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

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 ReifenbergerRudi 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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)293-302
Number of pages10
JournalActa Neuropathologica
Volume136
Issue number2
DOIs
StatePublished - Aug 1 2018

Fingerprint

Neurocytoma
DNA Methylation
Brain Neoplasms
Neoplasms
Epigenomics
RNA Sequence Analysis
Brain
Oligonucleotide Array Sequence Analysis
Methylation

Keywords

  • Brain tumor
  • DNA methylation profile
  • Extraventricular neurocytoma
  • FGFR
  • FGFR1–TACC1
  • Fusion
  • Molecular classification

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Sievers, P., Stichel, D., Schrimpf, D., Sahm, F., Koelsche, C., Reuss, D. E., ... von Deimling, A. (2018). FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma. Acta Neuropathologica, 136(2), 293-302. https://doi.org/10.1007/s00401-018-1882-3

FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma. / Sievers, Philipp; Stichel, Damian; Schrimpf, Daniel; Sahm, Felix; Koelsche, Christian; Reuss, David E.; Wefers, Annika K.; Reinhardt, Annekathrin; Huang, Kristin; Ebrahimi, Azadeh; Hou, Yanghao; Pajtler, Kristian W.; Pfister, Stefan M.; Hasselblatt, Martin; Stummer, Walter; Schick, Uta; Hartmann, Christian; Hagel, Christian; Staszewski, Ori; Reifenberger, Guido; Beschorner, Rudi; Coras, Roland; Keyvani, Kathy; Kohlhof, Patricia; Diomedi-Camassei, Francesca; Herold-Mende, Christel; Giangaspero, Felice; Rushing, Elisabeth; Giannini, Caterina; Korshunov, Andrey; Jones, David T.W.; von Deimling, Andreas.

In: Acta Neuropathologica, Vol. 136, No. 2, 01.08.2018, p. 293-302.

Research output: Contribution to journalArticle

Sievers, P, Stichel, D, Schrimpf, D, Sahm, F, Koelsche, C, Reuss, DE, Wefers, AK, Reinhardt, A, Huang, K, Ebrahimi, A, Hou, Y, Pajtler, KW, Pfister, SM, Hasselblatt, M, Stummer, W, Schick, U, Hartmann, C, Hagel, C, Staszewski, O, Reifenberger, G, Beschorner, R, Coras, R, Keyvani, K, Kohlhof, P, Diomedi-Camassei, F, Herold-Mende, C, Giangaspero, F, Rushing, E, Giannini, C, Korshunov, A, Jones, DTW & von Deimling, A 2018, 'FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma', Acta Neuropathologica, vol. 136, no. 2, pp. 293-302. https://doi.org/10.1007/s00401-018-1882-3
Sievers, Philipp ; Stichel, Damian ; Schrimpf, Daniel ; Sahm, Felix ; Koelsche, Christian ; Reuss, David E. ; Wefers, Annika K. ; Reinhardt, Annekathrin ; Huang, Kristin ; Ebrahimi, Azadeh ; Hou, Yanghao ; Pajtler, Kristian W. ; Pfister, Stefan M. ; Hasselblatt, Martin ; Stummer, Walter ; Schick, Uta ; Hartmann, Christian ; Hagel, Christian ; Staszewski, Ori ; Reifenberger, Guido ; Beschorner, Rudi ; Coras, Roland ; Keyvani, Kathy ; Kohlhof, Patricia ; Diomedi-Camassei, Francesca ; Herold-Mende, Christel ; Giangaspero, Felice ; Rushing, Elisabeth ; Giannini, Caterina ; Korshunov, Andrey ; Jones, David T.W. ; von Deimling, Andreas. / FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma. In: Acta Neuropathologica. 2018 ; Vol. 136, No. 2. pp. 293-302.
@article{dc925715898e45b4ab101c7952006ba8,
title = "FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma",
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.",
keywords = "Brain tumor, DNA methylation profile, Extraventricular neurocytoma, FGFR, FGFR1–TACC1, Fusion, Molecular classification",
author = "Philipp Sievers and Damian Stichel and Daniel Schrimpf and Felix Sahm and Christian Koelsche and Reuss, {David E.} and Wefers, {Annika K.} and Annekathrin Reinhardt and Kristin Huang and Azadeh Ebrahimi and Yanghao Hou and Pajtler, {Kristian W.} and Pfister, {Stefan M.} and Martin Hasselblatt and Walter Stummer and Uta Schick and Christian Hartmann and Christian Hagel and Ori Staszewski and Guido Reifenberger and Rudi Beschorner and Roland Coras and Kathy Keyvani and Patricia Kohlhof and Francesca Diomedi-Camassei and Christel Herold-Mende and Felice Giangaspero and Elisabeth Rushing and Caterina Giannini and Andrey Korshunov and Jones, {David T.W.} and {von Deimling}, Andreas",
year = "2018",
month = "8",
day = "1",
doi = "10.1007/s00401-018-1882-3",
language = "English (US)",
volume = "136",
pages = "293--302",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "2",

}

TY - JOUR

T1 - FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma

AU - Sievers, Philipp

AU - Stichel, Damian

AU - Schrimpf, Daniel

AU - Sahm, Felix

AU - Koelsche, Christian

AU - Reuss, David E.

AU - Wefers, Annika K.

AU - Reinhardt, Annekathrin

AU - Huang, Kristin

AU - Ebrahimi, Azadeh

AU - Hou, Yanghao

AU - Pajtler, Kristian W.

AU - Pfister, Stefan M.

AU - Hasselblatt, Martin

AU - Stummer, Walter

AU - Schick, Uta

AU - Hartmann, Christian

AU - Hagel, Christian

AU - Staszewski, Ori

AU - Reifenberger, Guido

AU - Beschorner, Rudi

AU - Coras, Roland

AU - Keyvani, Kathy

AU - Kohlhof, Patricia

AU - Diomedi-Camassei, Francesca

AU - Herold-Mende, Christel

AU - Giangaspero, Felice

AU - Rushing, Elisabeth

AU - Giannini, Caterina

AU - Korshunov, Andrey

AU - Jones, David T.W.

AU - von Deimling, Andreas

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

AB - 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.

KW - Brain tumor

KW - DNA methylation profile

KW - Extraventricular neurocytoma

KW - FGFR

KW - FGFR1–TACC1

KW - Fusion

KW - Molecular classification

UR - http://www.scopus.com/inward/record.url?scp=85049600612&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049600612&partnerID=8YFLogxK

U2 - 10.1007/s00401-018-1882-3

DO - 10.1007/s00401-018-1882-3

M3 - Article

C2 - 29978331

AN - SCOPUS:85049600612

VL - 136

SP - 293

EP - 302

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

IS - 2

ER -