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.
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
Defining the human neuroblastoma circulating miRNome.