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

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

Y1 - 2018/8

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 - Journal Article

U2 - 10.1007/s00401-018-1882-3

DO - 10.1007/s00401-018-1882-3

M3 - SCORING: Journal article

C2 - 29978331

VL - 136

SP - 293

EP - 302

JO - ACTA NEUROPATHOL

JF - ACTA NEUROPATHOL

SN - 0001-6322

IS - 2

ER -