Abstract
BackgroundAlthough, substantial experimental evidence related to diagnosis and treatment of pediatric central nervous system (CNS) neoplasms have been demonstrated, the understanding of the etiology and pathogenesis of the disease remains scarce. Recent microRNA (miRNA)-based research reveals the involvement of miRNAs in various aspects of CNS development and proposes that they might compose key molecules underlying oncogenesis. The current study evaluated miRNA differential expression detected between pediatric embryonal brain tumors and normal controls to characterize candidate biomarkers related to diagnosis, prognosis and therapy.MethodsOverall, 19 embryonal brain tumors; 15 Medulloblastomas (MBs) and 4 Atypical Teratoid/Rabdoid Tumors (AT/RTs) were studied. As controls, 13 samples were used; The First-Choice Human Brain Reference RNA and 12 samples from deceased children who underwent autopsy and were not present with any brain malignancy. RNA extraction was carried out using the Trizol method, whilst miRNA extraction was performed with the mirVANA miRNA isolation kit. The experimental approach included miRNA microarrays covering 1211 miRNAs. Quantitative Real-Time Polymerase Chain Reaction was performed to validate the expression profiles of miR-34a and miR-601 in all 32 samples initially screened with miRNA microarrays and in an additional independent cohort of 30 patients (21MBs and 9 AT/RTs). Moreover, meta-analyses was performed in total 27 embryonal tumor samples; 19 MBs, 8 ATRTs and 121 control samples. Twelve germinomas were also used as an independent validation cohort. All deregulated miRNAs were correlated to patients’ clinical characteristics and pathological measures.ResultsIn several cases, there was a positive correlation between individual miRNA expression levels and laboratory or clinical characteristics. Based on that, miR-601 could serve as a putative tumor suppressor gene, whilst miR-34a as an oncogene. In general, miR-34a demonstrated oncogenic roles in all pediatric embryonal CNS neoplasms studied.ConclusionsDeeper understanding of the aberrant miRNA expression in pediatric embryonal brain tumors might aid in the development of tumor-specific miRNA signatures, which could potentially afford promising biomarkers related to diagnosis, prognosis and patient targeted therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-014-0096-y) contains supplementary material, which is available to authorized users.
Highlights
Substantial experimental evidence related to diagnosis and treatment of pediatric central nervous system (CNS) neoplasms have been demonstrated, the understanding of the etiology and pathogenesis of the disease remains scarce
We found that certain miRNA profiles were relevant to each of the aforementioned variables and their possible combinations delivering potential reliable diagnostic, prognostic or therapy-related targets, while this is the first report that underlines the adverse role of miR-34a and its association with embryonal brain tumor patients’ inferior prognosis
MicroRNA expression profiling between tumor groups In the current study, we identified a total of 113 differentially expressed (DE) miRNAs (p < 0.05 and False Discovery Rate (FDR) < 0.05) in the embryonal tumor group (MBs, nmiRNA = 61 and Atypical terathoid/rhabdoid tumor (AT/RT), nmiRNA = 52) when compared to the non-malignant group of patients (Figure 1)
Summary
Substantial experimental evidence related to diagnosis and treatment of pediatric central nervous system (CNS) neoplasms have been demonstrated, the understanding of the etiology and pathogenesis of the disease remains scarce. Atypical teratoid/rhabdoid tumour is a highly malignant CNS tumour that represents 1-2% of pediatric brain tumours and accounts for at least 10% of CNS tumours in infants, due to the predominance in children younger of 3 years old. The survival of children younger than 3 years of age remains poor, for patients with supratentorial tumors and those with metastatic disease [2]. It can be supratentorial, especially in cerebral hem [6] ispheres, or infratentorial, especially in the cerebellar hemispheres, cerellopontine angle and brain stem mainly in children younger than 2 years of age. Prognosis of AT/RT is dismal, while there are no protocols aimed for this type [2]
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