EZHIP is a specific diagnostic biomarker for posterior fossa ependymomas, group PFA and diffuse midline gliomas H3-WT with EZHIP overexpression

Antin, C; Tauziède‐Espariat, Arnault; Debily, Marie‐Anne; Castel, David; Grill, Jacques; Pagès, Mélanie; Ayrault, Olivier; Chrétien, Fabrice; Gareton, Albane; Andreiuolo, Felipe; Lechapt‐Zalcman, Emmanuèle; Varlet, Pascale

doi:10.1186/s40478-020-01056-8

Cited by 41 publications

(25 citation statements)

References 8 publications

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“…Although genetic and epigenetic subtypes were highly associated with the prognosis in intracranial EPNs, the previous studies reported that they do not necessarily determine the grades because there are some exceptional cases, such as grade 2 PFA with good prognosis, and grade 3 PFB and ST-EPN-YAP1 with poor outcomes. [13,41] Reproducible cut-offs for Ki-67 labeling indices have been proposed in astrocytic and oligodendroglial tumors to predict the outcomes [42][43][44][45]. Similarly, our meta-analysis with 11 published papers showed that increased Ki-67 labeling indices were strongly correlated with poor OS and PFS of EPNs (both P < 0.0001).…”

Section: Discussionsupporting

confidence: 60%

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Molecular subtyping of ependymoma and prognostic impact of Ki-67

et al. 2021

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Although ependymomas (EPNs) have similar histopathology, they are heterogeneous tumors with diverse immunophenotypes, genetics, epigenetics, and different clinical behavior according to anatomical locations. We reclassified 141 primary EPNs from a single institute with immunohistochemistry (IHC) and next-generation sequencing (NGS). Supratentorial (ST), posterior fossa (PF), and spinal (SP) EPNs comprised 12%, 41%, and 47% of our cohort, respectively. Fusion genes were found only in ST-EPNs except for one SP-EPN with ZFTA-YAP1 fusion, NF2 gene alterations were found in SP-EPNs, but no driver gene was present in PF-EPNs. Surrogate IHC markers revealed high concordance rates between L1CAM and ZFTA-fusion and H3K27me3 loss or EZHIP overexpression was used for PFA-EPNs. The 7% cut-off of Ki-67 was sufficient to classify EPNs into two-tiered grades at all anatomical locations. Multivariate analysis also delineated that a Ki-67 index was the only independent prognostic factor in both overall and progression-free survivals. The gain of chromosome 1q and CDKN2A/2B deletion were associated with poor outcomes, such as multiple recurrences or extracranial metastases. In this study, we propose a cost-effective schematic diagnostic flow of EPNs by the anatomical location, three biomarkers (L1CAM, H3K27me3, and EZHIP), and a cut-off of a 7% Ki-67 labeling index.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Molecular subtyping of ependymoma and prognostic impact of Ki-67

et al. 2021

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“…2) [13,63]. Due to this high specificity, EZHIP expression is discussed as a simple but reliable prognostic IHC biomarker for PFA ependymomas and EZHIP expressing DMGs [2,49]. Outside the CNS, EZHIP expression is found in endometrial stromal III, the 10-year overall survival (OS), the abundance of the subtype within PFA ependymomas and the most occurring chromosomal aberrations sarcoma (ESS) [16] and squamous non-small cell lung cancer (NSCLC) [17].…”

Section: Ezhip In Pfa Ependymomasmentioning

confidence: 99%

EZHIP: a new piece of the puzzle towards understanding pediatric posterior fossa ependymoma

et al. 2021

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Ependymomas (EPN) are tumors of the central nervous system (CNS) that can arise in the supratentorial brain (ST-EPN), hindbrain or posterior fossa (PF-EPN) or anywhere in the spinal cord (SP-EPN), both in children and adults. Molecular profiling studies have identified distinct groups and subtypes in each of these anatomical compartments. In this review, we give an overview on recent findings and new insights what is driving PFA ependymomas, which is the most common group. PFA ependymomas are characterized by a young median age at diagnosis, an overall balanced genome and a bad clinical outcome (56% 10-year overall survival). Sequencing studies revealed no fusion genes or other highly recurrently mutated genes, suggesting that the disease is epigenetically driven. Indeed, recent findings have shown that the characteristic global loss of the repressive histone 3 lysine 27 trimethylation (H3K27me3) mark in PFA ependymoma is caused by aberrant expression of the enhancer of zeste homolog inhibitory protein (EZHIP) or in rare cases by H3K27M mutations, which both inhibit EZH2 thereby preventing the polycomb repressive complex 2 (PRC2) from spreading H3K27me3. We present the current status of the ongoing work on EZHIP and its essential role in the epigenetic disturbance of PFA biology. Comparisons to the oncohistone H3K27M and its role in diffuse midline glioma (DMG) are drawn, highlighting similarities but also differences between the tumor entities and underlying mechanisms. A strong focus is to point out missing information and to present directions of further research that may result in new and improved therapies for PFA ependymoma patients.

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“…Antin et al (2020) suggested complementing the routine IHC panels for CNS tumor diagnostics with anti-EZHIP staining. The intensive diffuse nuclear staining with >90% tumor cells immunopositive was obtained for PF-EPN-A (with the exception of rare H3 K27M-mutant tumors), diffuse midline gliomas with wild-type (non-mutant) H3F3A, and germinomas [78]. Nambirajan et al (2021) evaluated an extended panel of IHC markers (H3K27me3, acetyl-H3K27, H3K27M, ATRX, EZHIP, EPOP, and Tenascin-C) for the use in differential diagnostics of PF-EPNs.…”

Section: Differential Diagnosis Of Pf-epnsmentioning

confidence: 99%

Molecular Stratification of Childhood Ependymomas as a Basis for Personalized Diagnostics and Treatment

Zaytseva

Papusha

Novichkova

et al. 2021

Cancers

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Ependymomas are among the most enigmatic tumors of the central nervous system, posing enormous challenges for pathologists and clinicians. Despite the efforts made, the treatment options are still limited to surgical resection and radiation therapy, while none of conventional chemotherapies is beneficial. While being histologically similar, ependymomas show considerable clinical and molecular diversity. Their histopathological evaluation alone is not sufficient for reliable diagnostics, prognosis, and choice of treatment strategy. The importance of integrated diagnosis for ependymomas is underscored in the recommendations of Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy. These updated recommendations were adopted and implemented by WHO experts. This minireview highlights recent advances in comprehensive molecular-genetic characterization of ependymomas. Strong emphasis is made on the use of molecular approaches for verification and specification of histological diagnoses, as well as identification of prognostic markers for ependymomas in children.

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EZHIP is a specific diagnostic biomarker for posterior fossa ependymomas, group PFA and diffuse midline gliomas H3-WT with EZHIP overexpression

Cited by 41 publications

References 8 publications

Molecular subtyping of ependymoma and prognostic impact of Ki-67

Molecular subtyping of ependymoma and prognostic impact of Ki-67

EZHIP: a new piece of the puzzle towards understanding pediatric posterior fossa ependymoma

Molecular Stratification of Childhood Ependymomas as a Basis for Personalized Diagnostics and Treatment

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