Acta Neuropathologica Communications最新文献

{"title":"Neurotransmitter power plays: the synaptic communication nexus shaping brain cancer.","authors":"Jayanta Mondal, Jason T Huse","doi":"10.1186/s40478-025-02009-9","DOIUrl":"10.1186/s40478-025-02009-9","url":null,"abstract":"<p><p>Gliomas and brain metastases are notorious for their dismal prognosis and low survival rates, a challenge exacerbated by our incomplete grasp of the complex dynamics that govern brain cancers. Recently, a groundbreaking paradigm shift has emerged, highlighting the crucial role of synaptic communication between neurons and brain tumor cells in reshaping neuronal signaling to favor tumor growth. This review delves into the pivotal interplay of synaptic mechanisms, focusing on excitatory glutamatergic and inhibitory GABAergic pathways. Glutamatergic synapses utilize glutamate to propagate excitatory signals, while GABAergic synapses employ gamma-aminobutyric acid (GABA) to inhibit neuronal firing. Glutamatergic signaling can be broadly classified into ionotropic (NMDAR, AMPAR and kainite receptors) and metabotropic subtypes. The harmonious orchestration of these synaptic types is essential for normal brain function, and their dysregulation is implicated in neurodegenerative disorders such as Alzheimer's disease and epilepsy. Emerging evidence reveals that glioma and brain metastatic cells exploit these synaptic pathways and neurotransmitters to enhance their proliferation and survival. In this review, we will first explore the intricate mechanisms underlying glutamatergic and GABAergic signaling. Next, we will summarize recent advancements in understanding how brain cancer cells hijack these pathways to their advantage. Finally, we will propose novel therapeutic strategies aimed at disrupting the aberrant neuron-tumor synaptic communication, offering potential treatment strategies for combating these otherwise incurable brain cancers.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"85"},"PeriodicalIF":6.2,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholesterol-activated stress granules reduce the membrane localization of DRD2 and promote prolactinoma dopamine agonists resistance.","authors":"Yuyang Peng, Huachun Yin, Xiangdong Pei, Yuan Zhang, Chengcheng Wang, Xin Zheng, Hong Liang, Hui Yang, Song Li","doi":"10.1186/s40478-025-01986-1","DOIUrl":"10.1186/s40478-025-01986-1","url":null,"abstract":"<p><p>Prolactinoma is the most prevalent pituitary neuroendocrine tumor and dopamine agonists (DAs) targeting dopamine D2 receptor (DRD2) are recommended as the first-line treatment. However, varying degrees of DA resistance limit patient benefit. Our study used transcriptome sequencing of surgical tumor samples and found abnormal cholesterol metabolism in prolactinoma, especially in DA-resistant tumors. We found that cholesterol significantly enhanced the resistance of prolactinoma MMQ cell lines to cabergoline in vitro and in vivo xenografts. Further, cholesterol did not affect the total protein level of DRD2, but changed the distribution of DRD2 with downregulation of its membrane abundance and upregulation of cytoplasmic localization. Mechanistically, immunoprecipitation combined with mass spectrometry revealed cholesterol increased binding affinity between DRD2 and stress granules (SGs) core proteins, such as G3BP1. Western blot experiment of G3BP1 and fluorescent probe were used to confirm the formation of SGs after cholesterol treatment in MMQ cells and tumor xenografts, as well as in surgical tumor samples. Interfering the formation of SGs by overexpressing of USP10 and using the small molecule ISRIB reversed cholesterol's effect on DRD2 cellular distribution and DA resistance in MMQ cells. Finally, a non-specificity inhibitor of SGs, anisomycin identified by drug repositioning analysis, could attenuate cholesterol-induced cabergoline resistance in vitro. Taken together, our findings suggest that abnormal cholesterol metabolism reduces DRD2 membrane localization via stress granules formation, which may be an important reason for the DA resistance of prolactinoma patients.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"84"},"PeriodicalIF":6.2,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12023431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Premature skeletal muscle aging in VPS13A deficiency relates to impaired autophagy.","authors":"Veronica Riccardi, Carlo Fiore Viscomi, Marco Sandri, Angelo D'Alessandro, Monika Dzieciatkowska, Daniel Stephenson, Enrica Federti, Andreas Hermann, Leonardo Salviati, Angela Siciliano, Immacolata Andolfo, Seth L Alper, Jacopo Ceolan, Achille Iolascon, Gaetano Vattemi, Adrian Danek, Ruth H Walker, Alexander Mensch, Markus Otto, Marcus Deschauer, Moritz Armbrust, Cristiane Beninca', Valentina Salari, Paolo Fabene, Kevin Peikert, Lucia De Franceschi","doi":"10.1186/s40478-025-01997-y","DOIUrl":"10.1186/s40478-025-01997-y","url":null,"abstract":"<p><p>VPS13A disease (chorea-acanthocytosis), is an ultra-rare autosomal recessive neurodegenerative disorder caused by mutations of the VPS13A gene encoding Vps13A. Increased serum levels of the muscle isoform of creatine kinase associated with often asymptomatic muscle pathology are among the poorly understood early clinical manifestations of VPS13A disease. Here, we carried out an integrated analysis of skeletal muscle from Vps13a^-/- mice and from VPS13A disease patient muscle biopsies. The absence of Vps13A impaired autophagy, resulting in pathologic metabolic remodeling characterized by cellular energy depletion, increased protein/lipid oxidation and a hyperactivated unfolded protein response. This was associated with defects in myofibril stability and the myofibrillar regulatory proteome, with accumulation of the myocyte senescence marker, NCAM1. In Vps13a^-/- mice, the impairment of autophagy was further supported by the lacking effect of starvation alone or in combination with colchicine on autophagy markers. As a proof of concept, we showed that rapamycin treatment rescued the accumulation of terminal phase autophagy markers LAMP1 and p62 as well as NCAM1, supporting a connection between impaired autophagy and accelerated aging in the absence of VPS13A. The premature senescence was also corroborated by local activation of pro-inflammatory NF-kB-related pathways in both Vps13a^-/- mice and patients with VPS13A disease. Our data link for the first time impaired autophagy and inflammaging with muscle dysfunction in the absence of VPS13A. The biological relevance of our mouse findings, supported by human muscle biopsy data, shed new light on the role of VPS13A in muscle homeostasis.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"83"},"PeriodicalIF":6.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12023462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-grade astrocytoma with piloid features: a single-institution case series and literature review.","authors":"Eric A Goethe, Subhiksha Srinivasan, Swaminathan Kumar, Sujit S Prabhu, Maria A Gubbiotti, Sherise D Ferguson","doi":"10.1186/s40478-025-01987-0","DOIUrl":"10.1186/s40478-025-01987-0","url":null,"abstract":"<p><p>High-grade astrocytoma with piloid features (HGAP) is a recently described primary brain tumor and the first requiring a specific methylation pattern for diagnosis, as its histologic features are often compatible with other tumors such as glioblastoma (GBM). Characterized by molecular alterations in CDKN2A/B, NF1, BRAF, FGFR1, and ATRX, they may be located anywhere in the CNS but show a predilection for the posterior fossa. Reports are limited to retrospective case series, and the standard of care is not yet established. We performed a retrospective review of electronic medical records of all patients with HGAP at our institution. Records were queried for demographic, radiographic, clinical, surgical, pathologic, and outcome data. Eighteen patients were included with a median 17.1 months follow-up. Of these, 12 (63.2%) were women with a mean age of 43 years (range 24-67). The most common tumor locations were the cerebellum (8 patients, 42.1%) and thalamus (6 patients, 31.6%). On imaging, tumors were most commonly homogeneously contrast-enhancing (10 patients, 52.6%) or rim enhancing with central necrosis (5 patients, 26.3%). Ten patients (52.6%) underwent biopsy, while nine (47.4%) underwent resection, of which four (44.4%) underwent gross total resection. Adjuvant therapy included radiation in 16 patients (88.9%) and systemic treatment in 16 patients (88.9%). The initial systemic treatment was temozolomide in 14 patients (77.8%). One patient received upfront trametinib (a MEK1 inhibitor), and one patient received upfront dabrafenib (a BRAF inhibitor). At last follow up, 11 patients (57.9%) had progressive disease. Median progression-free survival (PFS) was 5.4 months (range 1.6-28.2 months), and median overall survival (OS) had not been reached. HGAP is a newly described rare glial tumor without an established standard of care. Its aggressive behavior and targetable mutations warrant further investigation regarding predictors of outcome for this entity.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"82"},"PeriodicalIF":6.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Establishment of a patient-derived 3D in vitro meningioma model in xeno-free hydrogel for clinical applications.","authors":"Mikkel Schou Andersen, Aaraby Yoheswaran Nielsen, Martin Wirenfeldt, Jeanette Krogh Petersen, Morten Winkler Møller, Christopher L Powell, Anavaleria Castro, Grayson Herrgott, Tiit Mathiesen, Charlotte Aaberg Poulsen, Birgitte Brinkmann Olsen, Henning Bünsow Boldt, Christian Bonde Pedersen, Bo Halle, Frantz Rom Poulsen","doi":"10.1186/s40478-025-02008-w","DOIUrl":"10.1186/s40478-025-02008-w","url":null,"abstract":"<p><strong>Background: </strong>Meningiomas exhibit a complex biology that, despite notable successes in preclinical studies, contributes to the failures of pharmaceutical clinical trials. Animal models using patient tumor cells closely mimic in vivo conditions but are labor-intensive, costly, and unsuitable for high-throughput pharmaceutical testing. In comparison, monolayer cell models (two-dimensional, 2D) are cost-efficient but lack primary tumor cell-cell interactions, potentially overestimating treatment effects. Three-dimensional (3D) models offer an alternative through more precise mimicking of tumor morphology and physiology than 2D models and are less costly than in vivo methods. Here, we aimed to establish a 3D cell model in a solid xeno-free medium using patient-derived tumors, thus creating a bench-to-clinic pathway for personalized pharmaceutical testing.</p><p><strong>Methods: </strong>Four WHO grade 1 and one WHO grade 2 (third-passage, fresh) and 12 WHO grade 1 patient-derived meningioma cells (sixth-passage, frozen) and the malignant IOMM-Lee cell line were used to establish 2D and 3D models. The 3D model was developed using a solid xeno-free medium. After 3 months for the primary tumor and 13 days for the IOMM-Lee cell line, the 3D models were extracted and assessed using histology, immunohistochemistry, and epigenetic analyses (EPICv2 array) on five pairs to evaluate their structural fidelity, cellular composition, and epigenetic landscape compared to the original tumor.</p><p><strong>Results: </strong>None of the frozen samples successfully generated 3D models. Models from fresh meningioma samples were more immunohistochemically similar to the primary tumors compared to 2D models, particularly regarding proliferation. 3D models displayed loss of fibrous tissue. All 3D models had similar copy number variation profiles, visually. Genome-wide DNA methylation level patterns were similar between pairs of 3D models and primary tumors. Correlation plots between CpG methylation levels showed high congruency between primary meningiomas and their corresponding 3D models for all samples (R > 0.95).</p><p><strong>Conclusions: </strong>Our patient-derived 3D meningioma models closely mimicked primary tumors in terms of cell morphology, immunohistochemical markers and genome-wide DNA methylation patterns, providing a cost-effective and accessible alternative to in vivo models. This approach has the potential to facilitate personalized treatment strategies for patients requiring additional therapy beyond surgery.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"81"},"PeriodicalIF":6.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Blocking peptidyl arginine deiminase 4 confers neuroprotective effect in the post-ischemic brain through both NETosis-dependent and -independent mechanisms.","authors":"Song-I Seol, Sang-A Oh, Dashdulam Davaanyam, Ja-Kyeong Lee","doi":"10.1186/s40478-025-01992-3","DOIUrl":"https://doi.org/10.1186/s40478-025-01992-3","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"80"},"PeriodicalIF":6.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12010573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophil infiltration and microglial shifts in sepsis induced preterm brain injury: pathological insights.","authors":"Jinjin Zhu, Tiantian He, Ziwei Huang, Wenkai Yu, Jinnan Lu, Shan Zhang, Xiaoli Zhang, Huifang Dong, Yiran Xu, Xiaoyang Wang, Changlian Zhu","doi":"10.1186/s40478-025-02002-2","DOIUrl":"10.1186/s40478-025-02002-2","url":null,"abstract":"<p><p>Preterm sepsis is a major contributor to brain injury and long-term neurodevelopmental impairments, but its molecular mechanisms remain poorly understood. This study integrated clinical and experimental approaches to investigate the pathological changes linking systemic inflammation to brain injury in preterm infants. Transcriptomic analysis of septic preterm infants' peripheral blood revealed upregulated immune, metabolic, and inflammatory pathways, suggesting a link between systemic and brain inflammation. Using P2 mice, we established a preterm white matter injury model through multiple doses of lipopolysaccharide, observing dose-dependent developmental delays, brain inflammation, and long-term behavioral deficits. Integrative analyses of peripheral blood and brain samples from both mice and preterm infants revealed consistent chemokine alterations and immune cell infiltration across peripheral and central compartments, highlighting the significant involvement of neutrophil extracellular traps in preterm brain injury. Furthermore, microglia exhibited significant transcriptional changes during the acute phase, accompanied by metabolic reprogramming from oxidative phosphorylation to glycolysis, with suggested involvement of Pgk1 and Pgam1. This shift intensified with escalating inflammation, along with PANoptosis-related gene upregulation, ultimately associated with microglial cell death. Collectively, these findings provide pathological insights into the immunometabolic alterations underlying sepsis-induced preterm brain injury and suggest potential targets for future therapeutic interventions to mitigate long-term neurodevelopmental deficits.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"79"},"PeriodicalIF":6.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12010587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biological profile of breast cancer brain metastasis.","authors":"Li Liu, Yuan He, Hongyu Du, Min Tang, Tingting Wang, Jieren Tan, Lisha Zha, Li Yang, Milad Ashrafizadeh, Yu Tian, Hui Zhou","doi":"10.1186/s40478-025-01983-4","DOIUrl":"10.1186/s40478-025-01983-4","url":null,"abstract":"<p><p>Breast cancer is one of the leading causes of death worldwide. The aggressive behaviour of breast tumor results from their metastasis. Notably, the brain tissue is one of the common regions of metastasis, thereby reducing the overall survival of patients. Moreover, the metastatic tumors demonstrate poor response or resistance to therapies. In addition, breast cancer brain metastasis provides the poor prognosis of patients. Therefore, it is of importance to understand the mechanisms in breast cancer brain metastasis. Both cell lines and animal models have been developed for the evaluation of breast cancer brain metastasis. Moreover, different tumor microenvironment components and other factors such as lymphocytes and astrocytes can affect brain metastasis. The breast cancer cells can disrupt the blood-brain barrier (BBB) during their metastasis into brain, developing blood-tumor barrier to enhance carcinogenesis. The breast cancer brain metastasis can be increased by the dysregulation of chemokines, STAT3, Wnt, Notch and PI3K/Akt. On the other hand, the effective therapeutics have been developed for the brain metastasis such as introduction of nanoparticles. Moreover, the disruption of BBB by ultrasound can increase the entrance of bioactive compounds to the brain tissue. In order to improve specificity and selectivity, the nanoparticles for the delivery of therapeutics and crossing over BBB have been developed to suppress breast cancer brain metastasis.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"78"},"PeriodicalIF":6.2,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12008903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VOPP1::EGFR fusion is associated with NFκB pathway activation in a glioneural tumor with histological features of ganglioglioma.","authors":"Max Braune, Mathias Stiller, Cordula Scherlach, Florian Wilhelmy, Katja Jähne, Wolf C Müller, Alonso Barrantes-Freer","doi":"10.1186/s40478-025-01994-1","DOIUrl":"10.1186/s40478-025-01994-1","url":null,"abstract":"<p><p>Glioneural tumors are primary brain tumors that consist of both neural and glial neoplastic cells, often presenting with seizures and primarily affecting children and young adults. Specifically, gangliogliomas are composed of neoplastic ganglion and glial cells, accompanied by other characteristic histological features such as lymphoid cuffing, eosinophilic granular bodies, and Rosenthal fibers. Oncogenic driver mutations and gene fusions have been shown to be of prognostic significance in gangliogliomas and can offer potential therapeutic targets. Typical molecular alterations are mitogen-activated protein kinase (MAPK) pathway activations with BRAF p.V600E being the most frequent one. Here, we report for the first time a gene fusion between epidermal growth factor receptor (EGFR) and vesicular, overexpressed in cancer, prosurvival protein 1 (VOPP1) as a potential oncogenic driver in a glioneuronal tumor morphologically resembling ganglioglioma. VOPP1::EGFR fusion associated with the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling. Furthermore, we provide histological and epigenetic findings and clinical outcome. The case expands the known molecular spectrum of oncogenic drivers in glioneuronal tumors and provides a link to potentially prognostic and therapeutically relevant alterations.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"76"},"PeriodicalIF":6.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characteristics and outcomes of diffuse non-midline gliomas with H3F3A gene mutation in the Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network): multicenter retrospective cohort study.","authors":"Hirokazu Nakatogawa, Junya Fukai, Hiroshi Kawaji, Nobuhide Hayashi, Ema Yoshioka, Yoshinori Kodama, Kosuke Nakajo, Takehiro Uda, Yoshiki Arakawa, Shigeki Takada, Noriyuki Kijima, Kenichi Ishibashi, Takeshi Okuda, Yukihiko Sonoda, Shiro Ohue, Hideyuki Arita, Masahide Matsuda, Tadateru Fukami, Takahiro Tomita, Akihiro Inoue, Takamune Achiha, Hideki Kashiwagi, Daisuke Kanematsu, Asako Katsuma, Miho Sumida, Tomoko Shofuda, Masayuki Mano, Manabu Kinoshita, Kanji Mori, Chikanori Inenaga, Yonehiro Kanemura","doi":"10.1186/s40478-025-01989-y","DOIUrl":"10.1186/s40478-025-01989-y","url":null,"abstract":"<p><p>Diffuse gliomas with H3F3A gene mutation such as H3.3 K27M and G34R/V are infrequently found in the cerebral hemisphere. These tumors may be called histone H3 K27M-mutant diffuse non-midline gliomas (NDMG) or H3 G34-mutant diffuse hemispheric gliomas (DHG), respectively. We investigated the clinical, radiological and molecular characteristics and treatment outcomes of patients with H3 K27-mutant NDMG compared with those with H3 G34-mutant DHG. We collected cases of histone H3-mutant diffuse glioma at non-midline location that were enrolled in the Kansai Molecular Diagnosis Network for CNS Tumors. The clinical, radiological and pathological characteristics and DNA methylation were retrospectively analyzed and then compared between cases of NDMG and DHG. We evaluated various factors to examine their effects on overall survival. Included in this study were 16 patients with H3 K27M-mutant NDMG and nine patients with H3 G34R/V-mutant DHG. Patients with NDMG were older than those with DHG (median age: 45 vs. 25 years old). Overall survival times of patients with NDMG were comparable to those of DHG (median overall survival: 20.0 vs. 22.5 months). Female sex, preoperative Karnofsky performance status score ≥ 80 and extensive surgical resection tended be related to better prognoses in the patients with these tumors. H3 K27M-mutant NDMGs were shown to possess similar DNA methylation properties to H3 K27M-mutant DMGs. Diffuse gliomas harboring histone H3 K27M mutation can arise in the cerebral hemisphere in older adults. These findings suggest that H3 K27M-mutant NDMGs show different clinical manifestations to H3 K27M-mutant DMGs and H3 G34R/V-mutant DHGs, despite having similar molecular properties to H3 K27M-mutant DMGs.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"77"},"PeriodicalIF":6.2,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12001451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}