PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum
(2021) In Acta Neuropathologica 142(5). p.841-857- 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... (More)
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.
(Less)
- author
- publishing date
- 2021
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Brain tumor, EWSR1, Gene fusion, MN1, Neuroepithelial, Neurooncology, PATZ1, Pediatric
- in
- Acta Neuropathologica
- volume
- 142
- issue
- 5
- pages
- 841 - 857
- publisher
- Springer
- external identifiers
-
- pmid:34417833
- scopus:85113151225
- ISSN
- 0001-6322
- DOI
- 10.1007/s00401-021-02354-8
- language
- English
- LU publication?
- no
- additional info
- Funding Information: For technical support and expertise, we thank the German Cancer Research Centre (DKFZ) Genomics and Proteomics Core Facility, and Hai-Yen Nguyen, Laura Doerner & Moritz Leon Schalles (Department of Neuropathology, Institute of Pathology at the University Hospital Heidelberg). We gratefully acknowledge Teresa de Rojas for support in collecting clinical metadata. This work was supported by the German Childhood Cancer Foundation (“Neuropath 2.0—Increasing diagnostic accuracy in pediatric neurooncology”; DKS 2015.01), the Everest Centre for Low-Grade Paediatric Brain Tumour Research (The Brain Tumour Charity, UK; GN-000382), the German Federal Ministry of Education and Research (BMBF), and Cancéropôle Lyon Auvergne Rhône-Alpes (CLARA). DNA methylation profiling at NYU was in part supported by grants from the Friedberg Charitable Foundation, the Sohn Conference Foundation and the Making Headway Foundation (to M. Snuderl.) Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
- id
- a50b9f78-0ada-4d16-a0ed-243c961da6cd
- date added to LUP
- 2021-09-06 08:35:16
- date last changed
- 2024-04-20 10:39:38
@article{a50b9f78-0ada-4d16-a0ed-243c961da6cd,
abstract = {{<p>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.</p>}},
author = {{Alhalabi, Karam T. and Stichel, Damian and Sievers, Philipp and Peterziel, Heike and Sommerkamp, Alexander C. and Sturm, Dominik and Wittmann, Andrea and Sill, Martin and Jäger, Natalie and Beck, Pengbo and Øra, Ingrid}},
issn = {{0001-6322}},
keywords = {{Brain tumor; EWSR1; Gene fusion; MN1; Neuroepithelial; Neurooncology; PATZ1; Pediatric}},
language = {{eng}},
number = {{5}},
pages = {{841--857}},
publisher = {{Springer}},
series = {{Acta Neuropathologica}},
title = {{PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum}},
url = {{http://dx.doi.org/10.1007/s00401-021-02354-8}},
doi = {{10.1007/s00401-021-02354-8}},
volume = {{142}},
year = {{2021}},
}