Acta Neuropathologica最新文献

{"title":"Prospective characterization of germline variants in patients with gliomas and glioneuronal tumors","authors":"Subhiksha Nandakumar,&nbsp;Miika Mehine,&nbsp;Yelena Kemel,&nbsp;Chaitanya Bandlamudi,&nbsp;Diana Mandelker,&nbsp;Marc K. Rosenblum,&nbsp;Tejus Bale,&nbsp;Matthias A. Karajannis,&nbsp;Sameer Farouk Sait,&nbsp;Kevin B. Elmore,&nbsp;Kate E. Therkelsen,&nbsp;Walid K. Chatila,&nbsp;Daniel Muldoon,&nbsp;Robert J. Young,&nbsp;Brandon S. Imber,&nbsp;Cameron Brennan,&nbsp;Nelson S. Moss,&nbsp;Kenny K. H. Yu,&nbsp;Viviane Tabar,&nbsp;Shahiba Ogilvie,&nbsp;Anita Bowman,&nbsp;Pallavi Akella,&nbsp;Yun-Te Lin,&nbsp;Igor T. Gavrilovic,&nbsp;Elena Pentsova,&nbsp;Lauren Schaff,&nbsp;Jacqueline Stone,&nbsp;Craig Nolan,&nbsp;Adrienne Boire,&nbsp;Christian Grommes,&nbsp;Bianca D. Santomasso,&nbsp;Eli L. Diamond,&nbsp;Jessica Wilcox,&nbsp;Anna Piotrowski,&nbsp;Thomas J. Kaley,&nbsp;Lisa M. DeAngelis,&nbsp;Ingo K. Mellinghoff,&nbsp;Michael Berger,&nbsp;Nikolaus Schultz,&nbsp;Zsofia K. Stadler,&nbsp;Andrew L. Lin","doi":"10.1007/s00401-025-02935-x","DOIUrl":"10.1007/s00401-025-02935-x","url":null,"abstract":"<div><p>Several tumor predisposition syndromes have been linked to the development of gliomas and glioneuronal tumors (glioma/GNT). For many pathogenic germline variants, the prevalence and clinical significance remain unclear. Germline variants and copy-number variants affecting 76–90 well-established cancer predisposing genes were identified in 2,187 patients with gliomas/GNT, who underwent prospective sequencing of their tumor and a matched normal sample. A germline pathogenic or likely pathogenic (P/LP) mutation was identified in 11% (250/2187, 95% CI 10.1–12.8%). Affected high- and moderate-penetrance genes included <i>BRCA2</i> (<i>n</i> = 11; 0.5%), <i>TP53</i> (<i>n</i> = 8; 0.4%), <i>NF1</i> (<i>n</i> = 8; 0.4%), <i>CHEK2</i> (<i>n</i> = 21, 0.9% excluding common variant I157T), and the mismatch repair (MMR) genes (<i>n</i> = 22, 1.0%). Biallelic inactivation was identified in 8/8 tumors with a germline <i>NF1</i> mutation, 7/8 tumors with a germline <i>TP53</i> alteration, and 10/19 tumors with a heterozygous germline MMR defect. Gliomas/GNT with biallelic inactivation of an MMR gene were characterized by hypermutation, microsatellite instability, and a distinct clinical phenotype. Assessment of zygosity identifies biallelic inactivation of DNA double-strand break repair alterations in a minority of tumors, including <i>BRCA2</i>-deficient gliomas with increased genomic scarring attributable to homologous recombination deficiency, and refutes the contribution of the most common P/LP germline variants. Irrespective of gene, tumors with biallelic inactivation were diagnosed at a younger age than tumors without a germline variant (<i>p</i> = 3.5 × 10^–6) and tumors with a monoallelic alteration (<i>p</i> = 0.00014). In conclusion, germline sequencing identifies a P/LP variant in a high proportion of patients with glioma/GNT. Biallelic inactivation was common in younger patients with germline variants and patients with neurofibromatosis type 1/Li-Fraumeni, but was only present in half of the patients with Lynch syndrome.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02935-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pineal region high-grade neuroepithelial tumors with NTRK fusions map to the novel methylation class “diffuse high-grade glioma, IDH-wild type, subtype E”","authors":"Felipe D’Almeida Costa,&nbsp;João Víctor Alves de Castro,&nbsp;Yuri Merlotti Gomes,&nbsp;Leslie Domenici Kulikowski,&nbsp;Beatriz Wolff,&nbsp;Lauro José Gregianin,&nbsp;Cristovam Scapulatempo Neto,&nbsp;Osama Al Dalahmah,&nbsp;Peter D. Canoll,&nbsp;Jeffrey N. Bruce,&nbsp;Kenneth Aldape,&nbsp;Zied Abdullaev,&nbsp;MacLean P. Nasrallah,&nbsp;Cherish Alex-Wele,&nbsp;Scott Palisoul,&nbsp;George Zanazzi,&nbsp;Madhumala K. Sadanandappa","doi":"10.1007/s00401-025-02934-y","DOIUrl":"10.1007/s00401-025-02934-y","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145021725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In memoriam Prof. Pawel P. Liberski, MD PhD (November 25, 1954–August 19, 2025)","authors":"Herbert Budka","doi":"10.1007/s00401-025-02932-0","DOIUrl":"10.1007/s00401-025-02932-0","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02932-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144998413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TDP-43 dysregulation impairs cholesterol metabolism linked with myelination defects","authors":"Irene García-Toledo,&nbsp;Juan M. Godoy-Corchuelo,&nbsp;Luis C. Fernández-Beltrán,&nbsp;Zeinab Ali,&nbsp;Ariadna Guindo-Arroyo,&nbsp;Irene Jiménez-Coca,&nbsp;Jesús Jiménez-Rodríguez,&nbsp;Karen Javaloyes-García,&nbsp;Marcos Viñuela,&nbsp;Ulises Gómez-Pinedo,&nbsp;Laura Saiz-Aúz,&nbsp;Alberto Rábano,&nbsp;Estela Área-Gómez,&nbsp;Thomas J. Cunningham,&nbsp;Silvia Corrochano","doi":"10.1007/s00401-025-02927-x","DOIUrl":"10.1007/s00401-025-02927-x","url":null,"abstract":"<div><p>TDP-43 is a nuclear protein encoded by the <i>TARDBP</i> gene, which forms pathological aggregates in various neurodegenerative diseases, collectively known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These diseases are characterized by multiple pathological mechanisms, with disruptions in lipid regulatory pathways emerging as a critical factor. However, the role of TDP-43 in the regulation of the brain lipid homeostasis and the potential connection of TDP-43 dysfunction to myelin alterations in TDP-43 proteionopathies remain poorly understood, despite the fact that lipids, particularly cholesterol, comprise nearly 70% of myelin. To investigate the causal relationship between TDP-43 dysfunction and disruptions in brain cholesterol homeostasis, we conducted multi-omics analyses (lipidomics, transcriptomics, and functional splicing) on the frontal cortex from the <i>Tardbp</i>^{<i>M323K/M323K</i>} knock-in mouse model. Lipidomic analysis revealed alterations in lipid pathways related to membrane composition and lipid droplet accumulation, particularly affecting cholesterol-related species. We found higher lipid droplet accumulation in primary fibroblasts derived from these mice, as well as in the brain of the mutant mice. Similarly, the immunohistochemical detection of a lipid droplet marker was higher in the postmortem frontal cortex, gray matter, and white matter of FTLD-TDP patients compared to non-neurological controls. Transcriptomic analyses showed that TDP-43 pathology led to transcriptional dysregulation of genes essential for myelin production and maintenance. We identified impaired cholesterol metabolism, mainly through the downregulation of endogenous cholesterol synthesis, alongside upregulated cholesterol transport pathways, which we further replicated in FTLD-TDP patients transcriptomic datasets. Collectively, our findings suggest that TDP-43 dysfunction disrupts brain cholesterol homeostasis, potentially compromising myelin integrity.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02927-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144934639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Down syndrome and a presenilin 2 variant: dual genetic risk of Alzheimer’s disease","authors":"Jordan Ogg,&nbsp;Nadia Postupna,&nbsp;Laura E. Gibbons,&nbsp;Jeanelle Ariza,&nbsp;Ming Xiao,&nbsp;Luciana M. Fonseca,&nbsp;Suman Jayadev,&nbsp;C. Dirk Keene,&nbsp;Thomas D. Bird,&nbsp;Caitlin S. Latimer","doi":"10.1007/s00401-025-02931-1","DOIUrl":"10.1007/s00401-025-02931-1","url":null,"abstract":"<div><p>Early onset familial Alzheimer’s disease (EOFAD) is rare compared to sporadic AD, but dominant variants in genes involved in amyloid β (Aβ) processing are well-described. One such variant is in the presenilin 2 (<i>PSEN2)</i> gene, N141I, and was first described in a family with Volga German descent. Separately, individuals with Down syndrome (DS) are also at risk for early onset AD, having an extra copy of an amyloid precursor protein gene. While either can drive EOFAD alone, it is extremely rare for both to occur within one individual. Here we describe a unique case of a 48-year-old individual, with both DS and the <i>PSEN2</i> N141I variant. We investigated whether having two high-risk AD variants results in worsened or distinct pathology compared to single variant carriers. Neuropathologic evaluation, quantitative pathology, and spatial proteomic profiling (NanoString Geomx Digital Spatial Profiling) were performed on post-mortem tissue of the index case compared to individuals with DS and N141I variants alone. Analysis in the index case revealed increased total Aβ burden in multiple brain regions compared to the average levels observed in <i>PSEN2</i> carriers and DS cases, but not for hyperphosphorylated tau or neuroinflammatory markers. Index case appeared to have more pronounced Aβ pathological burden than the <i>PSEN2</i> subgroup and was more similar to the DS subgroup in several measurements: the Aβ burden, density of Aβ plaques, fibrillar and dense-core plaques, and the density of ionized calcium binding adaptor molecule 1 (Iba1) labelling in MSTG. As such, it appears that compounded genetic risk for AD was additive for Aβ burden, but not tau or neuroinflammation. This rare case offers new insight into how compounded risk may additively enhance amyloid pathology independently from tau. This underscores the importance of investigating synergistic and additive risk in neurodegenerative disease.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02931-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144934638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare FN1 missense mutations indicate a protective role against Lewy body dementia in APOEε4 homozygous carriers","authors":"Paolo Reho,&nbsp;Anindita Ray,&nbsp;Karri Kaivola,&nbsp;International L. B. D. Genomics Consortium,&nbsp;Badri N. Vardarajan,&nbsp;Haotian Wu,&nbsp;Sonja W. Scholz","doi":"10.1007/s00401-025-02925-z","DOIUrl":"10.1007/s00401-025-02925-z","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02925-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144918649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation analysis reveals an epigenetic signature distinctive of high-grade oligodendroglioma","authors":"Katharina Johanna Weber,&nbsp;Mareike Dettki,&nbsp;Marco Münzberg,&nbsp;Pia Susann Zeiner,&nbsp;Marie-Thérèse Forster,&nbsp;Eike Steidl,&nbsp;Iris Divé,&nbsp;Patrick Nikolaus Harter,&nbsp;Michael Scherer","doi":"10.1007/s00401-025-02926-y","DOIUrl":"10.1007/s00401-025-02926-y","url":null,"abstract":"<div><p>IDH-mutant gliomas represent a subtype of diffuse gliomas that primarily affect patients in early to mid-adolescence. These tumors are classified into three distinct CNS WHO grades of malignancy. Accurate grading is essential for selecting an appropriate treatment maximizing anti-tumor efficacy while minimizing adverse effects. However, grading of oligodendrogliomas with 1p/19q codeletion currently relies on qualitative tumor characteristics that may be influenced by observer subjectivity, sampling bias, and tumor heterogeneity. This study aimed to explore DNA methylation-based tumor deconvolution into latent methylation components (LMCs) to evaluate their potential as objective grading tools in a cohort of 137 IDH-mutant gliomas. LMCs were analyzed in relation to malignancy markers, cellular composition, and underlying methylation signatures of the chromatin landscape. Glioma subtypes were associated with distinct LMCs. Two LMCs correlated with higher cellular density and advanced epigenetic age as well as with microvascular proliferation, necrosis, and epigenetically defined high-grade astrocytoma. The epigenetic patterns defining high-grade astrocytoma or oligodendroglioma, respectively, were similar. Higher-grade oligodendrogliomas, identified by LMC-based grading, were associated with more copy number alterations. Among patients of an external cohort who died during the assessment period, higher LMC1 proportions were associated with poorer overall survival. Therefore, LMCs hold the potential to support IDH-mutant glioma grading by incorporating objective epigenetic markers.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02926-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EGFR alteration is an adverse prognostic factor in IDH-mutant astrocytoma","authors":"Cheyanne C. Slocum,&nbsp;Phuong Nguyen,&nbsp;Meenakshi Vij,&nbsp;Raymund L. Yong,&nbsp;Jorge Samanamud,&nbsp;Satomi Hiya,&nbsp;Carolina Maldonado-Díaz,&nbsp;Melissa Umphlett,&nbsp;Thenzing J. Silva-Hurtado,&nbsp;Kimmo J. Hatanpaa,&nbsp;Mariano S. Viapiano,&nbsp;Matija Snuderl,&nbsp;Kalil G. Abdullah,&nbsp;Samuel K. McBrayer,&nbsp;Dolores Hambardzumyan,&nbsp;Jamie M. Walker,&nbsp;Nadejda M. Tsankova,&nbsp;Timothy E. Richardson","doi":"10.1007/s00401-025-02928-w","DOIUrl":"10.1007/s00401-025-02928-w","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02928-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144868859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic variants in DNAJC7 cause familial amyotrophic lateral sclerosis with the TDP-43 pathology","authors":"Toru Yamashita,&nbsp;Osamu Yokota,&nbsp;Daiki Ousaka,&nbsp;Hongming Sun,&nbsp;Takashi Haraguchi,&nbsp;Ricardo Satoshi Ota-Elliott,&nbsp;Chika Matsuoka,&nbsp;Tomohito Kawano,&nbsp;Hanae Nakashima-Yasuda,&nbsp;Yusuke Fukui,&nbsp;Yumiko Nakano,&nbsp;Ryuta Morihara,&nbsp;Masato Hasegawa,&nbsp;Yasuyuki Hosono,&nbsp;Seishi Terada,&nbsp;Manabu Takaki,&nbsp;Hiroyuki Ishiura","doi":"10.1007/s00401-025-02899-y","DOIUrl":"10.1007/s00401-025-02899-y","url":null,"abstract":"<div><p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. ALS pathology primarily involves the failure of protein quality control mechanisms, leading to the accumulation of misfolded proteins, particularly TAR DNA-binding protein 43 (TDP-43). TDP-43 aggregation is a central pathological feature of ALS. Maintaining protein homeostasis is critical and facilitated by heat shock proteins (HSPs), particularly the HSP40 family, which includes co-chaperones such as DNAJC7. Here, we report a family with three siblings affected by ALS who carry a homozygous c.518dupC frameshift variant in <i>DNAJC7</i>, a member of the HSP40 family. All three patients exhibited progressive muscle weakness, limb atrophy, bulbar palsy, and respiratory failure. Pathological examination revealed degeneration of both upper and lower motor neurons, with phosphorylated TDP-43-positive neuronal cytoplasmic inclusions in the frontal and temporal cortices. Immunoblot analysis were consistent with a type B pattern of phosphorylated TDP-43 in the precentral gyrus. Immunohistochemistry and RNA sequencing analyses demonstrated a substantial reduction in <i>DNAJC7</i> expression at both the protein and RNA levels in affected brain regions. In a TDP-43 cell model, <i>DNAJC7</i> knockdown impaired the disassembly of TDP-43 following arsenite-induced stress, whereas <i>DNAJC7</i> overexpression suppressed the assembly and promoted the disassembly of arsenite-induced TDP-43 condensates. Furthermore, in a zebrafish ALS model, <i>dnajc7</i> knockdown resulted in increased TDP-43 aggregation in motor neurons and reduced survival. To the best of our knowledge, this study provides the first evidence linking biallelic loss-of-function variants in <i>DNAJC7</i> to familial ALS with TDP-43 pathology.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02899-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144825766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diffuse leptomeningeal glioneuronal tumor (DLGNT): a comprehensive clinical and molecular analysis","authors":"Margit K. Mikkelsen,&nbsp;Xiaoyu Li,&nbsp;Kaiwen Yu,&nbsp;Anthony A. High,&nbsp;Haiyan Tan,&nbsp;Larissa V. Furtado,&nbsp;Nalin Leelatian,&nbsp;Jessica Bell,&nbsp;Julia D. Berry,&nbsp;Daniel R. Boué,&nbsp;Franklin Chien,&nbsp;Scott L. Coven,&nbsp;Michael C. Dewan,&nbsp;Jason Fangusaro,&nbsp;Jessica B. Foster,&nbsp;Lindsey Hoffman,&nbsp;Julia K. Kofler,&nbsp;Trisha Larkin,&nbsp;Margot Lazow,&nbsp;Adriana May,&nbsp;Bret C. Mobley,&nbsp;Dolly Noun,&nbsp;Benjamin Posorske,&nbsp;Jonathan Schwartz,&nbsp;Ivanna Sheila,&nbsp;Susan Spiller,&nbsp;Ryuma Tanaka,&nbsp;Ibrahim Qaddoumi,&nbsp;Christopher L. Tinkle,&nbsp;Junmin Peng,&nbsp;Giles W. Robinson,&nbsp;Daniel C. Moreira,&nbsp;Jason Chiang","doi":"10.1007/s00401-025-02924-0","DOIUrl":"10.1007/s00401-025-02924-0","url":null,"abstract":"<div><p>Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are rare, and optimal treatment remains undefined. We aim to comprehensively characterize their clinical and molecular features, offering granular insights into presentations and therapies to elucidate prognostic factors and therapeutic targets. Histologic, molecular, and clinical data of 30 patients with DLGNT were analyzed. Median age at diagnosis was 7.5 years (range: 0.9–20 years). Disease was localized at diagnosis in 16 patients (53.3%), predominantly in the spinal cord (14/16, 87.5%). <i>KIAA1549</i>::<i>BRAF</i> fusion occurred in 27 (96.4%) of 28 patients. DNA methylation profiling of 23 tumors classified 4 (17.4%) as DLGNT MC-1, 3 (13.0%) as DLGNT MC-2, and 16 (69.6%) as DLGNT, but not to a specific subclass. Median follow-up was 57.5 months. Most patients (90.0%) received adjuvant therapy. Chemotherapy was the first-line adjuvant therapy in 19 patients (70.4%); targeted therapy in 5 patients (18.5%), and radiotherapy in 2 patients (7.4%). Median progression-free survival (PFS) after first chemotherapy, targeted therapy, or radiotherapy was 44 (1–77) months, 18 (4–39) months, and 16.5 (9–23) months, respectively. Five-year PFS was 15.9% ± 8.0, and 5 year overall survival (OS) was 83.3% ± 8.8. Patients older than 9 years at diagnosis (<i>p</i> = 0.002) and those with MC-2 (<i>p</i> = 0.04) had worse 5 year OS. Multi-omic analysis revealed simultaneous activation of multiple signaling pathways, which may serve as potential therapeutic targets. DLGNT remains challenging to treat, with poor outcomes across modalities. Further investigation of treatment, including targeted therapies addressing activated pathways, is needed to improve patient survival.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02924-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144810969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}