Chromosome 1q gain and tenascin-C expression are candidate markers to define different risk groups in pediatric posterior fossa ependymoma

Abstract Introduction Young age is an adverse prognostic factor in children with ependymomas. Treatment of these infants is challenging since beneficial therapeutic options are limited. As ependymomas are considered a biologically heterogeneous group, we aimed to characterize infant ependymomas with regard to their histological and genetic features. Materials and methods We analyzed 28 ependymomas occurring in children younger than 18 months at diagnosis enrolled into the HIT2000-E protocols with the aim to postpone irradiation until the age of 18 months if possible. All cases underwent neuropathological review, including immunohistochemical characterization. Genome-wide copy number alterations (CNA) were assessed by molecular inversion probe assays, and RELA and YAP1 fusions were detected by RT-PCR and sequencing. Results All infant ependymomas were anaplastic (WHO grade III). Twenty-one (75%) cases were located in the posterior fossa. Gross total resection was accomplished in 12 (57%) of these cases. All posterior fossa tumors showed loss of H3-K27me3 characteristic of PFA ependymomas. CNA analysis showed a stable genome in all cases with lack of chromosome 1q gain, an adverse prognostic marker in PFA ependymomas of older children. However, after a median follow-up of 5.4 years, 15 (71%) relapsed, and 9 (43%) died. Seven ependymomas (25%) occurred in the supratentorial region. Gross total resection could be achieved in only two of these cases. Four tumors carried C11orf95-RELA fusions, and two cases had typical YAP1-MAMLD1 fusions (one case was not analyzable). The RELA-fused cases did not display CDKN2A loss as an adverse indicator of prognosis in this disease entity. Although three infants (43%) with supratentorial ependymomas relapsed, all patients survived (median follow-up, 8.0 years). Conclusion Infant ependymomas seem to fall into three biological entities, with supratentorial tumors carrying RELA or YAP fusions and PFA posterior fossa ependymomas. The latter showed a poor outcome even though chromosome 1q gain was absent.

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Telomerase activation in posterior fossa group A ependymomas is associated with dismal prognosis and chromosome 1q gain

Neuro-Oncology ◽

10.1093/neuonc/nox027 ◽

2017 ◽

Vol 19 (9) ◽

pp. 1183-1194 ◽

Cited By ~ 17

Author(s):

Johannes Gojo ◽

Daniela Lötsch ◽

Sabine Spiegl-Kreinecker ◽

Kristian W Pajtler ◽

Katharina Neumayer ◽

...

Keyword(s):

Posterior Fossa ◽

Chromosome 1Q ◽

Dismal Prognosis ◽

Group A ◽

1Q Gain

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Characterization of 2 Novel Ependymoma Cell Lines With Chromosome 1q Gain Derived From Posterior Fossa Tumors of Childhood

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlx040 ◽

2017 ◽

Vol 76 (7) ◽

pp. 595-604 ◽

Cited By ~ 6

Author(s):

Vladimir Amani ◽

Andrew M. Donson ◽

Seth C. Lummus ◽

Eric W. Prince ◽

Andrea M. Griesinger ◽

...

Keyword(s):

Cell Lines ◽

Posterior Fossa ◽

Posterior Fossa Tumors ◽

Chromosome 1Q ◽

1Q Gain

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Conformal Radiation Therapy for Pediatric Ependymoma, Chemotherapy for Incompletely Resected Ependymoma, and Observation for Completely Resected, Supratentorial Ependymoma

Journal of Clinical Oncology ◽

10.1200/jco.18.01765 ◽

2019 ◽

Vol 37 (12) ◽

pp. 974-983 ◽

Cited By ~ 34

Author(s):

Thomas E. Merchant ◽

Anne E. Bendel ◽

Noah D. Sabin ◽

Peter C. Burger ◽

Dennis W. Shaw ◽

...

Keyword(s):

Radiation Therapy ◽

Posterior Fossa ◽

Histologic Grade ◽

Subtotal Resection ◽

Total Resection ◽

Conformal Radiation Therapy ◽

Chromosome 1Q ◽

Supratentorial Ependymoma ◽

Infratentorial Tumors ◽

1Q Gain

PURPOSE The Children’s Oncology Group trial ACNS0121 estimated event-free survival (EFS) and overall survival for children with intracranial ependymoma treated with surgery, radiation therapy, and—selectively—with chemotherapy. Treatment was administered according to tumor location, histologic grade, and extent of resection. The impacts of histologic grade, focal copy number gain on chromosome 1q, and DNA methylation profiles were studied for those undergoing surgery and immediate postoperative conformal radiation therapy (CRT). METHODS ACNS0121 included 356 newly diagnosed patients (ages 1 to 21 years). Patients with classic supratentorial ependymoma were observed after gross total resection (GTR). Those undergoing subtotal resection received chemotherapy, second surgery, and CRT. The remaining patients received immediate postoperative CRT after near-total resection or GTR. CRT was administered with a 1.0-cm clinical target volume margin. The cumulative total dose was 59.4 Gy, except for patients who underwent GTR and were younger than age 18 months (who received 54 Gy). Patients were enrolled between October 2003 and September 2007 and were observed for 5 years. Supratentorial tumors were evaluated for RELA fusion; infratentorial tumors, for chromosome 1q gain. Classification of posterior fossa groups A and B was made by methylation profiles. RESULTS The 5-year EFS rates were 61.4% (95% CI, 34.5% to 89.6%), 37.2% (95% CI, 24.8% to 49.6%), and 68.5% (95% CI, 62.8% to 74.2%) for observation, subtotal resection, and near-total resection/GTR groups given immediate postoperative CRT, respectively. The 5-year EFS rates differed significantly by tumor grade ( P = .0044) but not by age, location, RELA fusion status, or posterior fossa A/posterior fossa B grouping. EFS was higher for patients with infratentorial tumors without 1q gain than with 1q gain (82.8% [95% CI, 74.4% to 91.2%] v 47.4% [95% CI, 26.0% to 68.8%]; P = .0013). CONCLUSION The EFS for patients with ependymoma younger than 3 years of age who received immediate postoperative CRT and for older patients is similar. Irradiation should remain the mainstay of care for most subtypes.

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Improved risk-stratification for posterior fossa ependymoma of childhood considering clinical, histological and genetic features – a retrospective analysis of the HIT ependymoma trial cohort

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0820-5 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 2

Author(s):

Stephanie T. Jünger ◽

Martin Mynarek ◽

Inken Wohlers ◽

Evelyn Dörner ◽

Anja zur Mühlen ◽

...

Keyword(s):

Risk Stratification ◽

Mitotic Activity ◽

Posterior Fossa ◽

Cox Regression ◽

Residual Tumor ◽

Histological Features ◽

Chromosome 1Q ◽

Risk Stratification Model ◽

Vascular Proliferation ◽

1Q Gain

Abstract Introduction Risk stratification of children with ependymomas of the posterior fossa in current therapeutic protocols is mainly based on clinical criteria. We aimed to identify independent outcome predictors for this disease entity by a systematic integrated analysis of clinical, histological and genetic information in a defined cohort of patients treated according to the German HIT protocols. Methods Tumor samples of 134 patients aged 0.2–15.9 years treated between 1999 and 2010 according to HIT protocols were analyzed for histological features including mitotic activity, necrosis and vascular proliferation and genomic alterations by SNP and molecular inversion probe analysis. Survival analysis was performed by Kaplan-Meier method with log rank test and multivariate Cox regression analysis. Results Residual tumor after surgery, chromosome 1q gain and structural genomic alterations were identified as predictors of significantly shorter event-free (EFS) and overall survival (OS). Furthermore, specific histological features including vascular proliferation, necrosis and high mitotic activity were predictive for shorter OS. Multivariate Cox regression revealed residual tumor, chromosome 1q gain and mitotic activity as independent predictors of both EFS and OS. Using these independent predictors of outcome, we were able to build a 3-tiered risk stratification model that separates patients with standard, intermediate and high risk, and which outperforms current stratification procedures. Conclusion The integration of defined clinical, histological and genetic parameters led to an improved risk-stratification model for posterior fossa ependymoma of childhood. After validation in independent cohorts this model may provide the basis for risk-adapted treatment of children with ependymomas of the posterior fossa.

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EPEN-38. EZH2 INHIBITORY PROTEIN (EZHIP/Cxorf67) EXPRESSION IS HIGHLY CONCORDANT WITH H3K27me3 LOSS AND IS A PROMISING SURROGATE MARKER FOR POSTERIOR FOSSA TYPE A EPENDYMOMAS

Neuro-Oncology ◽

10.1093/neuonc/noaa222.173 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii315-iii315

Author(s):

Aruna Nambirajan ◽

Madhu Rajeshwari ◽

Meher Boorgula ◽

Ramesh Doddamani ◽

Manmohan Singh ◽

...

Keyword(s):

Posterior Fossa ◽

In Situ Hybridisation ◽

Surrogate Marker ◽

Fluorescence In Situ Hybridisation ◽

Who Grade ◽

Tenascin C ◽

Grade Ii ◽

1Q Gain

Abstract BACKGROUND Gene expression and DNA methylation have identified 2 distinct clinicopathological subgroups among the WHO Grade II/III posterior fossa (PF) ependymomas (EPN), of which the PF-A molecular subgroup associates with poor outcome. OBJECTIVE To analyse the utility of immunohistochemistry for H3K27me3, Tenascin C, EZHIP (Cxorf67), EZH2 and fluorescence-in-situ-hybridisation for chromosome 1q21 locus gain in the prognostic stratification of PF-EPNs. METHODS All PF Grade II/III tumors were retrieved (2009–2019). Immunohistochemistry for H3K27me3, H3K27M-mutation-specific antibody, EZH2, EZHIP, Tenascin-C and fluorescence in-situ hybridisation for 1q21 locus was performed and compared with outcome. RESULTS 71 PF-EPNs were included. H3K27me3 loss (PF-A) was seen in 65% (46/71) of cases, of which majority were positive for EZHIP (73%, 24/33) and Tenascin C (65%, 28/43). Minority showed chromosome 1q gain (19%, 8/42). An EZHIP negative PF-A tumor was immunopositive for H3K27M-mutant staining, while all others were negative. PF-A EPNs occurred at a median age of 4.5 years (range 1–53), were predominantly grade III (Grade III:II – 1.6:1), and 50% (10/20) of patients on follow-up experienced tumor progression. EPNs with retained H3K27me3 (PF-B) did not show EZHIP expression (0/20) or 1q gain; however, tenascin C expression was seen in 47% (8/25) of them. They occurred predominantly in adults, showed Grade II preponderance and only 2/11 patients on follow-up experienced progression. EZH2 expression did not correlate with H3K27me3 loss but positively correlated with EZHIP expression (p=0.015). CONCLUSION H3K27me3 is a reliable surrogate for prognostic classification of PF-EPNs. EZHIP expression is highly concordant with H3K27me3 loss and is a valuable adjunct.

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