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

Acta Neuropathol. 2021 Nov;142(5):841-857. doi: 10.1007/s00401-021-02354-8. Epub 2021 Aug 21.

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.

Keywords: Brain tumor; EWSR1; Gene fusion; MN1; Neuroepithelial; Neurooncology; PATZ1; Pediatric.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / genetics
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology*
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Kruppel-Like Transcription Factors / genetics*
  • Male
  • Neoplasms, Neuroepithelial / genetics*
  • Neoplasms, Neuroepithelial / pathology*
  • Oncogene Fusion
  • Oncogene Proteins, Fusion / genetics
  • Repressor Proteins / genetics*

Substances

  • Biomarkers, Tumor
  • Kruppel-Like Transcription Factors
  • Oncogene Proteins, Fusion
  • PATZ1 protein, human
  • Repressor Proteins