title: 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 Francaise d'Oncologie Pediatrique (SFOP), and International Society for Pediatric Oncology (SIOP).
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  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.
authors.affiliation: Children's Brain Tumour Research Centre, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, United Kingdom.
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Kilday
authors.forename: Biswaroop
authors.initials: B
authors.lastname: Mitra
authors.forename: Caroline
authors.initials: C
authors.lastname: Domerg
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ward
authors.forename: Felipe
authors.initials: F
authors.lastname: Andreiuolo
authors.forename: Teresa
authors.initials: T
authors.lastname: Osteso-Ibanez
authors.forename: Audrey
authors.initials: A
authors.lastname: Mauguen
authors.forename: Pascale
authors.initials: P
authors.lastname: Varlet
authors.forename: Marie-Cecile
authors.initials: MC
authors.lastname: Le Deley
authors.forename: James
authors.initials: J
authors.lastname: Lowe
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.forename: Beth
authors.initials: B
authors.lastname: Coyle
authors.forename: Jacques
authors.initials: J
authors.lastname: Grill
authors.forename: Richard G
authors.initials: RG
authors.lastname: Grundy
mesh_terms: D000293:Adolescent; D001932:Brain Neoplasms / Q000235:genetics* / Q000601:surgery / Q000628:therapy; D059248:Chemoradiotherapy; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002986:Clinical Trials as Topic; D015331:Cohort Studies; D003131:Combined Modality Therapy; D018450:Disease Progression; D004806:Ependymoma / Q000235:genetics* / Q000601:surgery / Q000628:therapy; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D046228:Microarray Analysis / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016896:Treatment Outcome; D055815:Young Adult