MicroRNA expression profile predicts prognosis of pediatric adrenocortical tumors.

Pediatric adrenocortical tumors (ACT) are rare aggressive neoplasms with heterogeneous prognosis. Despite extensive efforts, identifying reliable prognostic factors for pediatric patients with ACT remains a challenge. MicroRNA (miRNA) signatures have been associated with cancer diagnosis, treatment response, and prognosis of several types of cancer. However, the role of miRNAs has been poorly explored in pediatric ACT. In this study, we performed miRNA microarray profiling on a cohort of 37 pediatric ACT and nine nonneoplastic adrenal (NNA) samples and evaluated the prognostic significance of abnormally expressed miRNAs using Kaplan-Meier plots, log-rank test, and Cox regression analysis. We identified a total of 98 abnormally expressed miRNAs; their expression profile discriminated ACT from NNAs. Among the 98 deregulated miRNAs, 17 presented significant associations with patients' survival. In addition, higher expression levels of hsa-miR-630, -139-3p, -125a-3p, -574-5p, -596, -564, -1321, and -423-5p and lower expression levels of hsa-miR-377-3p, -126-3p, -410, -136-3p, -29b-3p, -29a-3p, -337-5p, -143-3p, and 140-5p were significantly associated with poor prognosis, tumor relapse, and/or death. Importantly, the expression profile of these 17 miRNAs stratified patients into two groups of ACTs with different clinical outcomes. Although some individual miRNAs exhibit potential prognostic values in ACTs, only the 17 miRNA-based expression clustering was considered an independent prognostic factor for 5-year event-free survival (EFS) compared to other clinicopathological features. In conclusion, our study reports for the first time associations between miRNA profiles and childhood ACT prognosis, providing evidence that miRNAs could be useful biomarkers to discriminate patients with favorable and unfavorable clinical outcomes.

Minimal residual disease in cerebrospinal fluid at diagnosis: a more intensive treatment protocol was able to eliminate the adverse prognosis in children with acute lymphoblastic leukemia.

We analyzed cerebrospinal fluid (CSF) samples from 65 consecutive children with acute lymphoblastic leukemia (ALL) treated according to two different treatment protocols (GBTLI-ALL-93 and -99) with no puncture accident for minimal residual disease (MRD) in the central nervous system (CNS). Minimal residual disease was detected by polymerase chain reaction (PCR) with homo/heteroduplex analysis using consensus primers to IgH and TCR genes. MRD in the CSF at diagnosis was detected by PCR in 46.8% of children with no puncture accident or morphological involvement. In patients treated with GBTLI-ALL-93 a significantly lower 5-year event-free survival (EFS) was demonstrated for those with CSF involvement, in univariate (p = 0.01) and multivariate (p = 0.04) analysis. This observation was not true for patients treated with the more intensive protocol GBTLI-ALL-99 (p = 0.81). These findings suggest that MRD detection in the CSF is a common event in children with ALL. Treatment intensification provided by the GBTLI-ALL-99 apparently overcomes the detrimental effect of CNS minimal residual disease at diagnosis.

Differential miRNA expression in childhood acute lymphoblastic leukemia and association with clinical and biological features.

The present study aimed to analyze the expression profile of the microRNAs previously described as associated with childhood ALL, miR-92a, miR-100, miR-125a-5p, miR-128a, miR-181b, miR-196b and let-7e, and their association with biological/prognostic features in 128 consecutive samples of childhood acute lymphoblastic leukemia (ALL) by quantitative real-time PCR. A significant association was observed between higher expression levels of miR-196b and T-ALL, miR-100 and patients with low white blood cell count at diagnosis and t(12;21) positive ALL. These findings suggest a potential activity of these microRNAs in pediatric ALL biology.

Frequency of polymorphisms and protein expression of cyclin-dependent kinase inhibitor 1A (CDKN1A) in central nervous system tumors / Frequência dos polimorfismos e da expressão protéica do inibidor de quinase dependente de ciclina 1A (CDKN1A) em tumores do sistema nervoso central

Context and objective: Genetic investigation of central nervous system (CNS) tumors provides valuable information about the genes regulating proliferation, differentiation, angiogenesis, migration and apoptosis in the CNS. The aim of our study was to determine the prevalence of genetic polymorphisms (codon 31 and 3' untranslated region, 3'UTR) and protein expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A) gene in patients with and without CNS tumors. Design and setting: Analytical cross-sectional study with a control group, at the Molecular Biology Laboratory, Pediatric Oncology Department, Hospital das Clínicas de Ribeirão Preto. Methods: 41 patients with CNS tumors and a control group of 161 subjects without cancer and paires for sex, age and ethnicity were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Protein analysis was performed on 36 patients with CNS tumors, using the Western Blotting technique. Results: The frequencies of the heterozygote (Ser/Arg) and polymorphic homozygote (Arg/Arg) genotypes of codon 31 in the control subjects were 28.0 percent and 1.2 percent, respectively. However, the 3'UTR site presented frequencies of 24.2 percent (C/T) and 0.6 percent (T/T). These frequencies were not statistically different (P > 0.05) from those seen in the patients with CNS tumors (19.4 percent and 0.0 percent, codon 31; 15.8 percent and 2.6 percent, 3'UTR site). Regarding the protein expression in ependymomas, 66.67 percent did not express the protein CDKN1A. The results for medulloblastomas and astrocytomas were similar: neither of them expressed the protein (57.14 percent and 61.54 percent, respectively). Conclusion: No significant differences in protein expression patterns or polymorphisms of CDKN1A in relation to the three types of CNS tumors were observed among Brazilian subjects.

Contexto e objetivo: A investigação genética dos tumores do sistema nervoso central (SNC) provê valiosa informação sobre os genes que regulam a proliferação, diferenciação, angiogênese, migração e apoptose. O objetivo deste estudo é determinar a prevalência entre os polimorfismos genéticos (códon 31 e da região 3' não traduzida, 3'UTR) e a expressão protéica do gene inibidor de quinase dependente de ciclina 1A (CDKN1A) em pacientes com e sem tumor do SNC. Tipo de estudo e local: Estudo transversal analítico com grupo controle, desenvolvido no Laboratório de Biologia Molecular do Departamento de Oncologia Pediátrica do Hospital das Clínicas de Ribeirão Preto. Métodos: 41 pacientes com tumor do SNC e um grupo controle de 161 indivíduos sem câncer pareados por idade, sexo e etnia foram genotipados mediante uma reação de polimorfismo no comprimento de fragmentos de restrição (RFLP). A análise das proteínas foi realizada em 36 pacientes com tumor de SNC mediante Western Blotting. Resultados: A frequência do genótipo heterozigoto (Ser/Arg) e do homozigoto polimórfico (Arg/Arg) do códon 31 nos controles foi 28,0 por cento e 1,2 por cento, respectivamente. Entretanto, o sítio 3'UTR apresentou uma frequência de 24,2 por cento (C/T) e 0,6 por cento (T/T). Estas frequências não são significativamente diferentes (P > 0,05) daquelas observadas no grupo dos pacientes com tumor de SNC (19,4 por cento e 0,0 por cento, códon 31; 15,8 por cento e 2,6 por cento, sítio 3'UTR). Com respeito à expressão protéica, nos ependimomas, 66,67 por cento não expressaram a proteína CDKN1A. Estes resultados foram similares entre os meduloblastomas e os astrocitomas, os quais não expressaram a proteína com 57,14 por cento e 61,54 por cento, respectivamente. Conclusão: Não foram encontradas diferenças significativas entre o padrão de expressão protéica, polimorfismos de CDKN1A e os três tipos de tumores de SNC em indivíduos brasileiros.

Frequency of polymorphisms and protein expression of cyclin-dependent kinase inhibitor 1A (CDKN1A) in central nervous system tumors.

CONTEXT AND OBJECTIVE: Genetic investigation of central nervous system (CNS) tumors provides valuable information about the genes regulating proliferation, differentiation, angiogenesis, migration and apoptosis in the CNS. The aim of our study was to determine the prevalence of genetic polymorphisms (codon 31 and 3' untranslated region, 3'UTR) and protein expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A) gene in patients with and without CNS tumors. DESIGN AND SETTING: Analytical cross-sectional study with a control group, at the Molecular Biology Laboratory, Pediatric Oncology Department, Hospital das Clínicas de Ribeirão Preto. METHODS: 41 patients with CNS tumors and a control group of 161 subjects without cancer and paires for sex, age and ethnicity were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Protein analysis was performed on 36 patients with CNS tumors, using the Western Blotting technique. RESULTS: The frequencies of the heterozygote (Ser/Arg) and polymorphic homozygote (Arg/Arg) genotypes of codon 31 in the control subjects were 28.0% and 1.2%, respectively. However, the 3'UTR site presented frequencies of 24.2% (C/T) and 0.6% (T/T). These frequencies were not statistically different (P > 0.05) from those seen in the patients with CNS tumors (19.4% and 0.0%, codon 31; 15.8% and 2.6%, 3'UTR site). Regarding the protein expression in ependymomas, 66.67% did not express the protein CDKN1A. The results for medulloblastomas and astrocytomas were similar: neither of them expressed the protein (57.14% and 61.54%, respectively). CONCLUSION: No significant differences in protein expression patterns or polymorphisms of CDKN1A in relation to the three types of CNS tumors were observed among Brazilian subjects.