{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:17:28Z","timestamp":1790777848157,"version":"4.1.0"},"reference-count":17,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,8,23]],"date-time":"2025-08-23T00:00:00Z","timestamp":1755907200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,23]],"date-time":"2025-08-23T00:00:00Z","timestamp":1755907200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Natural Science Foundation of Beijing Municipality,China","award":["7254365"],"award-info":[{"award-number":["7254365"]}]},{"DOI":"10.13039\/501100010270","name":"The capital health research and development of special","doi-asserted-by":"crossref","award":["2022-2-2015"],"award-info":[{"award-number":["2022-2-2015"]}],"id":[{"id":"10.13039\/501100010270","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100010270","name":"The capital health research and development of special","doi-asserted-by":"crossref","award":["2022-2-2015"],"award-info":[{"award-number":["2022-2-2015"]}],"id":[{"id":"10.13039\/501100010270","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005090","name":"Beijing Nova program","doi-asserted-by":"crossref","award":["Z201100006820149"],"award-info":[{"award-number":["Z201100006820149"]}],"id":[{"id":"10.13039\/501100005090","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["acta neuropathol commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>H3K27-altered diffuse midline glioma (DMG) is a fatal disease, including four subtypes H3.3-mutant, H3.1\/H3.2-mutant, H3-wildtype with EZHIP overexpression, and <jats:italic>EGFR<\/jats:italic>-mutant. <jats:italic>H3F3B<\/jats:italic>, another gene encoding histone H3.3 in addition to <jats:italic>H3F3A<\/jats:italic>, was ever reported to be mutated in DMGs. However, the clinical and molecular characteristics of <jats:italic>H3F3B<\/jats:italic>-mutant DMGs is yet understood. The clinical and radiological information of 9 patients with <jats:italic>H3F3B<\/jats:italic>-mutant DMG were retrospectively collected. Tumor specimens underwent DNA methylation profiling and next-generation sequencing. All tumors harbored somatic <jats:italic>H3F3B<\/jats:italic> p.K27I mutation. Average patient age was 46\u2009\u00b1\u20096.86 years, 6 tumors located in spinal cord, 5 tumors involved brainstem and 2 arose in the thalamus. Immunohistochemistry showed these tumors exhibited completely or mosaic-like loss of H3K27me3 expression. Unsupervised t-distributed stochastic neighbor embedding (t-SNE) analysis of DNA methylation profiles showed that <jats:italic>H3F3B<\/jats:italic>-mutant DMGs formed a unique methylation cluster separate from other gliomas with H3K27me3 loss and DMGs with canonical histone H3 mutation. <jats:italic>PPM1D<\/jats:italic> and <jats:italic>NF1<\/jats:italic> were frequently mutated in <jats:italic>H3F3B<\/jats:italic>-mutant DMGs. Survival analysis showed that <jats:italic>H3F3B<\/jats:italic>-mutant DMGs had poor prognosis comparable to H3K27M-mutant DMGs. Taken together, <jats:italic>H3F3B<\/jats:italic> mutation also cause a loss of H3K27 trimethylation in DMGs and result in poor prognosis. The distinct characteristics of DNA methylation and mutational spectrum between <jats:italic>H3F3B<\/jats:italic>-mutant DMGs and canonical H3K27M-mutant DMGs might suggest divergent underlying mechanism of gliomagenesis.<\/jats:p>","DOI":"10.1186\/s40478-025-02101-0","type":"journal-article","created":{"date-parts":[[2025,8,23]],"date-time":"2025-08-23T05:01:18Z","timestamp":1755925278000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["H3F3B p.K27I-mutant diffuse midline glioma is a distinct subtype of H3K27-altered diffuse midline glioma"],"prefix":"10.1186","volume":"13","author":[{"given":"Lei","family":"Cheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongfang","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ni","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyong","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingwen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuowei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueling","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dehong","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianghong","family":"Teng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengzeng","family":"Jian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leiming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,23]]},"reference":[{"key":"2101_CR1","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1007\/s11060-022-04024-5","volume":"158","author":"CA L\u00f3pez-P\u00e9rez","year":"2022","unstructured":"L\u00f3pez-P\u00e9rez CA, Franco-Mojica X, Villanueva-Gaona R (2022) Adult diffuse midline gliomas h3 k27-altered: review of a redefined entity. J NEURO-ONCOL 158:369\u2013378","journal-title":"J NEURO-ONCOL"},{"key":"2101_CR2","first-page":"1231","volume":"23","author":"DN Louis","year":"2021","unstructured":"Louis DN, Perry A, Wesseling P (2021) The 2021 WHO classification of tumors of the central nervous system: a summary. Neurooncology 23:1231\u20131251","journal-title":"Neurooncology"},{"key":"2101_CR3","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1007\/s00401-020-02142-w","volume":"139","author":"D Castel","year":"2020","unstructured":"Castel D, Kergrohen T, Tauzi\u00e8de-Espariat A (2020) Histone h3 wild-type DIPG\/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 Inhibition beyond h3-k27m mutation. ACTA NEUROPATHOL 139:1109\u20131113","journal-title":"ACTA NEUROPATHOL"},{"key":"2101_CR4","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1007\/s00401-020-02155-5","volume":"139","author":"G Mondal","year":"2020","unstructured":"Mondal G, Lee JC, Ravindranathan A (2020) Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase Inhibition. ACTA NEUROPATHOL 139:1071\u20131088","journal-title":"ACTA NEUROPATHOL"},{"key":"2101_CR5","doi-asserted-by":"crossref","unstructured":"Diaz M, Rana S, Silva Correia CE (2023) Leptomeningeal disease in histone-mutant gliomas. Neuro-Oncology Adv ;5","DOI":"10.1093\/noajnl\/vdad068"},{"key":"2101_CR6","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1007\/s00401-019-02072-2","volume":"138","author":"EA Sloan","year":"2019","unstructured":"Sloan EA, Cooney T, Oberheim Bush NA (2019) Recurrent non-canonical histone h3 mutations in spinal cord diffuse gliomas. ACTA NEUROPATHOL 138:877\u2013881","journal-title":"ACTA NEUROPATHOL"},{"key":"2101_CR7","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.1007\/s10637-021-01116-3","volume":"39","author":"Y Wang","year":"2021","unstructured":"Wang Y, Xu J, Luo N (2021) Successful treatment of an adult patient with diffuse midline glioma employing Olaparib combined with bevacizumab. INVEST NEW DRUG 39:1432\u20131435","journal-title":"INVEST NEW DRUG"},{"key":"2101_CR8","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1007\/s00401-023-02609-6","volume":"146","author":"EA Williams","year":"2023","unstructured":"Williams EA, Brastianos PK, Wakimoto H (2023) A comprehensive genomic study of 390 h3f3a-mutant pediatric and adult diffuse high-grade gliomas, CNS WHO grade 4. ACTA NEUROPATHOL 146:515\u2013525","journal-title":"ACTA NEUROPATHOL"},{"key":"2101_CR9","doi-asserted-by":"crossref","unstructured":"Cheng L, Wang L, Yao Q (2021) Clinicoradiological characteristics of primary spinal cord h3 k27m-mutant diffuse midline glioma. J NEUROSURG-SPINE :1\u201312","DOI":"10.3171\/2021.4.SPINE2140"},{"key":"2101_CR10","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1007\/s11060-021-03890-9","volume":"155","author":"HG Vuong","year":"2021","unstructured":"Vuong HG, Le HT, Ngo TNM (2021) H3k27m-mutant diffuse midline gliomas should be further molecularly stratified: an integrated analysis of 669 patients. J NEURO-ONCOL 155:225\u2013234","journal-title":"J NEURO-ONCOL"},{"key":"2101_CR11","doi-asserted-by":"publisher","first-page":"6996","DOI":"10.1002\/cam4.3364","volume":"9","author":"YW Zhang","year":"2020","unstructured":"Zhang YW, Chai RC, Cao R (2020) Clinicopathological characteristics and survival of spinal cord Astrocytomas. CANCER MED-US 9:6996\u20137006","journal-title":"CANCER MED-US"},{"key":"2101_CR12","doi-asserted-by":"crossref","unstructured":"Lebrun L, Mel\u00e9ndez B, Blanchard O (2020) Clinical, radiological and molecular characterization of intramedullary Astrocytomas. ACTA NEUROPATHOL COM, p 8","DOI":"10.1186\/s40478-020-00962-1"},{"key":"2101_CR13","doi-asserted-by":"crossref","unstructured":"Chen LH, Pan C, Diplas BH (2020) The integrated genomic and epigenomic landscape of brainstem glioma. NAT COMMUN ;11","DOI":"10.1038\/s41467-020-16682-y"},{"key":"2101_CR14","doi-asserted-by":"publisher","first-page":"389","DOI":"10.4143\/crt.2020.694","volume":"53","author":"C Park","year":"2021","unstructured":"Park C, Kim TM, Bae JM (2021) Clinical and genomic characteristics of adult diffuse midline glioma. CANCER RES TREAT 53:389\u2013398","journal-title":"CANCER RES TREAT"},{"key":"2101_CR15","doi-asserted-by":"publisher","first-page":"1628","DOI":"10.3171\/2022.2.JNS211920","volume":"137","author":"Y Wang","year":"2022","unstructured":"Wang Y, Pan C, Xie M (2022) Adult diffuse intrinsic Pontine glioma: clinical, radiological, pathological, molecular features, and treatments of 96 patients. J NEUROSURG 137:1628\u20131638","journal-title":"J NEUROSURG"},{"key":"2101_CR16","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1002\/path.6084","volume":"260","author":"L Cheng","year":"2023","unstructured":"Cheng L, Zhang F, Zhao X (2023) Mutational landscape of primary spinal cord Astrocytoma. J Pathol 260:317\u2013328","journal-title":"J Pathol"},{"key":"2101_CR17","doi-asserted-by":"crossref","unstructured":"Chai RC, Yan H, An SY (2023) Genomic profiling and prognostic factors ofh3 k27m -mutant spinal cord diffuse glioma. BRAIN PATHOL ;33","DOI":"10.1111\/bpa.13153"}],"container-title":["Acta Neuropathologica Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-025-02101-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40478-025-02101-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-025-02101-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T20:14:40Z","timestamp":1757448880000},"score":1,"resource":{"primary":{"URL":"https:\/\/actaneurocomms.biomedcentral.com\/articles\/10.1186\/s40478-025-02101-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,23]]},"references-count":17,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["2101"],"URL":"https:\/\/doi.org\/10.1186\/s40478-025-02101-0","relation":{},"ISSN":["2051-5960"],"issn-type":[{"value":"2051-5960","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,23]]},"assertion":[{"value":"21 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 August 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was approved by the ethics committee of Xuanwu Hospital, Capital Medical University and was conducted in full compliance with all principles of the Helsinki Declaration. Written informed consent for participation was obtained from the patients or their parents.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent for publication was obtained from the patients or their parents.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"183"}}