Imaging, Diagnosis, Prognosis Copy Number Gain of 1q25 Predicts Poor Progression-Free Survival for Pediatric Intracranial Ependymomas and Enables Patient Risk Stratification: A Prospective European Clinical Trial Cohort Analysis on Behalf of the Children's Cancer Leukaemia Group (CCLG), Soci  et  e Fran¸ caise d'Oncologie P  ediatrique (SFOP), and International Society for Pediatric Oncology (SIOP) John-Paul Kilday 1 , Biswaroop Mitra 1 , Caroline Domerg 3 , Jennifer Ward 1 , Felipe Andreiuolo 5 , Teresa Osteso-Ibanez 1 , Audrey Mauguen 3 , Pascale Varlet 6 , Marie-Cecile Le Deley 2 , James Lowe 1,2 , David W. Ellison 7 , Richard J. Gilbertson 8 , Beth Coyle 1 , Jacques Grill 4,5 , and Richard G. Grundy 1 Abstract Purpose: The high incidence of recurrence and unpredictable clinical outcome for pediatric ependy- moma reflect the imprecision of current therapeutic staging and need for novel risk stratification markers. We therefore evaluated 1q25 gain across three age- and treatment-defined European clinical trial cohorts of pediatric intracranial ependymoma. Experimental Design: Frequency of 1q gain was assessed across 48 ependymomas (42 primary, 6 recurrent) using Affymetrix 500K single-nucleotide polymorphism arrays. Gain of 1q25 was then evaluated by interphase FISH across 189 tumors treated on the Children’s Cancer Leukaemia Group/International Society for Pediatric Oncology (SIOP) CNS9204 (n ¼ 60) and BBSFOP (n ¼ 65) adjuvant chemotherapy trials, or with primary postoperative radiotherapy (SIOP CNS9904/RT, n ¼ 64). Results were correlated with clinical, histologic, and survival data. Results: Gain of 1q was the most frequent imbalance in primary (7/42, 17%) and recurrent ependy- momas (2/6, 33%). Gain of 1q25 was an independent predictor of tumor progression across the pooled trial cohort [HR ¼ 2.55; 95% confidence interval (CI): 1.56–4.16; P ¼ 0.0002] and both CNS9204 (HR ¼ 4.03; 95% CI: 1.88–8.63) and BBSFOP (HR ¼ 3.10; 95% CI: 1.22–7.86) groups. The only clinical variable associated with adverse outcome was incomplete tumor resection. Integrating tumor resectability with 1q25 status enabled stratification of cases into disease progression risk groups for all three trial cohorts. Conclusions: This is the first study to validate a prognostic genomic marker for childhood ependymoma across independent trial groups. 1q25 gain predicts disease progression and can contribute to patient risk stratification. We advocate the prospective evaluation of 1q25 gain as an adverse marker in future international clinical trials. Clin Cancer Res; 18(7); 2001–11. Ó2012 AACR. Introduction Improvements in the risk stratification and treatment of several cancers have been achieved in the postgenomic era through an appreciation of tumor-specific molecular abnor- malities. Although our understanding of ependymoma biology has advanced in recent years with respect to tumor initiation and heterogeneity (1, 2), the development of novel prognostic classifications and targeted therapies is still required to enhance patient outcome for this tumor group, particularly in children. Ependymomas represent the third most common pedi- atric tumor of the central nervous system (3). Although able to arise at any age, the majority occurs in children aged below 5 years (4). Significant differences are now apparent Authors' Affiliations: 1 Children's Brain Tumour Research Centre, Univer- sity of Nottingham; 2 Department of Neuropathology, Nottingham Univer- sity Hospital, Queens Medical Centre, Nottingham, United Kingdom; Departments of 3 Biostatistics and Epidemiology and 4 Pediatric and Ado- lescent Oncology; 5 CNRS UMR 8203 "Vectorology and Anticancer Treat- ment", Gustave Roussy Institute, Universite Paris-Sud, Villejuif; 6 Depart- ment of Neuropathology, Sainte-Anne Hospital, Paris, France; and Depart- ments of 7 Pathology and 8 Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Corresponding Author: Richard G. Grundy, Children's Brain Tumour Research Centre, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, United Kingdom. Phone: 44-0-115-823-0620; Fax: 44-0-115-823-0696; E-mail: Richard.Grundy@nottingham.ac.uk doi: 10.1158/1078-0432.CCR-11-2489 Ó2012 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 2001 on March 5, 2016. © 2012 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Published OnlineFirst February 14, 2012; DOI: 10.1158/1078-0432.CCR-11-2489