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One proposed tumor type, CNS tumor with <jats:italic>BRD4::LEUTX<\/jats:italic> fusion, has been described. As only a few CNS tumors with <jats:italic>BRD4::LEUTX<\/jats:italic> fusions have been described, we herein characterize a cohort of 9 such cases (4 new, 5 previously published) to further describe their clinicopathologic and molecular features. We demonstrate that CNS embryonal tumor with <jats:italic>BRD4::LEUTX<\/jats:italic> fusion comprises a well-defined methylation class\/cluster. We find that patients are young (4\u00a0years or younger), with large tumors at variable locations, and frequently with evidence of leptomeningeal\/cerebrospinal fluid (CSF) dissemination. Histologically, tumors were highly cellular with high-grade embryonal features. Immunohistochemically, 5\/5 cases showed synaptophysin and 4\/5 showed OLIG2 expression, thus overlapping with CNS neuroblastoma, <jats:italic>FOXR2<\/jats:italic>-activated. DNA copy number profiles were generally flat; however, two tumors had chromosome 1q gains. No recurring genomic changes, besides the presence of the fusion, were found. The <jats:italic>LEUTX<\/jats:italic> portion of the fusion transcript was constant in all cases assessed, while the <jats:italic>BRD4<\/jats:italic> portion varied but included a domain with proto-oncogenic activity in all cases. Two patients with clinical follow up available had tumors with excellent response to chemotherapy. Two of our patients were alive without evidence of recurrence or progression after gross total resection and chemotherapy at 16 and 33\u00a0months. One patient relapsed, and the last of our four patients died of disease one month after diagnosis. Overall, this case series provides additional evidence for this as a distinct tumor type defined by the presence of a specific fusion as well as a distinct DNA methylation signature. Studies on larger series are required to further characterize these tumors.<\/jats:p>","DOI":"10.1186\/s40478-024-01746-7","type":"journal-article","created":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T09:02:23Z","timestamp":1710752543000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Molecular and clinicopathologic characteristics of CNS embryonal tumors with BRD4::LEUTX fusion"],"prefix":"10.1186","volume":"12","author":[{"given":"Felipe","family":"Andreiuolo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina K.","family":"Ferrone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharika","family":"Rajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arie","family":"Perry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekin","family":"Guney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Cham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Giannini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angus","family":"Toland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Willard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea Silveira","family":"de Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Dazelle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye-Jung","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omkar","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Conway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Coley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Dampier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zied","family":"Abdullaev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Drew","family":"Pratt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick J.","family":"Cimino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Quezado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5119-7550","authenticated-orcid":false,"given":"Kenneth","family":"Aldape","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,18]]},"reference":[{"key":"1746_CR1","doi-asserted-by":"publisher","first-page":"S16","DOI":"10.1093\/neuonc\/noab143","volume":"23","author":"D Pratt","year":"2021","unstructured":"Pratt D, Sahm F, Aldape K (2021) DNA methylation profiling as a model for discovery and precision diagnostics in neuro-oncology. 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