Multifactorial analysis of predictors of outcome in pediatric intracranial ependymoma

¹ Children's Brain Tumor Research Centre, University of Nottingham, Nottingham, UK
² Department of Pathology, Birmingham Children's Hospital, Birmingham, UK
³ St. Jude Children's Research Hospital, Memphis, TN, USA
⁴ Children's Brain Tumor Research Centre, University of Nottingham, Nottingham, UK; Department of Neuropathology, Nottingham University Hospital, Queens Medical Centre, Nottingham, UK
⁵ Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham, UK
⁶ West Midlands Regional Children's Tumor Registry, Birmingham Children's Hospital, Birmingham, UK

^* To whom correspondence should be addressed. E-mail: richard.grundy{at}nottingham.ac.uk.

	Abstract

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.

Key Words: ependymoma, nucleolin, pediatric, telomerase, telomere

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