YAP1::MAML2 fusion, a newly identified genetic anomaly in a posterior fossa infant tumor, associated with the methylation class “embryonal tumor with multilayered rosettes, non-C19MC- altered” in the Heidelberg central nervous system tumor classifier and “embryonal tumor with multilayered rosettes-DICER” in the NIH classifier

YAP1::MAML2 fusion, a newly identified genetic anomaly in a posterior fossa infant tumor, associated with the methylation class “embryonal tumor with multilayered rosettes, non-C19MC- altered” in the Heidelberg central nervous system tumor classifier and “embryonal tumor with multilayered rosettes-DICER” in the NIH classifier | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report YAP1::MAML2 fusion, a newly identified genetic anomaly in a posterior fossa infant tumor, associated with the methylation class “embryonal tumor with multilayered rosettes, non-C19MC- altered” in the Heidelberg central nervous system tumor classifier and “embryonal tumor with multilayered rosettes-DICER” in the NIH classifier Catherine Godfraind, Nabil Djebbour, Romain Appay, Anne Pagnier, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7193504/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Dec, 2025 Read the published version in Acta Neuropathologica Communications → Version 1 posted 9 You are reading this latest preprint version Abstract Embryonal tumors with multilayered rosettes (ETMR) are rare embryonal tumors that usually affect children under two years old. They are characterized histologically by the presence of multilayered rosettes and by the immunohistochemical expression of LIN28A. Their genetic hallmarks include C19MC amplification, which is most common, followed by DICER1 mutation. Each of these alterations correlates with a specific methylation class in the Heidelberg central nervous system tumor classifier and the National Institutes of Health brain tumor classifier. Meanwhile, 2.5 percent of LIN28A-positive embryonal tumors lack the previously mentioned genetic alterations associated with ETMR. Here, we present and discuss a case of this type. A posterior fossa tumor was found in a five-month-old infant. Histologically, the lesion appeared as an embryonal tumor, lacking multilayered rosettes but showing focal positivity for LIN28A. It did not show C19MC amplification or DICER1 mutation, yet it clustered within the ETMR non- C19MC -altered methylation class of the Heidelberg classifier (V12.5) and the ETMR-DICER class of the NIH classifier. Additionally, a YAP1::MAML2 fusion was identified, a finding not yet associated with these methylation classes. ETMR YAP1:MALM2 fusion DICER1 mutation ETMR non-C19MC methylation class ETMR DICER1-altered Figures Figure 1 Introduction Embryonal tumors with multilayered rosettes (ETMR) are a rare type of tumor that usually affects the cerebral hemisphere of infants under two years of age. The entity was introduced in the 2016 WHO update of Central Nervous System tumors (CNS, [ 3 ]). ETMR results from a combination of previously known tumors: embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL), as they share common markers: LIN28 immunohistochemical expression [ 12 ] and, for most, a genomic alteration first identified in ETANTR, which is the amplification of the C19MC miRNA cluster located at 19q13.42 ([ 19 ], [ 17 ]). The 2021 World Health Organization Central Nervous System classification identifies two distinct subtypes of ETMR [ 1 ]: the ETMR C19MC -altered, characterized by amplification of the C19MC locus, and the ETMR DICER1 -altered, which usually has a DICER1 mutation, linked or not to a hereditary cancer syndrome ([ 20 ],[ 11 ]) or, in rarer cases, an amplification of the miR-17-92 cluster ( MIR17HG ) or a remodeling of the C19MC genomic region [ 15 ]. Each subtype has its methylation class (MC) within the Heidelberg Central Nervous System tumor (CNS) classifier [ 2 ]: the MC Embryonal tumor with multilayered rosettes, C19MC -altered, and the MC Embryonal tumor with multilayered rosettes, non- C19MC -altered, as well as in the National Institutes of Health (NIH) classifier (Methylscape analysis, [ 29 ]): the MC Embryonal tumor with multilayered rosettes, C19MC -altered, and the MC Embryonal tumor with multilayered rosettes, DICER. However, some embryonal tumors expressing LIN28A lack the reported genomic alterations, except for the methylation profile associated with the MC embryonal tumor with multilayered rosettes, non- C19MC -altered, according to the Heidelberg CNS tumor classifier. Here, we describe such a tumor in a five-month-old girl. The lesion was located in the posterior fossa and exhibited an embryonal appearance similar to EBL, with LIN28A protein expression. No multilayered rosettes, C19MC amplification, DICER1 mutation, or MIR17HG amplification were detected. However, a YAP1::MAML2 fusion and an LZTR1 mutation were present; the significance of the latter remains uncertain. This is the first report of a YAP1 fusion in the MC embryonal tumor with multilayered rosettes, non- C19MC -altered, as classified by the Heidelberg CNS tumor classifier (V12.5), [ 2 ] and in the MC embryonal tumor with multilayered rosettes, DICER, from the NIH. It highlights the importance of testing for YAP1 fusion in ETMR tumors lacking C19MC alterations and DICER1 mutations, as well as MIR17HG amplifications, thereby broadening the spectrum of genetic alterations associated with ETMR and of tumors related to YAP1 fusion. Case Presentation Clinical presentation A five-month-old baby girl experienced vomiting and drowsiness for six weeks before hospitalization at the University Hospital of Grenoble because of further development of right torticollis and strabismus with loss of eye tracking. A posterior fossa mass measuring 55 x 51 x 48 mm was identified. It caused severe hydrocephalus with amygdala engagement. On T2-weighted imaging, the lesion appeared heterogeneous with mixed hyper- and hypo-intense regions (Fig. A, B). Echo gradient sequences revealed hemorrhagic areas and calcifications. Slight contrast enhancement was seen after gadolinium injection. ADC ratio indicated diffusion restriction. The child underwent complete surgical removal of the tumor, followed by chemotherapy (THIOTEPA) and then an autograft. Five years post-surgery, she remains relapse-free. Pathological findings At histology, the lesion resembled an embryonal tumor. Regions lacking specific architectural patterns (Fig. C) alternated with areas showing broad pseudo-perivascular rosettes, reminiscent of EBL (Fig. D). No rosettes, canals, or multilayered rosettes were observed despite extensive sampling of the lesion. The nuclei appeared hyperchromatic and often demonstrated molding (Fig. E). Mitoses were numerous and mostly atypical. Apoptotic bodies were seen. Necrosis, sometimes calcified, was noted. At immunohistochemistry (IHC, Fig. F to L), INI1 (Cell Marque, MRQ-27) and BRG1 (Abcam, ab110641) nuclear expressions were preserved. Vimentin (Dako, clone V9) was the only marker positive in all tumor cells. They also focally expressed GFAP (Cell Marque, EP672Y), synaptophysin (Ventana, SP11), LIN28 (Cell Signalling Technology, A177), and SALL4 (Cell Marque, 6E3). Ki67 (Ventana, 30 − 9) showed heterogeneity, reaching up to 60% in the most proliferative areas. Based on RNA-seq results, additional IHC was performed using an antibody targeting the C-terminal of YAP1 (Abcam, ab52771). It revealed a loss of nuclear expression in tumor cells, while the nuclei of endothelial cells remained positive (Fig. L). Molecular findings A SNP array (GeneChip R Oncoscan Array, Affymetrix) showed complete gains of chromosomes 2, 3, 5, 6, 7, 8, 10, 11, 12, and 18, as well as loss of heterozygosity without copy number variation for chromosomes 1 and 21. A custom NGS panel of 571 genes involved in oncogenesis, including DICER1 , NF1 , and NF2 (DRAGON: Detection of Relevant Alterations in Genes involved in Oncogenetics by NGS; SureSelect CD Curie CGP by Agilent), detected only an LZTR1 c.1922T > A/p.(Leu641*) pathogenic mutation with an allelic frequency of 49.4%. A custom RNA-seq panel dedicated to cerebral tumors (ArcherDx, Integrated DNA Technologies) revealed an in-frame YAP1::MAML2 fusion between exon 6 of YAP1 (11q22.1, breakpoint: chr11:102080295) and exon 2 of MAML2 (11q21, breakpoint: chr11:95826681). At that time, the DNA methylation profile (V1, EPIC Human Methylation microarray, Illumina, San Diego, USA) did not match any of the MCs of the Heidelberg CNS tumor classifier (V11.4) [ 2 ]. However, the UMAP analysis performed on the Epidip website clustered the lesion into ETMR [ 30 ]. An integrated diagnosis of ETMR was suggested. Later, the V12.5 of the Heidelberg CNS tumor classifier proposed an embryonal tumor with multilayered rosettes, non-C19MC-altered as MC (score: 0.92), and the NIH brain tumor classifier suggested, as family, the neuroblastic embryonal tumors (score 0.992) with ETMR DICER as MC (score 0.995). Discussion and Conclusions Advances in genetics have significantly impacted the classification of CNS-primitive neuroectodermal tumors [ 25 ]. Specifically, genomics has allowed the grouping of embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL) under one tumor type, the embryonal tumor with multilayered rosettes (EMTR), because they share C19MC amplification. This was reinforced by similarities in their methylation profiles, suggesting a common developmental lineage ([ 18 ];[ 13 ]). Furthermore, DICER1 mutation has been identified as another genetic factor associated with ETMR, although it is less common [ 28 ]. Consequently, the 2021 WHO CNS classification now recognizes two ETMR subtypes: ETMR C19MC -altered and ETMR DICER1 -mutated [ 1 ]. These subtypes correlate with specific methylation classes (MC) in the Heidelberg CNS tumor classifier: the EMTR C19MC -altered MC and the EMTR non- C19MC -altered MC [ 2 ], as well as in the NIH classifier [ 29 ], but with different names: ETMR MC and ETMR- DICER MC. Here, we report an unusual posterior fossa tumor in a five-month-old girl. Histologically, the tumor exhibited an embryonal appearance reminiscent of EBL and showed focal positivity for LIN28A. Multilayered rosettes, the hallmark feature of ETMR, were absent despite extensive sampling of the tumor. No C19MC amplification or DICER1 mutation was detected. The final diagnosis was based on the methylation profile, which classified the lesion in the MC of EMTR non- C19MC -altered with a confidence score of 0.92 using the Heidelberg classifier (V12.5), and within the neuroblastic embryonal tumor family (score 0.992) and the ETMR DICER class (score 0.995) of the NIH classifier. This highlights the importance of methylation profiling in the integrated diagnosis of tumors with unusual clinical, histological, or genomic features. Focal positivity for LIN28A is a key IHC hallmark of ETMR [ 12 ]. LIN28A is an RNA-binding protein that acts as an oncogene by inhibiting the tumor suppressor miRNA let-7 family ([ 6 ];[ 5 ];[ 7 ]). Interestingly, this microRNA family is also affected by DICER1 mutations, which are the most common genomic alterations in LIN28A-positive embryonal tumors lacking C19MC amplification [ 28 ]. In this group, other genetic changes, such as C19MC structural variations and MIR17HG amplifications, have been reported [ 17 ]. None of these changes were observed in our case, a situation reported in 2.5% of ETMRs expressing LIN28A; instead, a YAP1::MAML2 fusion was identified [ 17 ]. Meanwhile, their genomic instability has been well-documented; the only fusion previously reported in ETMR is a TTYH1::C19MC fusion ([ 16 ],[ 10 ]). In the current tumor, we identified a YAP1::MAML2 fusion. Oncogenic fusions involving YAP1 and various partners, such as MAML2 , MAMLD1 , FAM118B , or ZFTA , have been described in different CNS pediatric brain tumors [ 21 ]. The YAP1::MAML2 fusion is most often reported in meningiomas associated with neurofibromatosis type 2 (NF2) [ 24 ]. YAP1, the main effector of the Hippo signaling pathway, plays a critical role in cell proliferation, survival, and stem cell maintenance, acting as a tumor suppressor [ 23 ]. By interacting with transcriptional enhanced associate domain (TEAD) transcription factors, the C-terminal part of YAP1, which is the final nuclear effector of the Hippo pathway, turns this pathway on “OFF” [ 9 ]. When lost, as in YAP1 fusion demonstrated here by the IHC negativity of the tumoral cell nuclei for the YAP1-C terminal, the Hippo pathway remains in an “ON” state, thus promoting oncogenesis [ 26 ]. Other pathways also interact with TEAD, such as the WNT pathway, which is known to dysregulate the miRNA machinery in ETMR, along with the NOTCH and SHH pathways [ 23 ]. The current lesion also had a pathogenic LZTR1 mutation, a gene known to be mutated in schwannomatosis and Noonan syndrome (OMIM: 600574). This mutation is thus the second identified in the current lesion associated with the neurofibromatosis spectrum [ 14 ]. LZTR1 mutations are increasingly found in various cancers, including sporadic schwannomas [ 22 ], glioblastomas [ 4 ], and, more recently, in pediatric high-grade gliomas [ 27 ]. With an allelic frequency of 49.4%, the LZTR1 mutation is likely germline. Meanwhile, our proband showed no symptoms of Noonan syndrome or schwannomatosis, which may be due to the likely incomplete or very low penetrance of this mutation. Therefore, its significance remains uncertain. ETMRs lacking C19M amplification are mainly reported in the posterior fossa [ 17 ], a location similar to that of our patient. The observed symptoms were related to intracranial hypertension, a common feature of ETMRs, such as visual impairment and torticollis ([ 8 ],[ 17 ]). Additionally, ETMRs without C19M C amplification tend to have worse overall survival compared to tumors with amplification, often around one year [ 17 ]. In contrast, our patient was still alive and free of relapse five years after diagnosis. In conclusion, we report an unusual case of a posterior fossa tumor in an infant. Histologically, the tumor exhibited an embryonal appearance reminiscent of EBL, with focal expression of LIN28A, but lacked the characteristic multilayered rosettes of ETMR. The tumor also lacked C19MC amplification, DICER1 mutation, or other less common genetic alterations associated with ETMR; however, a YAP1::MAML2 fusion was identified. The methylation profile matched the ETMR non- C19MC -altered MC in the Heidelberg classifier and the ETMR DICER MC in the NIH. This, along with existing literature, suggests the need to revise the WHO terminology for the “ETMR DICER1 -mutated” subtype to account for the other genetic alterations observed in this ETMR subgroup. Additionally, it expands the spectrum of tumors linked to YAP1 fusions and genomic alterations associated with ETMR non- C19MC -altered MC, by reporting, for the first time, a YAP1::MAML2 fusion in this context. Abbreviations CNS central nervous system EBL ependymoblastoma ETANTR embryonal tumor with abundant neuropil and true rosettes ETMR embryonal tumor with multilayered rosettes HES hemalum, eosin, safran staining IHC immunohistochemistry MC methylation class MEPL medulloepithelioma NGS next generation sequencing NF2 neurofibromatosis type 2 NIH National Institutes of Health RNA-seq RNA sequencing SNP-array single nucleotide polymorphism array Declarations Acknowledgements : CG, JB, FF, and FV are members of the French neuropathological network, the RENOCLIP-LOC. Funding : Methylation analysis was made possible thanks to support from Canceropole Lyon Auvergne-Rhône-Alpes (CLARA). Authors' contributions: All authors participated in editing the manuscript and approved the final version. Additionally, CG, FF, FV, and JB contributed to diagnosis discussions. CG and ND authored the manuscript. AP assisted with the patient's clinical management and collected relevant clinical data. CG, JM, RA, and BD were involved in genetic analyses. ND provided editorial feedback on the manuscript. Availability of data : IDAT files were introduced in the DKFZ and NIH classifiers, with agreement to be used for research purposes. Idats files can be transferred upon request to CG. Ethics approval and consent to participate: Not applicable Consent for Publication: The p atient’s parents agree to introduce their child into the French RENOCLIP network, which is linked to a research agreement. 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Acta Neuropathol (Berl) 139:215–218. 10.1007/s00401-019-02095-9 Sturm D, Orr BA, Toprak UH, Hovestadt V, Jones DTW, Capper D, Sill M, Buchhalter I, Northcott PA, Leis I, Ryzhova M, Koelsche C, Pfaff E, Allen SJ, Balasubramanian G, Worst BC, Pajtler KW, Brabetz S, Johann PD, Sahm F, Reimand J, Mackay A, Carvalho DM, Remke M, Phillips JJ, Perry A, Cowdrey C, Drissi R, Fouladi M, Giangaspero F, Łastowska M, Grajkowska W, Scheurlen W, Pietsch T, Hagel C, Gojo J, Lötsch D, Berger W, Slavc I, Haberler C, Jouvet A, Holm S, Hofer S, Prinz M, Keohane C, Fried I, Mawrin C, Scheie D, Mobley BC, Schniederjan MJ, Santi M, Buccoliero AM, Dahiya S, Kramm CM, von Bueren AO, von Hoff K, Rutkowski S, Herold-Mende C, Frühwald MC, Milde T, Hasselblatt M, Wesseling P, Rößler J, Schüller U, Ebinger M, Schittenhelm J, Frank S, Grobholz R, Vajtai I, Hans V, Schneppenheim R, Zitterbart K, Collins VP, Aronica E, Varlet P, Puget S, Dufour C, Grill J, Figarella-Branger D, Wolter M, Schuhmann MU, Shalaby T, Grotzer M, van Meter T, Monoranu C-M, Felsberg J, Reifenberger G, Snuderl M, Forrester LA, Koster J, Versteeg R, Volckmann R, van Sluis P, Wolf S, Mikkelsen T, Gajjar A, Aldape K, Moore AS, Taylor MD, Jones C, Jabado N, Karajannis MA, Eils R, Schlesner M, Lichter P, von Deimling A, Pfister SM, Ellison DW, Korshunov A, Kool M (2016) New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. Cell 164:1060–1072. 10.1016/j.cell.2016.01.015 Szulzewsky F, Arora S, Hoellerbauer P, King C, Nathan E, Chan M, Cimino PJ, Ozawa T, Kawauchi D, Pajtler KW, Gilbertson RJ, Paddison PJ, Vasioukhin V, Gujral TS, Holland EC (2020) Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis. Genes Dev 34:1051–1064. 10.1101/gad.338681.120 Thomson N, Jewels E, Bergeron-Gravel S, Lagacé S, Hazrati L-N, Saikali S, Dunham C, Cheng S (2025) YAP1-MAML2 Fusion in Young Children With Pediatric High-Grade Glioma: A Case Report. Pediatr Blood Cancer 72:e31796. 10.1002/pbc.31796 Uro-Coste E, Masliah-Planchon J, Siegfried A, Blanluet M, Lambo S, Kool M, Roujeau T, Boetto S, Palenzuela G, Bertozzi A-I, Gambart M, Coupier I, Oliver-Petit I, Golmard L, Julia S, Savagner F, Mohand-Oumoussa B, Tauziede-Espariat A, Delisle M-B, Figarella-Branger D, Bourdeaut F, Rigau V (2019) ETMR-like infantile cerebellar embryonal tumors in the extended morphologic spectrum of DICER1-related tumors. Acta Neuropathol (Berl) 137:175–177. 10.1007/s00401-018-1935-7 Methylscape Analysis https://methylscape.ccr.cancer.gov/ EpiDiP http://s1665.rootserver.io/ Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 22 Dec, 2025 Read the published version in Acta Neuropathologica Communications → Version 1 posted Editorial decision: Revision requested 06 Sep, 2025 Reviews received at journal 02 Sep, 2025 Reviews received at journal 28 Aug, 2025 Reviewers agreed at journal 12 Aug, 2025 Reviewers agreed at journal 10 Aug, 2025 Reviewers invited by journal 09 Aug, 2025 Editor assigned by journal 03 Aug, 2025 Submission checks completed at journal 03 Aug, 2025 First submitted to journal 23 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7193504","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":499259854,"identity":"774c1fdc-c258-4586-979e-7347b0432e27","order_by":0,"name":"Catherine Godfraind","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABPElEQVRIie3RMUvDQBTA8QeB1+Xqra9csV/hpNAqiv0qgUBcKuhSBKE63VTtame/gCCIg8OFglnOzimdOphNMGRU0KSpQxoHR4f7L7k83m84DsBm+6fRGQAD8LST/22tp7z44M+hTMyK+K5T7KySjcs1WR8qJKsv/0b4+DaIgqfDZrfWT9JTBS2sXb3eJY+fxMXLMj0ZAHXLhqLY29Wxx/ZGb/diomBHsbAznxhJjeujtriZATV1iUgyHfGuHSaj4wenrr5cJB8XdSWH0iCIuoIhQYWQ1hcZ6ccZARdb8YpQz6DzkU1ok/BRTqY5wYIQFkQyRPELoQizu+iQSRO3BZvld/FxPlFtIoO4z2a0Sfh4GkRan/dk6C1TNoAWrz1jlKht4iN0FmxwsEmA3OpDlRcqE66rWzabzWYr9Q28Ymg2FL/zEwAAAABJRU5ErkJggg==","orcid":"","institution":"University Hospital of Clermont-Ferrand, UMR1071, Clermont Auvergne University","correspondingAuthor":true,"prefix":"","firstName":"Catherine","middleName":"","lastName":"Godfraind","suffix":""},{"id":499259855,"identity":"1fa466af-30ef-471f-a73f-be00dd86731e","order_by":1,"name":"Nabil Djebbour","email":"","orcid":"","institution":"University Hospital of Clermont-Ferrand","correspondingAuthor":false,"prefix":"","firstName":"Nabil","middleName":"","lastName":"Djebbour","suffix":""},{"id":499259856,"identity":"f571cc0a-b3c4-4d9e-9e1b-26ab2119dc5f","order_by":2,"name":"Romain Appay","email":"","orcid":"","institution":"University Hospital La Timone","correspondingAuthor":false,"prefix":"","firstName":"Romain","middleName":"","lastName":"Appay","suffix":""},{"id":499259857,"identity":"dd110560-a45e-4b01-94d0-cb345ce7d8f1","order_by":3,"name":"Anne Pagnier","email":"","orcid":"","institution":"University Hospital Center of Grenoble","correspondingAuthor":false,"prefix":"","firstName":"Anne","middleName":"","lastName":"Pagnier","suffix":""},{"id":499259860,"identity":"ac9ed26c-40c3-4fa6-8b58-c05a86612ea3","order_by":4,"name":"Julien Masliah-Planchon","email":"","orcid":"","institution":"Institut Curie","correspondingAuthor":false,"prefix":"","firstName":"Julien","middleName":"","lastName":"Masliah-Planchon","suffix":""},{"id":499259862,"identity":"a416588d-1e04-4903-ae1f-3f5d51565570","order_by":5,"name":"Fabien Forest","email":"","orcid":"","institution":"University Hospital of Saint Etienne","correspondingAuthor":false,"prefix":"","firstName":"Fabien","middleName":"","lastName":"Forest","suffix":""},{"id":499259864,"identity":"e240b639-d9c6-4e6c-9f01-4e3ba94c6e69","order_by":6,"name":"Fanny Burel-Vandenbos","email":"","orcid":"","institution":"Nice University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fanny","middleName":"","lastName":"Burel-Vandenbos","suffix":""},{"id":499259865,"identity":"06dc5ec7-f705-40d8-9baa-8f5fd6ed06de","order_by":7,"name":"Jean Boutonnat","email":"","orcid":"","institution":"University Hospital of Grenoble Alpes","correspondingAuthor":false,"prefix":"","firstName":"Jean","middleName":"","lastName":"Boutonnat","suffix":""},{"id":499259866,"identity":"966b4711-11bd-487d-af9c-577c098a17fa","order_by":8,"name":"Berengere Dadone-Montaudie","email":"","orcid":"","institution":"UMR 7284, INSERM U1081, University of Cote d’Azur (UCA), Nice University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Berengere","middleName":"","lastName":"Dadone-Montaudie","suffix":""}],"badges":[],"createdAt":"2025-07-23 07:53:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7193504/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7193504/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40478-025-02165-y","type":"published","date":"2025-12-22T15:57:09+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89629527,"identity":"d3b80861-6424-42ae-ab7b-65d80f32fa18","added_by":"auto","created_at":"2025-08-22 06:33:07","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2482507,"visible":true,"origin":"","legend":"\u003cp\u003eA-B: T2-weighted MRI showing a heterogeneous lesion with hyper- and hypo-intense regions. Figure C: H\u0026amp;E stain revealing a poorly differentiated tumor lacking an architectural pattern. Figure D: H\u0026amp;E stain showing a perivascular anucleated region. Figure E: H\u0026amp;E stain with hyperchromatic nuclei demonstrating molding. Figure F, G, J: IHC for synaptophysin, LIN28A, GFAP showing partial positivity. Figure H, I: IHC for IN1, BRG1 showing nuclear positivity. Figure K: IHC for Ki67 indicating a heterogeneous proliferation index, with regions reaching 60%. Figure L: IHC for YAP-C showing loss of nuclear expression in tumor cells.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7193504/v1/ffee5383892c37f34aaaf9e9.jpg"},{"id":99172233,"identity":"ec2d0dc7-9d7a-4d21-bf5c-f047313c2891","added_by":"auto","created_at":"2025-12-29 16:04:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3006010,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7193504/v1/d671f6fa-1fea-4904-9265-f202b194146d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"YAP1::MAML2 fusion, a newly identified genetic anomaly in a posterior fossa infant tumor, associated with the methylation class “embryonal tumor with multilayered rosettes, non-C19MC- altered” in the Heidelberg central nervous system tumor classifier and “embryonal tumor with multilayered rosettes-DICER” in the NIH classifier","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEmbryonal tumors with multilayered rosettes (ETMR) are a rare type of tumor that usually affects the cerebral hemisphere of infants under two years of age. The entity was introduced in the 2016 WHO update of Central Nervous System tumors (CNS, [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]). ETMR results from a combination of previously known tumors: embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL), as they share common markers: LIN28 immunohistochemical expression [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and, for most, a genomic alteration first identified in ETANTR, which is the amplification of the \u003cem\u003eC19MC\u003c/em\u003e miRNA cluster located at \u003cem\u003e19q13.42\u003c/em\u003e ([\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]).\u003c/p\u003e\u003cp\u003eThe 2021 World Health Organization Central Nervous System classification identifies two distinct subtypes of ETMR [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]: the ETMR \u003cem\u003eC19MC\u003c/em\u003e-altered, characterized by amplification of the \u003cem\u003eC19MC\u003c/em\u003e locus, and the ETMR \u003cem\u003eDICER1\u003c/em\u003e-altered, which usually has a \u003cem\u003eDICER1\u003c/em\u003e mutation, linked or not to a hereditary cancer syndrome ([\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e],[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]) or, in rarer cases, an amplification of the \u003cem\u003emiR-17-92\u003c/em\u003e cluster (\u003cem\u003eMIR17HG\u003c/em\u003e) or a remodeling of the \u003cem\u003eC19MC\u003c/em\u003e genomic region [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Each subtype has its methylation class (MC) within the Heidelberg Central Nervous System tumor (CNS) classifier [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]: the MC Embryonal tumor with multilayered rosettes, \u003cem\u003eC19MC\u003c/em\u003e-altered, and the MC Embryonal tumor with multilayered rosettes, non-\u003cem\u003eC19MC\u003c/em\u003e-altered, as well as in the National Institutes of Health (NIH) classifier (Methylscape analysis, [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]): the MC Embryonal tumor with multilayered rosettes, \u003cem\u003eC19MC\u003c/em\u003e-altered, and the MC Embryonal tumor with multilayered rosettes, DICER.\u003c/p\u003e\u003cp\u003eHowever, some embryonal tumors expressing LIN28A lack the reported genomic alterations, except for the methylation profile associated with the MC embryonal tumor with multilayered rosettes, non-\u003cem\u003eC19MC\u003c/em\u003e-altered, according to the Heidelberg CNS tumor classifier. Here, we describe such a tumor in a five-month-old girl. The lesion was located in the posterior fossa and exhibited an embryonal appearance similar to EBL, with LIN28A protein expression. No multilayered rosettes, \u003cem\u003eC19MC\u003c/em\u003e amplification, \u003cem\u003eDICER1\u003c/em\u003e mutation, or \u003cem\u003eMIR17HG\u003c/em\u003e amplification were detected. However, a \u003cem\u003eYAP1::MAML2\u003c/em\u003e fusion and an \u003cem\u003eLZTR1\u003c/em\u003e mutation were present; the significance of the latter remains uncertain. This is the first report of a \u003cem\u003eYAP1\u003c/em\u003e fusion in the MC embryonal tumor with multilayered rosettes, non-\u003cem\u003eC19MC\u003c/em\u003e-altered, as classified by the Heidelberg CNS tumor classifier (V12.5), [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] and in the MC embryonal tumor with multilayered rosettes, DICER, from the NIH. It highlights the importance of testing for \u003cem\u003eYAP1\u003c/em\u003e fusion in ETMR tumors lacking \u003cem\u003eC19MC\u003c/em\u003e alterations and \u003cem\u003eDICER1\u003c/em\u003e mutations, as well as \u003cem\u003eMIR17HG\u003c/em\u003e amplifications, thereby broadening the spectrum of genetic alterations associated with ETMR and of tumors related to \u003cem\u003eYAP1\u003c/em\u003e fusion.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eClinical presentation\u003c/p\u003e\u003cp\u003eA five-month-old baby girl experienced vomiting and drowsiness for six weeks before hospitalization at the University Hospital of Grenoble because of further development of right torticollis and strabismus with loss of eye tracking. A posterior fossa mass measuring 55 x 51 x 48 mm was identified. It caused severe hydrocephalus with amygdala engagement. On T2-weighted imaging, the lesion appeared heterogeneous with mixed hyper- and hypo-intense regions (Fig. A, B). Echo gradient sequences revealed hemorrhagic areas and calcifications. Slight contrast enhancement was seen after gadolinium injection. ADC \u003csub\u003eratio\u003c/sub\u003e indicated diffusion restriction. The child underwent complete surgical removal of the tumor, followed by chemotherapy (THIOTEPA) and then an autograft. Five years post-surgery, she remains relapse-free.\u003c/p\u003e\u003cp\u003ePathological findings\u003c/p\u003e\u003cp\u003eAt histology, the lesion resembled an embryonal tumor. Regions lacking specific architectural patterns (Fig. C) alternated with areas showing broad pseudo-perivascular rosettes, reminiscent of EBL (Fig. D). No rosettes, canals, or multilayered rosettes were observed despite extensive sampling of the lesion. The nuclei appeared hyperchromatic and often demonstrated molding (Fig. E). Mitoses were numerous and mostly atypical. Apoptotic bodies were seen. Necrosis, sometimes calcified, was noted. At immunohistochemistry (IHC, Fig. F to L), INI1 (Cell Marque, MRQ-27) and BRG1 (Abcam, ab110641) nuclear expressions were preserved. Vimentin (Dako, clone V9) was the only marker positive in all tumor cells. They also focally expressed GFAP (Cell Marque, EP672Y), synaptophysin (Ventana, SP11), LIN28 (Cell Signalling Technology, A177), and SALL4 (Cell Marque, 6E3). Ki67 (Ventana, 30\u0026thinsp;\u0026minus;\u0026thinsp;9) showed heterogeneity, reaching up to 60% in the most proliferative areas. Based on RNA-seq results, additional IHC was performed using an antibody targeting the C-terminal of YAP1 (Abcam, ab52771). It revealed a loss of nuclear expression in tumor cells, while the nuclei of endothelial cells remained positive (Fig. L).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eMolecular findings\u003c/p\u003e\u003cp\u003eA SNP array (GeneChip\u003csup\u003eR\u003c/sup\u003e Oncoscan Array, Affymetrix) showed complete gains of chromosomes 2, 3, 5, 6, 7, 8, 10, 11, 12, and 18, as well as loss of heterozygosity without copy number variation for chromosomes 1 and 21. A custom NGS panel of 571 genes involved in oncogenesis, including \u003cem\u003eDICER1\u003c/em\u003e, \u003cem\u003eNF1\u003c/em\u003e, and \u003cem\u003eNF2\u003c/em\u003e (DRAGON: Detection of Relevant Alterations in Genes involved in Oncogenetics by NGS; SureSelect CD Curie CGP by Agilent), detected only an \u003cem\u003eLZTR1\u003c/em\u003e c.1922T\u0026thinsp;\u0026gt;\u0026thinsp;A/p.(Leu641*) pathogenic mutation with an allelic frequency of 49.4%. A custom RNA-seq panel dedicated to cerebral tumors (ArcherDx, Integrated DNA Technologies) revealed an in-frame \u003cem\u003eYAP1::MAML2\u003c/em\u003e fusion between exon 6 of \u003cem\u003eYAP1\u003c/em\u003e (11q22.1, breakpoint: chr11:102080295) and exon 2 of \u003cem\u003eMAML2\u003c/em\u003e (11q21, breakpoint: chr11:95826681). At that time, the DNA methylation profile (V1, EPIC Human Methylation microarray, Illumina, San Diego, USA) did not match any of the MCs of the Heidelberg CNS tumor classifier (V11.4) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, the UMAP analysis performed on the Epidip website clustered the lesion into ETMR [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. An integrated diagnosis of ETMR was suggested. Later, the V12.5 of the Heidelberg CNS tumor classifier proposed an embryonal tumor with multilayered rosettes, non-C19MC-altered as MC (score: 0.92), and the NIH brain tumor classifier suggested, as family, the neuroblastic embryonal tumors (score 0.992) with ETMR DICER as MC (score 0.995).\u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003cp\u003eAdvances in genetics have significantly impacted the classification of CNS-primitive neuroectodermal tumors [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Specifically, genomics has allowed the grouping of embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL) under one tumor type, the embryonal tumor with multilayered rosettes (EMTR), because they share \u003cem\u003eC19MC\u003c/em\u003e amplification. This was reinforced by similarities in their methylation profiles, suggesting a common developmental lineage ([\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e];[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]). Furthermore, \u003cem\u003eDICER1\u003c/em\u003e mutation has been identified as another genetic factor associated with ETMR, although it is less common [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Consequently, the 2021 WHO CNS classification now recognizes two ETMR subtypes: ETMR \u003cem\u003eC19MC\u003c/em\u003e-altered and ETMR \u003cem\u003eDICER1\u003c/em\u003e-mutated [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. These subtypes correlate with specific methylation classes (MC) in the Heidelberg CNS tumor classifier: the EMTR \u003cem\u003eC19MC\u003c/em\u003e-altered MC and the EMTR non-\u003cem\u003eC19MC\u003c/em\u003e-altered MC [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], as well as in the NIH classifier [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], but with different names: ETMR MC and ETMR-\u003cem\u003eDICER\u003c/em\u003e MC.\u003c/p\u003e\u003cp\u003eHere, we report an unusual posterior fossa tumor in a five-month-old girl. Histologically, the tumor exhibited an embryonal appearance reminiscent of EBL and showed focal positivity for LIN28A. Multilayered rosettes, the hallmark feature of ETMR, were absent despite extensive sampling of the tumor. No \u003cem\u003eC19MC\u003c/em\u003e amplification or \u003cem\u003eDICER1\u003c/em\u003e mutation was detected. The final diagnosis was based on the methylation profile, which classified the lesion in the MC of EMTR non-\u003cem\u003eC19MC\u003c/em\u003e-altered with a confidence score of 0.92 using the Heidelberg classifier (V12.5), and within the neuroblastic embryonal tumor family (score 0.992) and the ETMR DICER class (score 0.995) of the NIH classifier. This highlights the importance of methylation profiling in the integrated diagnosis of tumors with unusual clinical, histological, or genomic features.\u003c/p\u003e\u003cp\u003eFocal positivity for LIN28A is a key IHC hallmark of ETMR [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. LIN28A is an RNA-binding protein that acts as an oncogene by inhibiting the tumor suppressor miRNA \u003cem\u003elet-7\u003c/em\u003e family ([\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e];[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e];[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]). Interestingly, this microRNA family is also affected by \u003cem\u003eDICER1\u003c/em\u003e mutations, which are the most common genomic alterations in LIN28A-positive embryonal tumors lacking \u003cem\u003eC19MC\u003c/em\u003e amplification [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In this group, other genetic changes, such as \u003cem\u003eC19MC\u003c/em\u003e structural variations and \u003cem\u003eMIR17HG\u003c/em\u003e amplifications, have been reported [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. None of these changes were observed in our case, a situation reported in 2.5% of ETMRs expressing LIN28A; instead, a \u003cem\u003eYAP1::MAML2\u003c/em\u003e fusion was identified [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMeanwhile, their genomic instability has been well-documented; the only fusion previously reported in ETMR is a \u003cem\u003eTTYH1::C19MC\u003c/em\u003e fusion ([\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e],[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]). In the current tumor, we identified a \u003cem\u003eYAP1::MAML2\u003c/em\u003e fusion. Oncogenic fusions involving \u003cem\u003eYAP1\u003c/em\u003e and various partners, such as \u003cem\u003eMAML2\u003c/em\u003e, \u003cem\u003eMAMLD1\u003c/em\u003e, \u003cem\u003eFAM118B\u003c/em\u003e, or \u003cem\u003eZFTA\u003c/em\u003e, have been described in different CNS pediatric brain tumors [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The \u003cem\u003eYAP1::MAML2\u003c/em\u003e fusion is most often reported in meningiomas associated with neurofibromatosis type 2 (NF2) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. YAP1, the main effector of the Hippo signaling pathway, plays a critical role in cell proliferation, survival, and stem cell maintenance, acting as a tumor suppressor [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. By interacting with transcriptional enhanced associate domain (TEAD) transcription factors, the C-terminal part of YAP1, which is the final nuclear effector of the Hippo pathway, turns this pathway on \u0026ldquo;OFF\u0026rdquo; [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. When lost, as in \u003cem\u003eYAP1\u003c/em\u003e fusion demonstrated here by the IHC negativity of the tumoral cell nuclei for the YAP1-C terminal, the Hippo pathway remains in an \u0026ldquo;ON\u0026rdquo; state, thus promoting oncogenesis [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Other pathways also interact with TEAD, such as the WNT pathway, which is known to dysregulate the miRNA machinery in ETMR, along with the NOTCH and SHH pathways [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe current lesion also had a pathogenic \u003cem\u003eLZTR1\u003c/em\u003e mutation, a gene known to be mutated in schwannomatosis and Noonan syndrome (OMIM: 600574). This mutation is thus the second identified in the current lesion associated with the neurofibromatosis spectrum [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. \u003cem\u003eLZTR1\u003c/em\u003e mutations are increasingly found in various cancers, including sporadic schwannomas [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], glioblastomas [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], and, more recently, in pediatric high-grade gliomas [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. With an allelic frequency of 49.4%, the \u003cem\u003eLZTR1\u003c/em\u003e mutation is likely germline. Meanwhile, our proband showed no symptoms of Noonan syndrome or schwannomatosis, which may be due to the likely incomplete or very low penetrance of this mutation. Therefore, its significance remains uncertain.\u003c/p\u003e\u003cp\u003eETMRs lacking \u003cem\u003eC19M\u003c/em\u003e amplification are mainly reported in the posterior fossa [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], a location similar to that of our patient. The observed symptoms were related to intracranial hypertension, a common feature of ETMRs, such as visual impairment and torticollis ([\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e],[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]). Additionally, ETMRs without \u003cem\u003eC19M\u003c/em\u003eC amplification tend to have worse overall survival compared to tumors with amplification, often around one year [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In contrast, our patient was still alive and free of relapse five years after diagnosis.\u003c/p\u003e\u003cp\u003eIn conclusion, we report an unusual case of a posterior fossa tumor in an infant. Histologically, the tumor exhibited an embryonal appearance reminiscent of EBL, with focal expression of LIN28A, but lacked the characteristic multilayered rosettes of ETMR. The tumor also lacked C19MC amplification, DICER1 mutation, or other less common genetic alterations associated with ETMR; however, a YAP1::MAML2 fusion was identified. The methylation profile matched the ETMR non-\u003cem\u003eC19MC\u003c/em\u003e-altered MC in the Heidelberg classifier and the ETMR DICER MC in the NIH. This, along with existing literature, suggests the need to revise the WHO terminology for the \u0026ldquo;ETMR \u003cem\u003eDICER1\u003c/em\u003e-mutated\u0026rdquo; subtype to account for the other genetic alterations observed in this ETMR subgroup. Additionally, it expands the spectrum of tumors linked to \u003cem\u003eYAP1\u003c/em\u003e fusions and genomic alterations associated with ETMR non-\u003cem\u003eC19MC\u003c/em\u003e-altered MC, by reporting, for the first time, a \u003cem\u003eYAP1::MAML2\u003c/em\u003e fusion in this context.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCNS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecentral nervous system\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEBL\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eependymoblastoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eETANTR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eembryonal tumor with abundant neuropil and true rosettes\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eETMR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eembryonal tumor with multilayered rosettes\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHES\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ehemalum, eosin, safran staining\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIHC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eimmunohistochemistry\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emethylation class\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMEPL\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emedulloepithelioma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNGS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003enext generation sequencing\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNF2\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eneurofibromatosis type 2\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNIH\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNational Institutes of Health\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRNA-seq\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRNA sequencing\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSNP-array\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003esingle nucleotide polymorphism array\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: CG, JB, FF, and FV are members of the French neuropathological network, the RENOCLIP-LOC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: Methylation analysis was made possible thanks to support from Canceropole Lyon Auvergne-Rh\u0026ocirc;ne-Alpes (CLARA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors participated in editing the manuscript and approved the final version. Additionally, CG, FF, FV, and JB contributed to diagnosis discussions. CG and ND authored the manuscript. AP assisted with the patient\u0026apos;s clinical management and collected relevant clinical data. CG, JM, RA, and BD were involved in genetic analyses. ND provided editorial feedback on the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIDAT files were introduced in the DKFZ and NIH classifiers, with agreement to be used for research purposes. Idats files can be transferred upon request to CG.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/em\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for Publication: The p\u003c/em\u003eatient\u0026rsquo;s parents agree to introduce their child into the French RENOCLIP network, which is linked to a research agreement.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests:\u003c/em\u003e NA\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBoard WC of TE Central Nervous System Tumours\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCapper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D, Koelsche C, Sahm F, Chavez L, Reuss DE, Kratz A, Wefers AK, Huang K, Pajtler KW, Schweizer L, Stichel D, Olar A, Engel NW, Lindenberg K, Harter PN, Braczynski AK, Plate KH, Dohmen H, Garvalov BK, Coras R, H\u0026ouml;lsken A, Hewer E, Bewerunge-Hudler M, Schick M, Fischer R, Beschorner R, Schittenhelm J, Staszewski O, Wani K, Varlet P, Pages M, Temming P, Lohmann D, Selt F, Witt H, Milde T, Witt O, Aronica E, Giangaspero F, Rushing E, Scheurlen W, Geisenberger C, Rodriguez FJ, Becker A, Preusser M, Haberler C, Bjerkvig R, Cryan J, Farrell M, Deckert M, Hench J, Frank S, Serrano J, Kannan K, Tsirigos A, Br\u0026uuml;ck W, Hofer S, Brehmer S, Seiz-Rosenhagen M, H\u0026auml;nggi D, Hans V, Rozsnoki S, Hansford JR, Kohlhof P, Kristensen BW, Lechner M, Lopes B, Mawrin C, Ketter R, Kulozik A, Khatib Z, Heppner F, Koch A, Jouvet A, Keohane C, M\u0026uuml;hleisen H, Mueller W, Pohl U, Prinz M, Benner A, Zapatka M, Gottardo NG, Driever PH, Kramm CM, M\u0026uuml;ller HL, Rutkowski S, von Hoff K, Fr\u0026uuml;hwald MC, Gnekow A, Fleischhack G, Tippelt S, Calaminus G, Monoranu C-M, Perry A, Jones C, Jacques TS, Radlwimmer B, Gessi M, Pietsch T, Schramm J, Schackert G, Westphal M, Reifenberger G, Wesseling P, Weller M, Collins VP, Bl\u0026uuml;mcke I, Bendszus M, Debus J, Huang A, Jabado N, Northcott PA, Paulus W, Gajjar A, Robinson GW, Taylor MD, Jaunmuktane Z, Ryzhova M, Platten M, Unterberg A, Wick W, Karajannis MA, Mittelbronn M, Acker T, Hartmann C, Aldape K, Sch\u0026uuml;ller U, Buslei R, Lichter P, Kool M, Herold-Mende C, Ellison DW, Hasselblatt M, Snuderl M, Brandner S, Korshunov A, von Deimling A, Pfister SM (2018) DNA methylation-based classification of central nervous system tumours. 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Acta Neuropathol (Berl) 137:175\u0026ndash;177. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00401-018-1935-7\u003c/span\u003e\u003cspan address=\"10.1007/s00401-018-1935-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMethylscape Analysis \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://methylscape.ccr.cancer.gov/\u003c/span\u003e\u003cspan address=\"https://methylscape.ccr.cancer.gov/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEpiDiP \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://s1665.rootserver.io/\u003c/span\u003e\u003cspan address=\"http://s1665.rootserver.io/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"acta-neuropathologica-communications","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anec","sideBox":"Learn more about [Acta Neuropathologica Communications](https://actaneurocomms.biomedcentral.com/)","snPcode":"40478","submissionUrl":"https://submission.springernature.com/new-submission/40478/3","title":"Acta Neuropathologica Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"ETMR, YAP1:MALM2 fusion, DICER1 mutation, ETMR non-C19MC methylation class, ETMR DICER1-altered","lastPublishedDoi":"10.21203/rs.3.rs-7193504/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7193504/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eEmbryonal tumors with multilayered rosettes (ETMR) are rare embryonal tumors that usually affect children under two years old. They are characterized histologically by the presence of multilayered rosettes and by the immunohistochemical expression of LIN28A. Their genetic hallmarks include \u003cem\u003eC19MC\u003c/em\u003e amplification, which is most common, followed by \u003cem\u003eDICER1\u003c/em\u003e mutation. Each of these alterations correlates with a specific methylation class in the Heidelberg central nervous system tumor classifier and the National Institutes of Health brain tumor classifier. Meanwhile, 2.5 percent of LIN28A-positive embryonal tumors lack the previously mentioned genetic alterations associated with ETMR. Here, we present and discuss a case of this type. A posterior fossa tumor was found in a five-month-old infant. Histologically, the lesion appeared as an embryonal tumor, lacking multilayered rosettes but showing focal positivity for LIN28A. It did not show \u003cem\u003eC19MC\u003c/em\u003e amplification or \u003cem\u003eDICER1\u003c/em\u003e mutation, yet it clustered within the ETMR non-\u003cem\u003eC19MC\u003c/em\u003e-altered methylation class of the Heidelberg classifier (V12.5) and the ETMR-DICER class of the NIH classifier. Additionally, a \u003cem\u003eYAP1::MAML2\u003c/em\u003e fusion was identified, a finding not yet associated with these methylation classes.\u003c/p\u003e","manuscriptTitle":"YAP1::MAML2 fusion, a newly identified genetic anomaly in a posterior fossa infant tumor, associated with the methylation class “embryonal tumor with multilayered rosettes, non-C19MC- altered” in the Heidelberg central nervous system tumor classifier and “embryonal tumor with multilayered rosettes-DICER” in the NIH classifier","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-22 06:33:02","doi":"10.21203/rs.3.rs-7193504/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-06T18:54:33+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-02T17:41:50+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-28T18:16:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"291626872992128886845026765238583717084","date":"2025-08-12T08:49:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"277011063499778403987905529008104035235","date":"2025-08-10T10:54:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-09T16:17:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-04T02:01:34+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-04T02:00:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"Acta Neuropathologica Communications","date":"2025-07-23T07:38:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"acta-neuropathologica-communications","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anec","sideBox":"Learn more about [Acta Neuropathologica Communications](https://actaneurocomms.biomedcentral.com/)","snPcode":"40478","submissionUrl":"https://submission.springernature.com/new-submission/40478/3","title":"Acta Neuropathologica Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"937c46e4-b4f0-4774-acb6-1048402d4d12","owner":[],"postedDate":"August 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-29T15:59:24+00:00","versionOfRecord":{"articleIdentity":"rs-7193504","link":"https://doi.org/10.1186/s40478-025-02165-y","journal":{"identity":"acta-neuropathologica-communications","isVorOnly":false,"title":"Acta Neuropathologica Communications"},"publishedOn":"2025-12-22 15:57:09","publishedOnDateReadable":"December 22nd, 2025"},"versionCreatedAt":"2025-08-22 06:33:02","video":"","vorDoi":"10.1186/s40478-025-02165-y","vorDoiUrl":"https://doi.org/10.1186/s40478-025-02165-y","workflowStages":[]},"version":"v1","identity":"rs-7193504","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7193504","identity":"rs-7193504","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}