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. 2014 Aug;128(2):279-89.
doi: 10.1007/s00401-013-1228-0. Epub 2013 Dec 14.

Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity

Andrey Korshunov  1 , Dominik Sturm, Marina Ryzhova, Volker Hovestadt, Marco Gessi, David T W Jones, Marc Remke, Paul Northcott, Arie Perry, Daniel Picard, Marc Rosenblum, Manila Antonelli, Eleonora Aronica, Ulrich Schüller, Martin Hasselblatt, Adelheid Woehrer, Olga Zheludkova, Ella Kumirova, Stephanie Puget, Michael D Taylor, Felice Giangaspero, V Peter Collins, Andreas von Deimling, Peter Lichter, Annie Huang, Torsten Pietsch, Stefan M Pfister, Marcel Kool
Affiliations

Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity

Andrey Korshunov et al. Acta Neuropathol. 2014 Aug.

Abstract

Three histological variants are known within the family of embryonal rosette-forming neuroepithelial brain tumors. These include embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL). In this study, we performed a comprehensive clinical, pathological, and molecular analysis of 97 cases of these rare brain neoplasms, including genome-wide DNA methylation and copy number profiling of 41 tumors. We identified uniform molecular signatures in all tumors irrespective of histological patterns, indicating that ETANTR, EBL, and MEPL comprise a single biological entity. As such, future WHO classification schemes should consider lumping these variants into a single diagnostic category, such as embryonal tumor with multilayered rosettes (ETMR). We recommend combined LIN28A immunohistochemistry and FISH analysis of the 19q13.42 locus for molecular diagnosis of this tumor category. Recognition of this distinct pediatric brain tumor entity based on the fact that the three histological variants are molecularly and clinically uniform will help to distinguish ETMR from other embryonal CNS tumors and to better understand the biology of these highly aggressive and therapy-resistant pediatric CNS malignancies, possibly leading to alternate treatment strategies.

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Figures

Fig. 1
Fig. 1
Microscopical appearance (a, d, g), FISH analysis of the 19q13.42 locus (b, e, h), LIN28A immunohistochemistry (c, f, i) of ETANTR (a–c), EBL (d–f) and MEPL (g–i). Amplification of 19q13.42 (b, e, h) and LIN28A immunoexpression (c, f, i) was detected in all three histological ETMR subtypes. For the FISH analysis the C19MC 19q13.42 probe (green signals) and a reference 19p13 probe were used (red signals)
Fig. 2
Fig. 2
Two examples of primary ETANTR (a, c) with further tumor transformation in either EBL (b) or MEPL (d) histology as it has been identified during analysis of the recurrence samples
Fig. 3
Fig. 3
Overall survival curves generated for ETANTR (32 cases, blue), EBL (17 cases, red), and MEPL (6 cases, green). No differences in survival time were found (log-rank, p = 0.63)
Fig. 4
Fig. 4
Cluster analyses of DNA methylation profiles of ETMR alone and compared to various other pediatric brain tumors and normal cerebellum. a Unsupervised cluster analysis of ETMR samples only shows that DNA methylation profiles of the histological variants ETANTR, EBL and MEPL are not distinct. Also, clusters outlined do not differ in terms of clinical findings, including age, gender, tumor location and outcome. b DNA methylation profiles of ETMRs are distinct from other pediatric brain tumors and normal cerebellum
Fig. 5
Fig. 5
Copy number plots generated from 450 k methylation data. Amplifications and gains are indicated in green, losses in red. a Example of an ETANTR showing amplification 19q13.42, gain of 2 and loss of 19q13.3. b Example of an EBL showing amplification 19q13.42, gain of 2, and losses of 6q and 17p. c Example of a MEPL showing amplification 19q13.42, trisomy of 2, 17 and 19. d Summarizing profiles for all 41 cases analyzed
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