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.

FGFR- gene family alterations in low-grade neuroepithelial tumors

“…In the absence of elevated proliferative rate/mitotic activity, and particularly after complete resection, the rate of recurrence is low [25,41]. While definitive grading criteria have yet to be established and survival data studied in additional independent cohorts, EVN corresponds histologically to WHO grade II, which is in keeping with reported survival data in molecularly-defined EVN, including those bearing FGFR1-TACC1 fusions [67].…”

“…DNA methylation-based analysis of a cohort of EVN found that while a subset of histologically diagnosed EVN could be regrouped with other defined, established entities, a large fraction formed a clearly distinct, separate epigenetic group. Importantly, copy number analysis and RNA sequencing demonstrated FGFR1-TACC1 fusion as a recurrent feature within the EVN methylation group (60%), in addition to a small number of other FGFR rearrangements (FGFR3-TACC3, FGFR1-EVI5) [67].…”

Invited Review: DNA methylation‐based classification of paediatric brain tumours

“…A graphical summary of the evolution of the field within the context of brain tumours is displayed in Figure . DNA methylation is further gaining importance for tumour entity definition and is increasingly being used for the allocation of rare cancers into either known tumour classes or the identification of new entities , a collection of which are summarized in Figure .…”

“…Among paediatric low‐grade gliomas and glioneuronal tumours, at least nine main DNA methylation classes have so far been established and seem sufficiently distinct for tumour classification . The molecular classes are clearly related to the established histological tumour classes although there is typically some degree of reallocation when molecular classes are overlaid on histological series . Figure lists the main molecular classes.…”

Identification of a novel RUNX1‐TACC1 fusion transcript in acute myeloid leukaemia

“…In tumours, TACC1 expression significantly associates with lymph node metastasis and poor prognosis (Ding et al , ; Lv et al , ). A FGFR1‐TACC1 fusion capable of constitutive tyrosine kinase activation was found in extraventricular neurocytoma and glioblastoma (Lasorella, Sanson, & Iavarone, ; Sievers et al , ). However, the role of TACC1 has not been described in leukaemia so far.…”