Ependymoma with C11orf95-MAML2 fusion: presenting with granular cell and ganglion cell features

Tamai, Sho; Nakano, Yoshiko; Kinoshita, Masashi; Sabit, Hemragul; Nobusawa, Sumihito; Arai, Yasuhito; Hama, Natsuko; Totoki, Yasushi; Shibata, Tatsuhiro; Ichimura, Koichi; Nakada, Mitsutoshi

doi:10.1007/s10014-020-00388-6

Cited by 15 publications

(25 citation statements)

References 20 publications

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“…The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (c-IMPACT NOW) Update 7 recently proposed the nosology “ST-EPN, C11orf95- fusion positive” instead of “ST-EPN, RELA- fusion positive” [ 5 ]. This modification reinforces the idea that when ST-EPN exhibits fusion that implicates the C11orf95 gene with or without the RELA gene, it represents the same histomolecular entity [ 4 , 6 – 8 ]. In recent papers, the methylation classifier based on Forest plot random classification highighted that cases with C11orf95- fusion without RELA presented epigenetic vicinity with tumors of the EPN-RELA methylation class (MC) and subdivided them into two satellite clusters (2 and 4) by multidimensional reductionality (more specifically t-Distributed Stochastic Neighbor Embedding (t-SNE) analysis) [ 8 , 9 ].…”

Section: Introductionsupporting

confidence: 78%

“…Statistical analyses were performed using JMP software (version 14.3.0, SAS Institute Inc, Cary, USA). We pooled our data with that of previously reported cases of ST non- RELA ZFTA -fused EPN [ 6 – 8 ] and compared them to the data in the literature concerning known EPN with ZFTA:RELA fusion, and the other histopathological differential diagnoses such as EPN, YAP1 -fusion positive, HGNET- BCOR, and HGNET- MN1 [ 2 , 3 , 10 – 22 ].…”

Section: Methodsmentioning

confidence: 99%

“…However, these alternative partners to RELA seem to produce original morphological patterns which challenge the histopathological diagnosis. In fact, recent studies have reported a large spectrum of morphologies, including glial, glioneuronal, embryonal and even mesenchymal and epithelial patterns in tumors harboring C11orf95- fusions without RELA [ 6 , 7 , 9 ]. In this study, we performed a clinico-pathological and molecular analysis (including DNA-methylation profiling and the identification of the new clusters of methylation) of 13 new cases of ST-EPN with C11orf95 (now called ZFTA for Zing Finger Translocation Associated by the new HUGO gene Nomenclature Committee) fusion without the RELA gene to more suitably characterize these tumors and compare them with their counterparts which have classical ZFTA:RELA fusion.…”

Section: Introductionmentioning

confidence: 99%

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

Tauziède‐Espariat

Siegfried

Nicaise

et al. 2021

acta neuropathol commun

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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.

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Section: Introductionsupporting

confidence: 78%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Tauziède‐Espariat

Siegfried

Nicaise

et al. 2021

acta neuropathol commun

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“…The function of L1CAM may be required in the most proliferative components with ambiguous differentiation in ELTMDs, and its expression may be lost along with mesenchymal, glioneuronal, and ependymal (in the recurrent tumor of case 2) differentiation with lower proliferative activity. L1CAM expression, though in few cases, was also reported in ST ependymomas with C11orf95 ‐ YAP1 and C11orf95 ‐ MAML2 (4,12). In ST ependymomas with YAP1 ‐ MAMLD1 , another molecular subgroup of ST ependymoma, no positivity for L1CAM was observed in any of the 11 cases tested (39).…”

Section: Discussionmentioning

confidence: 97%

“…In ST ependymomas, C11orf95 is also the fusion partner of other rare fusions with genes encoding transcription factors, such as NCOA1 , YAP1 , and MAML2 , each with only one or two cases reported (4,5,12). The case of ependymoma with C11orf95 ‐ NCOA1 presented clear cell morphology and was diagnosed as anaplastic ependymoma (5); however, histology was not detailed for the other cases (4).…”

Section: Introductionmentioning

confidence: 99%

Ependymoma‐like tumor with mesenchymal differentiation harboring C11orf95‐NCOA1/2 or ‐RELA fusion: A hitherto unclassified tumor related to ependymoma

Tomomasa

Arai²,

Kawabata‐Iwakawa

et al. 2021

Brain Pathology

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Recurrent fusion genes involving C11orf95, C11orf95-RELA, have been identified only in supratentorial ependymomas among primary CNS tumors. Here, we report hitherto histopathologically unclassifiable high-grade tumors, under the tentative label of "ependymoma-like tumors with mesenchymal differentiation (ELTMDs)," harboring C11orf95-NCOA1/2 or -RELA fusion. We examined the clinicopathological and molecular features in five cases of ELTMDs.Except for one adult case (50 years old), all cases were in children ranging from 1 to 2.5 years old. All patients presented with a mass lesion in the cerebral hemisphere. Histologically, all cases demonstrated a similar histology with a mixture of components. The major components were embryonal-appearing components forming well-delineated tumor cell nests composed of small uniform cells with high proliferative activity, and spindle-cell mesenchymal components with a low-to high-grade sarcoma-like appearance. The embryonal-appearing components exhibited minimal ependymal differentiation including a characteristic EMA positivity and tubular structures, but histologically did not fit with ependymoma because they lacked perivascular pseudorosettes, a histological hallmark of ependymoma, formed well-delineated nests, and had diffuse and strong staining for CAM5.2. Molecular analysis identified C11orf95-NCOA1, -NCOA2, and -RELA in two, one, and two cases, respectively. t-distributed 2 of 14 | TOMOMASA eT Al.

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Transcriptional profiling of paediatric ependymomas identifies prognostically significant groups

Łastowska

Matyja

Sobocińska

et al. 2021

The Journal of Pathology CR

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The majority of supratentorial ependymomas in children contain oncogenic fusions, such as ZFTA–RELA or YAP1‐MAMLD1. In contrast, posterior fossa (PF) ependymomas lack recurrent somatic mutations and are classified based on gene expression or methylation profiling into group A (PFA) and group B (PFB). We have applied a novel method, NanoString nCounter Technology, to identify four molecular groups among 16 supratentorial and 50 PF paediatric ependymomas, using 4–5 group‐specific signature genes. Clustering analysis of 16 supratentorial ependymomas revealed 9 tumours with a RELA fusion‐positive signature (RELA+), 1 tumour with a YAP1 fusion‐positive signature (YAP1+), and 6 not‐classified tumours. Additionally, we identified one RELA+ tumour among historically diagnosed CNS primitive neuroectodermal tumour samples. Overall, 9 of 10 tumours with the RELA+ signature possessed the ZFTA‐RELA fusion as detected by next‐generation sequencing (p = 0.005). Similarly, the only tumour with a YAP1+ signature exhibited the YAP1‐MAMLD1 fusion. Among the remaining unclassified ependymomas, which did not exhibit the ZFTA‐RELA fusion, the ZFTA‐MAML2 fusion was detected in one case. Notably, among nine ependymoma patients with the RELA+ signature, eight survived at least 5 years after diagnosis. Clustering analysis of PF tumours revealed 42 samples with PFA signatures and 7 samples with PFB signatures. Clinical characteristics of patients with PFA and PFB ependymomas corroborated the previous findings. In conclusion, we confirm here that the NanoString method is a useful single tool for the diagnosis of all four main molecular groups of ependymoma. The differences in reported survival rates warrant further clinical investigation of patients with the ZFTA‐RELA fusion.

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Ependymoma with C11orf95-MAML2 fusion: presenting with granular cell and ganglion cell features

Cited by 15 publications

References 20 publications

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

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

Ependymoma‐like tumor with mesenchymal differentiation harboring C11orf95‐NCOA1/2 or ‐RELA fusion: A hitherto unclassified tumor related to ependymoma

Transcriptional profiling of paediatric ependymomas identifies prognostically significant groups

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