Free Neuropathology 5:34 (2024)

Letter

A novel FUS::BEND2 fusion expanding the molecular spectrum of astroblastomas

Arnault Tauziède-Espariat^1,2, Benjamin Bonhomme³, Nathalène Truffaux³, Volodia Dangouloff-Ros⁴, Nathalie Boddaert⁴, Kévin Beccaria⁵, Lauren Hasty¹, Alice Métais^1,2, Pascale Varlet^1,2

1. Department of Neuropathology, GHU Paris - Psychiatry and Neuroscience, Sainte-Anne Hospital, Paris, France
2. Institut de Psychiatrie et Neurosciences de Paris (IPNP), UMR S1266, INSERM, IMA-BRAIN, Paris, France
3. Department of Biopathology, Institut Bergonié, Bordeaux, France
4. Pediatric Radiology Department, Hôpital Necker Enfants Malades, AP-HP, University de Paris, Paris, France
5. Department of Pediatric Neurosurgery, Necker Hospital, APHP, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Corresponding author:
Arnault Tauziède-Espariat · Department of Neuropathology · Sainte-Anne Hospital · 1, rue Cabanis, 75014 · Paris · France
a.tauziede-espariat@ghu-paris.fr

Additional resources and electronic supplementary material: supplementary material

Submitted: 23 October 2024
Accepted: 21 November 2024
Copyedited by: Shino Magaki
Published: 10 December 2024

https://doi.org/10.17879/freeneuropathology-2024-5983

Keywords: FUS, BEND2, Astroblastoma

Introduction

The name astroblastoma was modified to include “MN1-altered” in the latest World Health Organization (WHO) Classification of Tumors of the Central Nervous System (2021) [1], after the discovery of MN1 fusions (with BEND2 as the main partner gene) [2]. The presence of this alteration constitutes an essential diagnostic criterion for this tumor type, and for unresolved lesions, a DNA-methylation profile is necessary to confirm this diagnosis. The recent literature has concluded that BEND2 fusions (without the MN1 gene) may occur in this tumor type. Herein, we report one case of astroblastoma with a novel FUS::BEND2 fusion. We compare its clinical, histopathological, immunophenotypic, genetic, and epigenetic features with those previously described in astroblastomas, MN1 and/or BEND2 fusion-positive.

Case presentation

In 2007, a 4-year-old girl presented with a hyperdense and calcified mass extending from the third to the fourth ventricle with hydrocephalus and intraventricular hemorrhage (Figure 1 A–B). The tumor was partially resected, and a diagnosis of ependymoma was made according to the 2007 WHO Classification. The tumor recurred 14 months later, and the patient died 69 months after the initial diagnosis. In 2024, a review of the diagnosis was performed. Microscopically, the re-examination showed a tumor having an ependymoma-like pattern with astroblastic pseudorosettes (Figure 1C). There was no clear cell component, no hyalinized fibrous stroma nor PAS-positive eosinophilic granular bodies. There was no microvascular proliferation or necrosis. Mitotic figures were scarce, and the MIB1-labeling index was low (5 %). The expression of BRG1, INI1 and H3K27me3 was retained. The tumor cells expressed GFAP and EMA with a dot-like and a microlumen pattern (Figure 1 D–E). There was no immunoreactivity for OLIG2, CK18, LIN28A, NFκB, L1CAM or neurofilaments. FISH analysis of the MN1 gene failed to reveal a rearrangement, and RNA sequencing evidenced a FUS::BEND2 gene fusion (Figure 2A–B). Additionally, DNA-methylation analysis was conducted. The tumor was not classifiable using the Heidelberg Brain Tumor Classifier (v12.8) and the Bethesda Brain Tumor Classifier (v2), but clustered within astroblastoma, EWSR1::BEND2 methylation class using the uniform manifold approximation and projection (UMAP) method (Supplementary Figure 1). Because of the histopathological features and the presence of a BEND2 fusion, the integrated diagnosis was an astroblastoma, BEND2 fusion-positive.

Discussion and conclusions

The current literature review includes 92 cases of astroblastomas that either carried a MN1 fusion or had a methylation profile compatible with astroblastoma, MN1-altered [2–28] (see Supplementary Table 1 for literature review). The majority of cases are supratentorial (84 %, 72/86 tumors with available data) [2–28]. Most patients are pediatric (78 %, 67/86 cases with available data) [2–28]. However, this tumor occurs in a wide age range (0–60 years) [11,23]. Typical histopathological features include an ependymoma-like pattern, astroblastic pseudorosettes and stromal sclerosis. As ependymomas, tumor cells frequently express GFAP [3,4,6–11,14–19,22–25,27] and EMA [3,4,6,8–11,14,16–19,21,22,25,28] with a variable OLIG2 immunopositivity [3,4,7,9–11,11,13,15–17,19,21–25,28]. A MN1 gene fusion is found in 84 % of astroblastomas (54/64 reported cases with genetic analyses, the 28 remaining cases being only diagnosed using DNA-methylation profiling analysis), mainly in association with the BEND2 gene (94 %, 17/18 cases with RNA-sequencing data, the 36 remaining cases being only diagnosed using FISH MN1) [2–4,6–16,18–28]. One tumor harbored a MN1::CXXC5 fusion [2]. Alternative fusions including the BEND2 gene without MN1 have been reported in ten tumors (7 with EWSR1, 2 with MAMLD1, and one with YAP1) [3,4,8,19,22,23,27]. Moreover, an EWSR1::EZHIP fusion was identified in an astroblastoma; however, no methylation-based classification was available for this tumor [29]. In this study, we report for the first time a FUS::BEND2 fusion in astroblastoma. This novel gene rearrangement results in an in-frame fusion of exons 1 to 5 of the FUS gene and exons 2 to 14 of the BEND2 gene, the same breakpoint as previously reported [3,4]. In the literature, we identified two reports of a nasopharyngeal and soft tissue sarcoma harboring a FUS::BEND8 (another gene encoding a BEN domain containing protein) fusion [30,31]. The FUS gene belongs to the FET family of genes which encode for RNA-binding proteins, like EWSR1 [32]. The predicted FUS-BEND2 chimeric protein maintained two BEN domains in the C-terminus encoded by BEND2, which are involved in transcription and chromatin regulation [33].

As was found for our case, clinical findings seem to be different for patients who have an astroblastoma, BEND2 fusion-positive. They tend to present in a younger population (median age of 6 years-old at diagnosis), affect females less frequently (with a female-to-male ratio of 1.75), and be mainly infratentorial (73 % of cases) compared to the astroblastomas, MN1-altered (presenting at a median age of 10 years, a female-to-male ratio of 7.5 and only making up 8 % of infratentorial tumors) [2–4,6–16,18–28]. Most likely due to the tumor location, the prognosis of patients with astroblastomas, BEND2 fusion-positive is worse (33 %, 3/9, patients died with a median overall survival of 25 months [1;276]) than those with astroblastomas, MN1-altered (14 % of patients, 9/62, died with a median overall survival of 70 months [3;324]). The analysis of the recent literature seems to suggest that it may be BEND2, rather than MN1, which has a more critical functional role in the oncogenesis of astroblastomas [34].

In conclusion, we expanded the astroblastoma genetic spectrum with one novel fusion FUS::BEND2. Reminiscent of the terminological history of supratentorial ependymomas, originally referred to as “RELA-fusion positive” and afterward “ZFTA-fused”, our case supports the consideration of a BEND2 fusion as the defining alteration for astroblastoma, rather than the MN1 rearrangement.

Ethics approval

This study was approved by the GHU Paris Psychiatrie Neurosciences, Sainte-Anne Hospital’s local ethic committee.

Consent for publication

The patient signed informed consent forms before treatment was started.

Competing interests

The authors declare that they have no conflicts of interest directly related to the topic of this article.

Funding Statement

The authors declare that they have not received any funding.

Authors’ contributions

ATE, VDR, KB and NB compiled the MRI and clinical records; ATE, AM and PV conducted the neuropathological examinations; BB conducted the molecular studies; ATE, LH, and PV drafted the manuscript. All authors reviewed the manuscript.

Acknowledgements

We would like to thank the laboratory technicians at the GHU Paris Neuro Sainte-Anne for their assistance.

  Supplementary material

Supplementary Table 01 (download) - Literature review (PDF)

Supplementary Figure 01 (download) - Uniform manifold approximation and projection (UMAP) analysis (PDF)

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