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), Societe Française d'Oncologie Pediatrique (SFOP), and International Society for Pediatric Oncology (SIOP)

• Published in: Clinical cancer research 2012-04, Vol.18 (7), p.2001-2011
• Main Authors: KILDAY, John-Paul, MITRA, Biswaroop, ELLISON, David W, GILBERTSON, Richard J, COYLE, Beth, GRILL, Jacques, GRUNDY, Richard G, DOMERG, Caroline, WARD, Jennifer, ANDREIUOLO, Felipe, OSTESO-IBANEZ, Teresa, MAUGUEN, Audrey, VARLET, Pascale, DELEY, Marie-Cecile Le, LOWE, James
• Format: Article
• Language: English
• Subjects: Adjuvants; Adolescent; Antineoplastic agents; Biological and medical sciences; Brain Neoplasms - genetics; Brain Neoplasms - surgery; Brain Neoplasms - therapy; Cancer; Chemoradiotherapy; Chemotherapy; Child; Child, Preschool; Children; Chromosome Aberrations; Chromosomes, Human, Pair 1 - genetics; Clinical trials; Clinical Trials as Topic; Cohort Studies; Combined Modality Therapy; copy number; Data processing; Disease Progression; Ependymoma - genetics; Ependymoma - surgery; Ependymoma - therapy; Female; Fluorescence in situ hybridization; genomics; Hematologic and hematopoietic diseases; Humans; In Situ Hybridization, Fluorescence; Infant; Interphase; Kaplan-Meier Estimate; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Microarray Analysis - methods; Neurology; Oncology; Pediatrics; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide; Prognosis; Radiotherapy; Risk groups; Single-nucleotide polymorphism; Survival; Treatment Outcome; Tumors; Tumors of the nervous system. Phacomatoses; Young Adult
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-2489

The high incidence of recurrence and unpredictable clinical outcome for pediatric ependymoma 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. 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 = 60) and BBSFOP (n = 65) adjuvant chemotherapy trials, or with primary postoperative radiotherapy (SIOP CNS9904/RT, n = 64). Results were correlated with clinical, histologic, and survival data. Gain of 1q was the most frequent imbalance in primary (7/42, 17%) and recurrent ependymomas (2/6, 33%). Gain of 1q25 was an independent predictor of tumor progression across the pooled trial cohort [HR = 2.55; 95% confidence interval (CI): 1.56-4.16; P = 0.0002] and both CNS9204 (HR = 4.03; 95% CI: 1.88-8.63) and BBSFOP (HR = 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. 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.