In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 14_Supplement ( 2020-07-15), p. B71-B71
Abstract:
Introduction: One of the DNA methylation-based molecular subgroups of supratentorial ependymoma (ST-EPN), designated ST-EPN-RELA, mostly harbors fusions of the uncharacterized gene C11orf95 and RELA (ST-EPN-RELA). Rarely, no C11orf95-RELA fusion is detected in tumors predicted to belong to the ST-EPN-RELA group. With this study we aimed to refine the molecular classification of ST-EPN and to identify alternative oncogenic mechanisms in the absence of a classic fusion type. Methods and Materials: In an unbiased approach, t-Distributed Stochastic Neighbor Embedding was applied to 53,468 DNA methylation profiles from brain tumors, other cancer types, and control tissues. Only samples clustering with a reference set of ST-EPN-RELA were selected for further analyses (n=614), including RNA- and/or DNA-panel sequencing, histopathologic reevaluation, and immunohistochemistry for L1CAM. Fusions were validated using RT-PCR on total RNA and Sanger sequencing. Clinical data were analyzed retrospectively for 150 patients. Results: We identified one large and four satellite clusters. The large cluster (n=479; designated ST-EPN-RELA 1) and one of the satellite clusters (n=12; ST-EPN-RELA 2) predominantly contained samples with a calibrated score ≥ 0.9 for ST-EPN-RELA based on the current version of the Heidelberg Brain Tumor Classifier. Samples of the three other satellite clusters (n=41, n=17, and n=25 samples) contained 65.9%, 88.2%, and 96.0% of samples with a calibrated score & lt; 0.9 for any methylation class, and were thus predicted as unclassifiable. These clusters were provisionally designated ST-EPN-RELA-like A, B, and C, and initial histologic diagnoses showed a wide spectrum of rare morphologies beside EPN, e.g., sarcoma and teratoma. Within clusters ST-EPN-RELA-like A and C, sequencing revealed fusions of C11orf95 with different partner genes, including MAML2 (n=14), MAML3 (n=2), and NCOA2 (n=7), while ST-EPN-RELA-like B included classic C11orf95-RELA fusions (n=11) in samples with initial diagnoses other than EPN. Copy number variation analysis showed clear differences between the clusters. L1CAM-positivity was observed in all groups. Within the cluster ST-EPN-RELA 1, samples separated according to fusion types, 1 versus 2/3. Analysis of clinical data showed significant differences in overall survival between cases with confirmed C11orf95-RELA fusion type 1 (n=25, median OS=88 months) and type 2/3 (n=20, median OS=67 months). Clinical data collection for the satellite clusters is currently ongoing. Conclusion: Molecular refinement of ST-EPN-RELA revealed novel subgroups harboring fusions of C11orf95 with numerous fusion partners different from RELA, which will be included in the next update of the Heidelberg Classifier. Preliminary analysis suggests differences in clinical outcome related to the fusion type. Findings of this study will improve diagnostic accuracy and clinical management and need to be considered when developing targeted treatment strategies against ST-EPN. Citation Format: D.R. Ghasemi, K. Okonechnikov, A. Korshunov, M. Sill, T. Zheng, J.M. Huebner, K.K. Maass, J. Benzel, M. Snuderl, J. Gojo, U. Schüller, N.U. Gerber, I. Stoler, P. Hernáiz-Driever, T. Milde, D. Sturm, R. Chapman, R.G. Grundy, A. von Deimling, D. Kawauchi, D.T.W. Jones, M. Kool, S.M. Pfister, F. Sahm, K.W. Pajtler. Molecular heterogeneity and novel oncogenic fusions in RELA- and YAP1-negative supratentorial ependymoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B71.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.PEDCA19-B71
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2020
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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