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The cIMPACT-NOW Update 7 has replaced the WHO nosology of “ependymoma,  RELA  fusion positive” by “Supratentorial-ependymoma,  C11orf95 -fusion positive”. This modification reinforces the idea that supratentorial-ependymomas exhibiting fusion that implicates the  C11orf95  (now called  ZFTA ) gene with or without the  RELA  gene, represent the same histomolecular entity. A hot off the press molecular study has identified distinct clusters of the DNA methylation class of  ZFTA  fusion-positive tumors. Interestingly, clusters 2 and 4 comprised tumors of different morphologies, with various  ZFTA  fusions without involvement of  RELA.  In this paper, we present a detailed series of thirteen cases of non- RELA ZFTA -fused supratentorial tumors with extensive clinical, radiological, histopathological, immunohistochemical, genetic and epigenetic (DNA methylation profiling) characterization. Contrary to the age of onset and MRI aspects similar to  RELA  fusion-positive EPN, we noted significant histopathological heterogeneity (pleomorphic xanthoastrocytoma-like, astroblastoma-like, ependymoma-like, and even sarcoma-like patterns) in this cohort. Immunophenotypically, these NFκB immunonegative tumors expressed GFAP variably, but EMA constantly and L1CAM frequently. Different gene partners were fused with  ZFTA :  NCOA1/2 ,  MAML2  and for the first time  MN1 . These tumors had epigenetic homologies within the DNA methylation class of ependymomas-RELA and were classified as satellite clusters 2 and 4. Cluster 2 (n = 9) corresponded to tumors with classic ependymal histological features (n = 4) but also had astroblastic features (n = 5). Various types of  ZFTA  fusions were associated with cluster 2, but as in the original report,  ZFTA:MAML2  fusion was frequent. Cluster 4 was enriched with sarcoma-like tumors. Moreover, we reported a novel anatomy of three  ZFTA:NCOA1/2  fusions with only 1 ZFTA zinc finger domain in the putative fusion protein, whereas all previously reported non- RELA ZFTA  fusions have 4 ZFTA zinc fingers. All three cases presented a sarcoma-like morphology. This genotype/phenotype association requires further studies for confirmation. Our series is the first to extensively characterize this new subset of supratentorial  ZFTA -fused ependymomas and highlights the usefulness of  ZFTA  FISH analysis to confirm the existence of a rearrangement without  RELA  abnormality.   Supplementary Information  The online version contains supplementary material available at 10.1186/s40478-021-01238-y.

acta neuropathologica communications

Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2 fusions