma miRNome, 743 miRNAs were screened in 2 independent cohorts of 131 and 54 patients. Evaluation of serum miRNA variance in a model testing for tumor stage, MYCN status, age at diagnosis, and overall survival revealed tumor stage as the most significant factor impacting miRNA abundance in neuroblastoma serum. Differential abundance analysis between patients with metastatic and localized disease revealed 9 miRNAs strongly associated with metastatic stage 4 disease in both patient cohorts. Increasing levels of these miRNAs were also observed in serum from xenografted mice bearing human neuroblastoma tumors. Moreover, murine serum miRNA levels were strongly associated with tumor volume. These findings were validated in longitudinal serum samples from metastatic neuroblastoma patients, where the 9 miRNAs were associated with disease burden and treatment response.

Authors

Fjoralba Zeka, Anneleen Decock, Alan Van Goethem, Katrien Vanderheyden, Fleur Demuynck, Tim Lammens, Hetty H. Helsmoortel, Joëlle Vermeulen, Rosa Noguera, Ana P. Berbegall, Valérie Combaret, Gudrun Schleiermacher, Geneviève Laureys, Alexander Schramm, Johannes H. Schulte, Sven Rahmann, Julie Bienertová-Vašků, Pavel Mazánek, Marta Jeison, Shifra Ash, Michael D. Hogarty, Mirthala Moreno-Smith, Eveline Barbieri, Jason Shohet, Frank Berthold, Tom Van Maerken, Frank Speleman, Matthias Fischer, Katleen De Preter, Pieter Mestdagh, Jo Vandesompele

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Figure 3

Identification of serum miRNAs as potential markers for disease burden in patient cohort 1.

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Identification of serum miRNAs as potential markers for disease burden i...
(A) Fold change (log2 scale) of miRNA abundance in serum (x axis) against statistical significance (y axis, –log10 of the P value) between patients with metastatic (stage 4) neuroblastoma (n = 76) and patients with localized (stage 1 and stage 2) neuroblastoma (n = 33). Higher-fold change denotes higher abundance in metastatic serum. Pink dots represent miRNAs with at least 2-fold (1 log2 unit) higher abundance, and red dots represent miRNAs with at least a 4-fold higher abundance in serum from metastatic patients; blue dots represent miRNAs with at least 2-fold higher abundance in serum from patients with localized disease. For the selection of differentially abundant miRNAs, a Mann-Whitney U test was used at 0.05 significance level (corrected for multiple-testing by the Benjamini-Hochberg method). (B) Heatmap depicting hierarchical clustering of serum samples (cohort 1) based on 9 miRNAs with at least 4-fold higher abundance in serum from metastatic patients. (C) Fold change distribution of miRNA abundance in localized versus metastatic serum. The bar colors correspond to dot colors in plot A. (D) Boxplot of average miRNA expression for the selected set of 9 miRNAs in serum from stage 1, 2, 3, 4, and 4S patients.

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