Genetic expression profiles of adult and pediatric ependymomas: Molecular pathways, prognostic indicators, and therapeutic targets

Nagasawa, Daniel T.; Trang, Andy; Choy, Winward; Spasić, Marko; Yew, Andrew; Zarinkhou, Golmah; Garcia, Heather M.; Yang, Isaac

doi:10.1016/j.clineuro.2012.12.006

Cited by 18 publications

(20 citation statements)

References 115 publications

(247 reference statements)

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“…TP53INP1 co‐localizes with TP53 and homeodomain‐interacting protein kinase‐2 within the promyelocytic leukemia protein nuclear bodies modulating TP53 transcriptional activity on several TP53 target genes . Alterations in TP53 ‐mediated growth arrest in ependymoma might be associated with the radioresistance of these tumors . Thus, TP53INP1 appears to be a key element in TP53 ‐mediated cell death and cell cycle arrest, induced by cellular stress.…”

Section: Discussionmentioning

confidence: 99%

Prognostic relevance of miR‐124‐3p and its target TP53INP1 in pediatric ependymoma

Margolin-Miller

Yanichkin

Shichrur

et al. 2017

Genes Chromosomes & Cancer

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Ependymoma is a malignant pediatric brain tumor, often incurable under the current treatment regimen. We aimed to evaluate the expression of microRNAs (miRs) in pediatric ependymoma tumors in an attempt to identify prognostic molecular markers which would lead to potential therapeutic targets. Following miR-array expression analysis, we focused on 9 miRs that correlated with relapse which were further validated by quantitative real-time PCR (qRT-PCR) in a cohort of 67 patients. Western blotting and immunohistochemistry were used to measure target protein expression in 20 and 34 tumor samples, respectively. High expression of miR-124-3p significantly correlated with the lower progression-free survival (PFS) of 16% compared to 67% in those expressing low levels (P = .002). Interestingly, in the group of patients with local disease (n = 56) expression levels of this miR distinguished 2 subgroups with a significantly different outcome (P = .001). miR-124-3p was identified as an independent prognostic factor of relapse in the multivariate analysis performed in the whole cohort and in the group with localized disease. In the localized group, a patient expressing high levels of miR-124-3p had a 4.1-fold increased risk for relapse (P = .005). We demonstrated the direct binding of miR-124-3p to its target TP53INP1. Negative TP53INP1 protein levels correlated with a poor outcome (P = .034). We propose miR-124-3p and TP53INP1 as new biomarkers for prognostic stratification that may be possible therapeutic targets for ependymoma.

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Section: Discussionmentioning

confidence: 99%

Prognostic relevance of miR‐124‐3p and its target TP53INP1 in pediatric ependymoma

Margolin-Miller

Yanichkin

Shichrur

et al. 2017

Genes Chromosomes & Cancer

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“…Similarly, subtypes of NSCLC with EML4-ALK translocation or mutant EGFR respond to crizotinib and erlotinib, respectively (13–15), whereas these agents have little impact on survival in unselected patients. With increasing ‘omics’ analysis of childhood cancers, subsets have also been identified for ependymoma (16,17), medulloblastoma (18,19), neuroblastoma (20–22), sarcomas (23–26), and acute leukemias (27), diseases previously considered rather homogeneous entities. Thus, there is a need to represent more diverse genotypes/phenotypes in the preclinical models.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis

et al. 2016

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Traditional approaches to evaluating antitumor agents using human tumor xenograft models have generally used cohorts of 8–10 mice against a limited panel of tumor models. An alternative approach is to use fewer animals per tumor line, allowing a greater number of models that capture greater molecular/genetic heterogeneity of the cancer type. We retrospectively analyzed 67 agents evaluated by the Pediatric Preclinical Testing Program (PPTP) to determine whether a single mouse, chosen randomly from each group of a study, predicted the median response for groups of mice using 83 xenograft models. The individual tumor response from a randomly chosen mouse was compared to the group median response using established response criteria. A total of 2134 comparisons were made. The single tumor response accurately predicted the group median response in 1604 comparisons (75.16%). The mean tumor response correct prediction rate for 1,000 single mouse random samples was 78.09%. Models had a range for correct prediction (60%–87.5%). Allowing for mis-prediction of ± one response category, the overall mean correct single mouse prediction rate was 95.28%, and predicted overall objective response rates for group data in 66 of 67 drug studies. For molecularly targeted agents occasional exceptional responder models were identified and the activity of that agent confirmed in additional models with the same genotype. Assuming that large treatment effects are targeted, this alternate experimental design has similar predictive value as traditional approaches, allowing for far greater numbers of models to be used that more fully encompass the heterogeneity of disease types.

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“…Os ependimomas são tumores raros com um comportamento diferente de acordo com a localização, a idade ao diagnóstico e o grau histológico (Boop and Sgouros 2009;Gilbert, Ruda et al 2010;Nagasawa, Trang et al 2013). …”

Section: Spearman (Figura 15)unclassified

“…Apesar dos ependimomas serem considerados como uma única doença devido às mesmas características histológicas, a maioria dos estudos mostra um perfil de expressão gênica diferente dependendo da localização do tumor e da idade do paciente ao diagnóstico (Hirose, Aldape et al 2001;Dyer, Prebble et al 2002;Taylor, Poppleton et al 2005;Modena, Lualdi et al 2006;Kilday, Rahman et al 2009;Palm, Figarella-Branger et al 2009;Andreiuolo, Puget et al 2010;Johnson, Wright et al 2010;Witt, Mack et al 2011;Nagasawa, Trang et al 2013). Dez genes foram selecionados para estudo da expressão gênica e para correlação dessa expressão com os dados clínicos da casuística apresentada.…”

Section: Spearman (Figura 15)unclassified

“…Essa observação pode ter relação com a desregulação de vias de sinalização nessa região que tem a ciclina D1 como efetor, já que translocações e amplificações genômicas no locus da ciclina D1 são incomuns nos ependimomas (Kilday, Rahman et al 2009;Yao, Mack et al 2011) Deleções e metilações no locus do supressor de tumor p16 INK4A (proteína CDKN2A) foram descritas em ependimomas supratentoriais ou anaplásicos (Huang, Starostik et al 2003;Korshunov, Neben et al 2003;Rousseau, Ruchoux et al 2003;Taylor, Poppleton et al 2005;Godfraind 2009;Johnson, Wright et al 2010;Korshunov, Witt et al 2010;Yao, Mack et al 2011;Modena, Buttarelli et al 2012;Witt, Korshunov et al 2012;Kim, Huang et al 2013;Nagasawa, Trang et al 2013). CDKN2A age inibindo a ligação entre a proteína CDK4 e ciclina D1, e, assim, previne a fosforilação de Rb (Gadd, Pisc et al 2001).…”

Genetic expression profiles of adult and pediatric ependymomas: Molecular pathways, prognostic indicators, and therapeutic targets

Cited by 18 publications

References 115 publications

Prognostic relevance of miR‐124‐3p and its target TP53INP1 in pediatric ependymoma

Prognostic relevance of miR‐124‐3p and its target TP53INP1 in pediatric ependymoma

Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis

Estudo das alterações na expressão gênica dos ependimomas

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