Multifactorial analysis of predictors of outcome in pediatric intracranial ependymoma. Neuro Oncol

Children's Brain Tumor Research Centre, University of Nottingham, Nottingham, UK.
Neuro-Oncology (Impact Factor: 5.56). 09/2008; 10(5):675-89. DOI: 10.1215/15228517-2008-036
Source: PubMed


Pediatric ependymomas are enigmatic tumors, and their clinical management remains one of the more difficult in pediatric oncology. The identification of biological correlates of outcome and therapeutic targets remains a significant challenge in this disease. We therefore analyzed a panel of potential biological markers to determine optimal prognostic markers. We constructed a tissue microarray from 97 intracranial tumors from 74 patients (WHO grade II-III) and analyzed the candidate markers nucleolin, telomerase catalytic subunit (hTERT; antibody clone 44F12), survivin, Ki-67, and members of the receptor tyrosine kinase I (RTK-I) family by immunohistochemistry. Telomerase activity was determined using the in vitro-based telomere repeat amplification protocol assay, and telomere length was measured using the telomere restriction fragment assay. Primary tumors with low versus high nucleolin protein expression had a 5-year event-free survival of 74%+/-13% and 31%+/-7%, respectively. Multivariate analysis identified low nucleolin expression to be independently associated with a more favorable prognosis (hazard ratio=6.25; 95% confidence interval, 1.6-24.2; p=0.008). Ki-67 and survivin correlated with histological grade but not with outcome. Immunohistochemical detection of the RTK-I family did not correlate with grade or outcome. Telomerase activity was evident in 19 of 22 primary tumors, with telomere lengthening and/or maintenance occurring in five of seven recurrent cases. Low nucleolin expression was the single most important biological predictor of outcome in pediatric intracranial ependymoma. Furthermore, telomerase reactivation and maintenance of telomeric repeats appear necessary for childhood ependymoma progression. These findings require corroboration in a clinical trial setting.

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    • "Nucleolin is also involved in pathological processes, particularly cancer. It is overexpressed in highly proliferative cells, especially in several malignant cells, including neuroblastoma, cutaneous melanoma, pediatric intracranial ependymoma, breast cancer, lung cancer, colon cancer [11-16]. Nucleolin functions as a oncogene and regulates the abilities of cancer cells to grow and proliferate, overcome senescence, evade apoptosis and the immune system, invade and metastasize other tissues and promote angiogenesis. "
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    ABSTRACT: Background Nucleolin, as a multifunctional protein, has been demonstrated to play an oncogenic role in human hepatocellular carcinoma (HCC). The aim of this study was to investigate the expression pattern of nucleolin in HCC and determine its correlation with tumor progression and prognosis.Methods Nucleolin expression at both mRNA and protein levels in HCC and adjacent nonneoplastic tissues were respectively detected by quantitative real time polymerase chain reaction (Q-PCR), immunohistochemistry and western blotting.ResultsNucleolin expression, at both mRNA and protein levels, was significantly higher in HCC tissues than in the adjacent nonneoplastic tissues (both P¿<¿0.001). In addition, the elevated nucleolin expression was markedly correlated with advanced tumor stage (P¿=¿0.001), high tumor grade (P¿=¿0.02) and serum AFP level (P¿=¿0.008). Moreover, HCC patients with high nucleolin expression had shorter 5-year disease-free survival and shorter 5-year overall survival than those with low expression (both P¿<¿0.001). Furthermore, the Cox proportional hazards model showed that nucleolin expression was an independent poor prognostic factor for both 5-year disease-free survival (hazards ratio [HR]¿=¿3.696, 95% confidence interval[CI]¿=¿1.662-8.138, P¿=¿0.01) and 5-year overall survival (HR¿=¿3.872, CI¿=¿1.681-8.392, P¿=¿0.01) in HCC.Conclusion These results showed that the markedly and consistently increasing expression of nucleolin may be associated with aggressive characteristics of HCC, and implied that nucleolin expression may serve as a promising biochemical marker for predicting the clinical outcome of patients with this malignancy.Virtual SlidesThe virtual slide(s) for this article can be found here:
    Full-text · Article · Sep 2014 · Diagnostic Pathology
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    • "Immunohistochemistry. Immunohistochemistry was carried out on TMAs and whole sections as described previously (Ridley et al, 2008). Slides were incubated with b-catenin (1 in 500, Cell Signaling Technology, Danvers, MA, USA), map2 (1 in 200, Abcam, Cambridge, UK) and synaptophysin (1 in 200, Dako, Ely, UK). "
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    ABSTRACT: Background: Central nervous system primitive neuroectodermal tumours (CNS PNETs) are embryonal tumours occurring predominantly in children. Current lack of knowledge regarding their underlying biology hinders development of more effective treatments. We previously identified WNT/β-catenin pathway activation in one-third of CNS PNETs, which was potentially linked to a better prognosis. In this study, we have extended our cohort, achieving a statistically significant correlation with prognosis. We additionally investigated the biological effects of WNT/β-catenin pathway activation in tumour pathogenesis. Methods: A total of 42 primary and 8 recurrent CNS PNETs were analysed for WNT/β-catenin pathway status using β-catenin immunohistochemistry. Genomic copy number and mRNA expression data were analysed to identify a molecular profile linked to WNT/β-catenin pathway activation. Results: Pathway activation was seen in 26% of CNS PNETs and was significantly associated with longer overall survival. Genes displaying a significant difference in expression levels, between tumours with and without WNT/β-catenin pathway activation, included several involved in normal CNS development suggesting aberrant pathway activation may be disrupting this process. Conclusion: We have identified WNT/β-catenin pathway status as a marker, which could potentially be used to stratify disease risk for patients with CNS PNET. Gene expression data suggest pathway activation is disrupting normal differentiation in the CNS.
    Full-text · Article · Apr 2013 · British Journal of Cancer
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    • "Among the putative oncogenes in ependymoma are NOTCH1, NOTCH4, and JAG1, which are two of the membrane receptors and one of the ligands, respectively, of the Notch signaling pathway, suggesting the involvement of Notch signaling in ependymoma tumorigenesis. Furthermore, recurrent gains at 5p15.33, which includes the human telomerase reverse transcriptase (hTERT) gene, were validated by immunohistochemistry. Elevated hTERT expression has been shown to be associated with ependymoma progression and recurrence and is currently the most important predictor of survival for pediatric intracranial ependymomas independent of other clinicopathologic prognostic features[78],[98]–[100]. Furthermore, hTERT expression relates with telomerase activity[99]. "
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    ABSTRACT: Brain tumors are the leading cause of cancer death in children, with ependymoma being the third most common and posing a significant clinical burden. Its mechanism of pathogenesis, reliable prognostic indicators, and effective treatments other than surgical resection have all remained elusive. Until recently, ependymoma research was hindered by the small number of tumors available for study, low resolution of cytogenetic techniques, and lack of cell lines and animal models. Ependymoma heterogeneity, which manifests as variations in tumor location, patient age, histological grade, and clinical behavior, together with the observation of a balanced genomic profile in up to 50% of cases, presents additional challenges in understanding the development and progression of this disease. Despite these difficulties, we have made significant headway in the past decade in identifying the genetic alterations and pathways involved in ependymoma tumorigenesis through collaborative efforts and the application of microarray-based genetic (copy number) and transcriptome profiling platforms. Genetic characterization of ependymoma unraveled distinct mRNA-defined subclasses and led to the identification of radial glial cells as its cell type of origin. This review summarizes our current knowledge in the molecular genetics of ependymoma and proposes future research directions necessary to further advance this field.
    Full-text · Article · Oct 2011 · Chinese journal of cancer
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