EWSR1‐PATZ1 gene fusion may define a new glioneuronal tumor entity

Abstract

We investigated the challenging diagnostic case of a ventricular cystic glioneuronal tumor with papillary features, by RNA sequencing using the Illumina TruSight RNA Fusion panel. We did not retrieve the SLC44A1-PRKCA fusion gene specific for papillary glioneuronal tumor, but an EWSR1-PATZ1 fusion transcript. RT-PCR followed by Sanger sequencing confirmed the EWSR1-PATZ1 fusion. It matched with canonic EWSR1 fusion oncogene, juxtaposing the entire N-terminal transcriptional activation domain of EWSR1 gene and the C-terminal DNA binding domain of a transcription factor gene, PATZ1. PATZ1 protein belongs to the BTB-ZF (broad-complex, tramtrack and bric-à-brac -zinc finger) family. It directly regulates Pou5f1 and Nanog and is essential to maintaining stemness by inhibiting neural differentiation. EWSR1-PATZ1 fusion is a rare event in tumors: it was only reported in six round cell sarcomas and in three gliomas of three exclusively molecular studies. The first reported glioma was a BRAF negative ganglioglioma, the second a BRAF negative glioneuronal tumor, not otherwise specified and the third, very recently reported, a high grade glioma, not otherwise specified. In our study, forty BRAF negative gangliogliomas were screened by FISH using EWSR1 break-apart probes. We performed methylation profiling for the index case and for seven out of the ten FISH positive cases. The index case clustered apart from other pediatric low grade glioneuronal entities, and specifically from the well-defined ganglioglioma methylation group. An additional pediatric intraventricular ganglioglioma clustered slightly more closely with ganglioglioma, but showed differences from the main ganglioglioma group and similarities with the index case. Both cases harbored copy number variations at the PATZ1 locus. EWSR1-PATZ1 gene fusion might define a new type of glioneuronal tumors, distinct from gangliogliomas.

Diffuse leptomeningeal glioneuronal tumor: a double misnomer? A report of two cases

“…The diagnosis was "benign glioneuronal tumor compatible with ganglioglioma grade I". In 2018, this case was included in the series of cases of gangliogliomas lacking BRAF V600E mutation in order to search for EWSR1-PATZ1 mutation and to perform methylation profiling [12]. Methylation profile did not yield a high-confidence score based on the https://www.molecularneuropathology.…”

Round Cell Sarcoma with EWSR1‐PATZ1 Gene Fusion in the Neck: Case Report and Review of the Literature

“…For EWSR1-PATZ1, most cases have occurred in soft tissue sarcomas, but have also been reported in a number of central nervous tumors. 6 To our knowledge, only 15 cases of non-brain EWSR1-PATZ1 fusion sarcomas have been reported (Table II). 2,[7][8][9] No previous report has detailed the presentation, imaging, and treatment course of an EWSR1-PATZ1 sarcoma of the head and neck.…”

“…PATZ1 is located in close proximity to EWSR1 on chromosome 22 and regulates the transcription of multiple genes. 5,6 The EWSR1-PATZ1 fusion is hypothesized to suppress the N-terminal receptor of the PATZ1 gene responsible for repression of transcription, and subsequently lead to overexpression. 7 Only two prior cases of this variant have been reported in the head and neck since 2000, but in brief as part of a case series.…”

Structural analysis of the PATZ1 BTB domain homodimer

“…Chromosome 22specific inversions that translocate the transcription factor EWSR1 with PATZ1 have been observed in various sarcomas. While EWSR1 translocates with ETS family proteins in Ewing's sarcoma, it potentially encodes two fusion proteins EWSR1-PATZ1 and PATZ1-EWSR1, the latter of which will contain the BTB domain (Siegfried et al, 2019;Bridge et al, 2019;Chougule et al, 2019;Sankar & Lessnick, 2011;Mastrangelo et al, 2000;Im et al, 2000). The dimerization and co-repressor interaction properties of PATZ1 identified in this study may shed light on the mechanism of these sarcomas.…”