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Microrna expression signatures predict patient progression and disease outcome in pediatric embryonal central nervous system neoplasms.

Braoudaki M, Lambrou GI, Giannikou K, Milionis V, Stefanaki K, Birks DK, Prodromou N, Kolialexi A, Kattamis A, Spiliopoulou CA, Tzortzatou-Stathopoulou F, Kanavakis E - J Hematol Oncol (2014)

Bottom Line: All deregulated miRNAs were correlated to patients' clinical characteristics and pathological measures.In several cases, there was a positive correlation between individual miRNA expression levels and laboratory or clinical characteristics.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.

View Article: PubMed Central - PubMed

ABSTRACT

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.

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Related in: MedlinePlus

Overlapping relationship of the differentially expressed miRNAs. Venn diagrams illustrate the overlapping relationship of the number of up-regulated miRNAs among MBs and AT/RTs in initial and meta-analysis data. In particular, 6 DE miRNAs were common in MB and ATRT samples from the initial experiments (A). Two were common in Down-regulated miRNAs between both MBs and ATRTs (B), as well as four were common in up-regulated miRNAs between MBs and ATRTs (C). Further, 242 common down-regulated miRNAs were identified between MBs, ATRT and GE samples in all experimental datasets (meta-analysis) (D). Additionally, six miRNAs appeared to be unique in Germinoma samples (D). Finally, 150 miRNAs were identified to be common in up-regulated MB, ATRT and GE samples from the meta-analysis results (E). Additionally, six miRNAs appeared to be unique in ATRT samples, within the same analysis, as well as 20 miRNAs were common between MB and GE samples (E) (Legend: MB: Medulloblastoma, ATRT: Atypical Teratoid/Rhabdoid Tumor, GE: Germinoma).
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Fig2: Overlapping relationship of the differentially expressed miRNAs. Venn diagrams illustrate the overlapping relationship of the number of up-regulated miRNAs among MBs and AT/RTs in initial and meta-analysis data. In particular, 6 DE miRNAs were common in MB and ATRT samples from the initial experiments (A). Two were common in Down-regulated miRNAs between both MBs and ATRTs (B), as well as four were common in up-regulated miRNAs between MBs and ATRTs (C). Further, 242 common down-regulated miRNAs were identified between MBs, ATRT and GE samples in all experimental datasets (meta-analysis) (D). Additionally, six miRNAs appeared to be unique in Germinoma samples (D). Finally, 150 miRNAs were identified to be common in up-regulated MB, ATRT and GE samples from the meta-analysis results (E). Additionally, six miRNAs appeared to be unique in ATRT samples, within the same analysis, as well as 20 miRNAs were common between MB and GE samples (E) (Legend: MB: Medulloblastoma, ATRT: Atypical Teratoid/Rhabdoid Tumor, GE: Germinoma).

Mentions: Overall, the majority of the 113 DE miRNAs initially observed were down-regulated with a total of 54 miRNAs (47.8%) exhibiting increased expression and 59 miRNAs (52.2%) showing decreased expression. Among them, 107 miRNAs were characterized as tissue-specific, whilst 6 miRNAs; miR-34a, miR-548j, miR-607, miR-891a, miR-3191 and miR-3912 were found to be consistently differentially expressed in both MBs and AT/RTs (Figure 2A). Of note, the majority of them were also found differentially expressed in both MBs and AT/RTs, following our meta-analyses. Specifically, miR-34a was found overexpressed in all embryonal tumor samples tested when compared to the control group, following both our initial and meta-analyses (including GEs) (Figure 2A, 2C, 2E). Further on, miR-548j, miR-3191 and miR-3912 were found overexpressed by our initial analysis only (Figure 2C), whereas miR-607 and miR-891a were found down-regulated in all embryonal tumor samples tested as compared to the control group, following our initial analysis only (Figure 2B). The overlapping relationship of the DE miRNAs among both tumor types following initial and meta-analyses is depicted in Figure 2. In addition, all commonly down- or up-regulated miRNAs are presented in Additional file 1: Table S2.Figure 2


Microrna expression signatures predict patient progression and disease outcome in pediatric embryonal central nervous system neoplasms.

Braoudaki M, Lambrou GI, Giannikou K, Milionis V, Stefanaki K, Birks DK, Prodromou N, Kolialexi A, Kattamis A, Spiliopoulou CA, Tzortzatou-Stathopoulou F, Kanavakis E - J Hematol Oncol (2014)

Overlapping relationship of the differentially expressed miRNAs. Venn diagrams illustrate the overlapping relationship of the number of up-regulated miRNAs among MBs and AT/RTs in initial and meta-analysis data. In particular, 6 DE miRNAs were common in MB and ATRT samples from the initial experiments (A). Two were common in Down-regulated miRNAs between both MBs and ATRTs (B), as well as four were common in up-regulated miRNAs between MBs and ATRTs (C). Further, 242 common down-regulated miRNAs were identified between MBs, ATRT and GE samples in all experimental datasets (meta-analysis) (D). Additionally, six miRNAs appeared to be unique in Germinoma samples (D). Finally, 150 miRNAs were identified to be common in up-regulated MB, ATRT and GE samples from the meta-analysis results (E). Additionally, six miRNAs appeared to be unique in ATRT samples, within the same analysis, as well as 20 miRNAs were common between MB and GE samples (E) (Legend: MB: Medulloblastoma, ATRT: Atypical Teratoid/Rhabdoid Tumor, GE: Germinoma).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4342799&req=5

Fig2: Overlapping relationship of the differentially expressed miRNAs. Venn diagrams illustrate the overlapping relationship of the number of up-regulated miRNAs among MBs and AT/RTs in initial and meta-analysis data. In particular, 6 DE miRNAs were common in MB and ATRT samples from the initial experiments (A). Two were common in Down-regulated miRNAs between both MBs and ATRTs (B), as well as four were common in up-regulated miRNAs between MBs and ATRTs (C). Further, 242 common down-regulated miRNAs were identified between MBs, ATRT and GE samples in all experimental datasets (meta-analysis) (D). Additionally, six miRNAs appeared to be unique in Germinoma samples (D). Finally, 150 miRNAs were identified to be common in up-regulated MB, ATRT and GE samples from the meta-analysis results (E). Additionally, six miRNAs appeared to be unique in ATRT samples, within the same analysis, as well as 20 miRNAs were common between MB and GE samples (E) (Legend: MB: Medulloblastoma, ATRT: Atypical Teratoid/Rhabdoid Tumor, GE: Germinoma).
Mentions: Overall, the majority of the 113 DE miRNAs initially observed were down-regulated with a total of 54 miRNAs (47.8%) exhibiting increased expression and 59 miRNAs (52.2%) showing decreased expression. Among them, 107 miRNAs were characterized as tissue-specific, whilst 6 miRNAs; miR-34a, miR-548j, miR-607, miR-891a, miR-3191 and miR-3912 were found to be consistently differentially expressed in both MBs and AT/RTs (Figure 2A). Of note, the majority of them were also found differentially expressed in both MBs and AT/RTs, following our meta-analyses. Specifically, miR-34a was found overexpressed in all embryonal tumor samples tested when compared to the control group, following both our initial and meta-analyses (including GEs) (Figure 2A, 2C, 2E). Further on, miR-548j, miR-3191 and miR-3912 were found overexpressed by our initial analysis only (Figure 2C), whereas miR-607 and miR-891a were found down-regulated in all embryonal tumor samples tested as compared to the control group, following our initial analysis only (Figure 2B). The overlapping relationship of the DE miRNAs among both tumor types following initial and meta-analyses is depicted in Figure 2. In addition, all commonly down- or up-regulated miRNAs are presented in Additional file 1: Table S2.Figure 2

Bottom Line: All deregulated miRNAs were correlated to patients' clinical characteristics and pathological measures.In several cases, there was a positive correlation between individual miRNA expression levels and laboratory or clinical characteristics.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.

View Article: PubMed Central - PubMed

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus