PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum

Abstract

Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.

A novel LARGE1-AFF2 fusion expanding the molecular alterations associated with the methylation class of neuroepithelial tumors with PATZ1 fusions

“…Here, we report an intracerebral tumor harboring a novel LARGE1-AFF2 fusion, with clinical, radiological, histopathological, and epigenetic similarities to NET- PATZ1. Like most NET- PATZ1 , our observation concerned a supratentorial tumor in a child (Table S1) [ 1 – 8 , 11 ]. Whereas neuroradiological data of this recently described tumor type is scarce, our case presented as a solid and cystic lesion with T2-weighted hypointensity suggesting fibrotic content, well-circumscribed from the brain parenchyma, as previously reported [ 4 , 8 , 11 ].…”

“…NET- PATZ1 encompassed a wide variety of morphologies in the literature, including glial, glioneuronal, embryonal tumors and sarcomas (Table S1). Based on the literature review and our case, the presence of a collagenous stroma and microcysts seem to be frequent in NET- PATZ1 (Table S1) [ 1 , 4 , 8 , 11 ] . Because of this pattern and because some of them present pseudorosettes (not seen in our case), pathologists tend to consider them a differential diagnosis for astroblastoma, MN1 -fused [ 1 , 2 , 8 ].…”

“…Based on the literature review and our case, the presence of a collagenous stroma and microcysts seem to be frequent in NET- PATZ1 (Table S1) [ 1 , 4 , 8 , 11 ] . Because of this pattern and because some of them present pseudorosettes (not seen in our case), pathologists tend to consider them a differential diagnosis for astroblastoma, MN1 -fused [ 1 , 2 , 8 ]. However, NET- PATZ1 , as with our case, exhibit frequent glioneuronal immunoprofiles and an extravascular expression of CD34 may be found, which is rare in astroblastomas (Table S1) [ 1 , 11 , 14 ].…”

“…Because of this pattern and because some of them present pseudorosettes (not seen in our case), pathologists tend to consider them a differential diagnosis for astroblastoma, MN1 -fused [ 1 , 2 , 8 ]. However, NET- PATZ1 , as with our case, exhibit frequent glioneuronal immunoprofiles and an extravascular expression of CD34 may be found, which is rare in astroblastomas (Table S1) [ 1 , 11 , 14 ]. The histopathological and epigenetic distinction between sarcomas with EWSR1-PATZ1 fusion and NET, PATZ1- fusion positive is still not clear.…”

“…Neuroepithelial tumors (NET) with PATZ1 fusions (NET- PATZ1 ) have been isolated by a distinct DNA methylation profile and are characterized by recurrent fusions of PATZ1 in association with EWSR1 or MN1 genes [ 1 ]. These tumors present a wide variety of morphologies and immunophenotypes, having been initially classified as glioneuronal tumors, astroblastomas, ependymomas, glioblastomas, pleomorphic xanthoastrocytomas, primary neuroepithelial tumors, and round cell sarcomas, with different histopathological grades [ 2 – 11 ].…”