RESUMEN
BACKGROUND: Although, 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. METHODS: Overall, 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. RESULTS: In 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. CONCLUSIONS: Deeper 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.
Asunto(s)
Neoplasias del Sistema Nervioso Central/genética , MicroARNs/biosíntesis , Neoplasias de Células Germinales y Embrionarias/genética , Adolescente , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/metabolismo , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Meduloblastoma/genética , Meduloblastoma/metabolismo , MicroARNs/genética , Neoplasias de Células Germinales y Embrionarias/metabolismo , Valor Predictivo de las Pruebas , Pronóstico , Teratoma/genética , Teratoma/metabolismo , Resultado del TratamientoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Encefálicas/metabolismo , Ganglioneuroma/metabolismo , Leucemia Mieloide Aguda/inducido químicamente , Leucemia Mieloide Aguda/metabolismo , Neoplasias Primarias Secundarias/metabolismo , Proteoma/análisis , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Astrocitoma/tratamiento farmacológico , Astrocitoma/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/metabolismo , Preescolar , Femenino , Ganglioneuroma/tratamiento farmacológico , Humanos , Metaboloma , ProteómicaRESUMEN
The objective of this study was to quantify improvements in survival due to chemotherapy among children with medulloblastoma treated during the last three decades at a university unit in Greece, compare these gains with figures derived from a specialized unit in the United States and explore the role of extrinsic factors affecting survival. The records of all children with medulloblastoma (n=50) treated at the University Childhood Oncology Unit in Athens, Greece during the period 1973-2003 were reviewed. The role on survival of socio-demographic factors was studied by modeling the data through Cox's proportional-hazards regression, controlling for the mode of treatment (chemotherapy, yes vs. no), whereas survival of children with medulloblastoma treated in Greece was compared with that of 76 children treated in a specialized center in the United States during a respective period. After adjustment for demographic factors, children with medulloblastoma who received adjuvant therapy in Greece had an approximately four times higher instantaneous rate of remaining alive than those who did not (P=0.05). The 5-year survival of children with medulloblastoma treated at specialized medical centers in Greece and the United States was 66 and 63%, respectively. Despite the comparable figure with that of an acceptable standard, however, there was a suggestion (P=0.07) that a rural place of residence in Greece is a poor prognostic indicator. Assuming inherently similar age of occurrence in urban and rural areas, children from rural areas in this study had a more advanced age at diagnosis than those residing in urban Greece (mean age: 7.9 vs. 6.6 years) with a 5-year survival of 57 and 73%, respectively. As expected, incorporation of adjuvant chemotherapy in the treatment of Greek children with medulloblastoma has yielded remarkable improvement in 5-year survival, comparable to that of technologically advanced countries. On the contrary, children residing in rural areas of the country seem to enjoy less favorable prognosis, possibly owing to delays in diagnosis or limited access to optimal treatment facilities.
