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05.07.2018 | Original Paper | Ausgabe 2/2018

Acta Neuropathologica 2/2018

FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma

Zeitschrift:
Acta Neuropathologica > Ausgabe 2/2018
Autoren:
Philipp Sievers, Damian Stichel, Daniel Schrimpf, Felix Sahm, Christian Koelsche, David E. Reuss, Annika K. Wefers, Annekathrin Reinhardt, Kristin Huang, Azadeh Ebrahimi, Yanghao Hou, Kristian W. Pajtler, Stefan M. Pfister, Martin Hasselblatt, Walter Stummer, Uta Schick, Christian Hartmann, Christian Hagel, Ori Staszewski, Guido Reifenberger, Rudi Beschorner, Roland Coras, Kathy Keyvani, Patricia Kohlhof, Francesca Diomedi-Camassei, Christel Herold-Mende, Felice Giangaspero, Elisabeth Rushing, Caterina Giannini, Andrey Korshunov, David T. W. Jones, Andreas von Deimling
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s00401-018-1882-3) contains supplementary material, which is available to authorized users.
David T. W. Jones and Andreas von Deimling share senior authorship.

Abstract

Extraventricular neurocytoma (EVN) is a rare primary brain tumor occurring in brain parenchyma outside the ventricular system. Histopathological characteristics resemble those of central neurocytoma but exhibit a wider morphologic spectrum. Accurate diagnosis of these histologically heterogeneous tumors is often challenging because of the overlapping morphological features and the lack of defining molecular markers. Here, we explored the molecular landscape of 40 tumors diagnosed histologically as EVN by investigating copy number profiles and DNA methylation array data. DNA methylation profiles were compared with those of relevant differential diagnoses of EVN and with a broader spectrum of diverse brain tumor entities. Based on this, our tumor cohort segregated into different groups. While a large fraction (n = 22) formed a separate epigenetic group clearly distinct from established DNA methylation profiles of other entities, a subset (n = 14) of histologically diagnosed EVN grouped with clusters of other defined entities. Three cases formed a small group close to but separated from the epigenetically distinct EVN cases, and one sample clustered with non-neoplastic brain tissue. Four additional samples originally diagnosed otherwise were found to molecularly resemble EVN. Thus, our results highlight a distinct DNA methylation pattern for the majority of tumors diagnosed as EVN, but also indicate that approximately one third of morphological diagnoses of EVN epigenetically correspond to other brain tumor entities. Copy number analysis and confirmation through RNA sequencing revealed FGFR1–TACC1 fusion as a distinctive, recurrent feature within the EVN methylation group (60%), in addition to a small number of other FGFR rearrangements (13%). In conclusion, our data demonstrate a specific epigenetic signature of EVN suitable for characterization of these tumors as a molecularly distinct entity, and reveal a high frequency of potentially druggable FGFR pathway activation in this tumor group.

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Zusatzmaterial
Supplementary material 1 (EPS 15793 kb) Supplementary Fig. 1 Molecular Classification of EVN by DNA methylation profiling. Unsupervised hierarchical clustering analysis of 40 histologically diagnosed EVN samples shows that the cohort segregates into different groups based on DNA methylation data. While a larger fraction forms a distinct group clearly separated from the reference entities (including 4 additional samples previously diagnosed otherwise), a subset of the original EVN tumors clusters with reference tumors or cannot be clearly classified. All EVN samples are colored in black, reference samples are colored according to their molecular reference entity. In addition, fusion transcripts of samples within the methylation class EVN are indicated
401_2018_1882_MOESM1_ESM.eps
Supplementary material 2 (DOCX 20 kb)
401_2018_1882_MOESM2_ESM.docx
Supplementary material 3 (DOCX 19 kb)
401_2018_1882_MOESM3_ESM.docx
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