Posterior fossa ependymoma H3 K27-mutant: an integrated radiological and histomolecular tumor analysis

• Published in: Acta neuropathologica communications Vol. 10; no. 1; p. 137
• Main Authors: Mariet, Cassandra, Castel, David, Grill, Jacques, Saffroy, Raphaël, Dangouloff-Ros, Volodia, Boddaert, Nathalie, Llamas-Guttierrez, Francisco, Chappé, Céline, Puget, Stéphanie, Hasty, Lauren, Chrétien, Fabrice, Métais, Alice, Varlet, Pascale, Tauziède-Espariat, Arnault
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 14-09-2022; BioMed Central; BMC
• Subjects: Brain cancer; Brain Neoplasms - diagnostic imaging; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Child; Cloning; DNA; DNA binding proteins; DNA methylation; Ependymoma; Ependymoma - diagnostic imaging; Ependymoma - genetics; Ependymoma - pathology; Genomes; Glioma - genetics; Gliomas; Histones; Histones - genetics; Histopathology; Humans; Methylation; Molecular biology; Mutation; Neuropathology; Posterior fossa; Radiology; Radiotherapy; Retrospective Studies; Software; Tumors; Denmark; France; Histones; DNA-methylation; Posterior fossa; Ependymoma
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-022-01442-4

Posterior fossa group A ependymomas (EPN_PFA) are characterized by a loss of H3 K27 trimethylation due to either EZHIP overexpression or H3 p.K27M mutation, similar to H3 K27-altered diffuse midline gliomas (DMG), but in reverse proportions. Very little data is available in the literature concerning H3 K27M-mutant EPN_PFA. Here, we retrospectively studied a series of nine pediatric tumors initially diagnosed as H3 K27M-mutant EPN_PFA to compare them to EZHIP-overexpressing EPN_PFA in terms of radiology, follow-up, histopathology, and molecular biology (including DNA-methylation profiling). Seven tumors clustered within EPN_PFA by DNA-methylation analysis and t-distributed stochastic neighbor embedding. Among the two remaining cases, one was reclassified as a DMG and the last was unclassified. H3 K27M-mutant EPN_PFA cases were significantly older than their counterparts with an EZHIP overexpression. Radiological and histopathological central review of our seven H3 K27M-mutant EPN_PFA cases found them to be similar to their counterparts with an EZHIP overexpression. Sequencing analyses revealed HIST1H3B (n = 2), HIST1H3C (n = 2), H3F3A (n = 1), and HIST1H3D (n = 1) K27M mutations (no sequencing analysis available for the last case which was immunopositive for H3K27M). Consequently, HIST1H3C/D mutations are more frequently observed in EPN_PFA than in classic pontine DMG, H3K27-mutant. Overall survival and event-free survival of EZHIP-overexpressing and H3 K27M-mutant EPN_PFA were similar. After surgery and radiation therapy, 5/7 patients were alive at the end of the follow-up. In summary, the diagnosis of EPN_PFA must include tumor location, growth pattern, Olig2 expression, and DNA-methylation profiling before it can be differentiated from DMG, H3 K27-altered.