Abstract
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.
Highlights
Improvements in the risk stratification and treatment of several cancers have been achieved in the postgenomic era through an appreciation of tumor-specific molecular abnormalities
Gain of 1q25 was an independent predictor of tumor progression across the pooled trial cohort [HR 1⁄4 2.55; 95% confidence interval (CI): 1.56–4.16; P 1⁄4 0.0002] and both CNS9204 (HR 1⁄4 4.03; 95% CI: 1.88–8.63) and BBSFOP (HR 1⁄4 3.10; 95% CI: 1.22–7.86) groups
500K single-nucleotide polymorphism (SNP) array analysis Clinical characteristics of the SNP array ependymoma cohort are summarized in Table 1, with results from survival analysis shown in Table 2 (Comprehensive clinicopathologic data and chromosome arm imbalance results for each tumor sample are provided in Supplementary Table S1)
Summary
Improvements in the risk stratification and treatment of several cancers have been achieved in the postgenomic era through an appreciation of tumor-specific molecular abnormalities. 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, in children. Because current clinicopathologic classification criteria for pediatric intracranial ependymoma are inconsistent, the introduction of novel prognostic markers for therapeutic stratification is an important requirement of future clinical trials. In this study of age- and treatmentdefined trial cohorts, 1q25 gain was identified as an independent and reproducible marker of intracranial ependymoma progression in all patients, in the younger children treated according to European primary postoperative chemotherapy protocols. Incorporating degree of surgical resection with tumor 1q25 status enabled patient stratification according to disease progression risk groups across all 3 trial cohorts, irrespective of patient age or adjuvant therapy administered. We advocate the prospective evaluation of 1q25 gain as an adverse risk marker in future international trials
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