Acta Neuropathologica Communications最新文献

{"title":"Molecular characteristics of isocitrate dehydrogenase 1 R132C-mutant diffuse gliomas: association with TP53 alterations and Li-Fraumeni syndrome.","authors":"Shinji Yamashita, Fumitaka Matsumoto, Kiyotaka Saito, Masato Hidaka, Souma Arikawa, Tomoki Kawano, Tomohiro Kawano, Mitsuru Tamura, Hironobu Okuyama, Nayuta Higa, Ryosuke Hanaya, Toshiaki Akahane, Akihide Tanimoto, Yuichiro Sato, Yoshiko Okita","doi":"10.1186/s40478-026-02369-w","DOIUrl":"10.1186/s40478-026-02369-w","url":null,"abstract":"<p><strong>Background: </strong>The non-canonical isocitrate dehydrogenase 1 (IDH1) R132C mutation is rare in diffuse gliomas but appears to be enriched in tumors associated with Li-Fraumeni syndrome (LFS), which is caused by germline tumor protein p53 (TP53) mutations. However, the molecular relationship between TP53 alterations and IDH1 R132C, as well as the prevalence of LFS among patients with R132C-mutant gliomas, remains unclear.</p><p><strong>Methods: </strong>We analyzed 93 consecutive patients retrospectively with IDH1-mutant diffuse gliomas (Central Nervous System World Health Organization (CNS WHO) Grades 2 and 3) treated at our institution between 2005 and 2025. IDH, TP53, and ATRX status were assessed by immunohistochemistry, Sanger sequencing, multiplex ligation-dependent probe amplification, and targeted next-generation sequencing. Germline TP53 mutations were assessed using peripheral blood samples. DNA methylation profiling was performed using the Methylscape platform and the DKFZ methylation classifier.</p><p><strong>Results: </strong>Three of 90 IDH1-mutant gliomas (3%) harbored the R132C variant. All three tumors were astrocytomas with concurrent TP53 mutation, ATRX alteration, and 1p/19q non-codeletion. Exploratory cancer cell fraction analysis suggested that both IDH1 R132C and TP53 mutations were present in the major tumor cell population, supporting a biological association between TP53 alterations and the occurrence of the IDH1 R132C variant. One patient harbored a pathogenic germline TP53 mutation despite lacking a family history or fulfilling the established clinical diagnostic criteria for LFS. DNA methylation analysis demonstrated partial overlap with conventional IDH-mutant astrocytoma and also revealed atypical clustering patterns.</p><p><strong>Conclusions: </strong>IDH1 R132C-mutant gliomas are characterized by concurrent TP53 mutation, ATRX alteration, and 1p/19q non-codeletion. Although based on a small cohort, our findings support a biological association between TP53 alterations and the rare IDH1 R132C variant and suggest that germline TP53 testing may be considered in selected patients, particularly younger individuals, to identify previously unrecognized Li-Fraumeni syndrome.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381398","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":"Phenotype-specific muscle proteomic profiling in titinopathies.","authors":"Aurélien Perrin, Marie-Rocio Casenave-Camgaston, Baptiste Rabillard, Fabrice Raynaud, Serge Urbach, Martial Seveno, Ana Maria Navarro, Anas Tendero-Baziou, Stephan Matecki, Claude Cancès, Julien Durigneux, Valérie Biancalana, Florence Petit, Céline Tard, Arnaud Molin, Manon Godin, Xénia Latypova, John Rendu, Médéric Jeanne, Raul Juntas Morales, Emmanuelle Salort-Campana, Annie Verschueren, Martin Krahn, Svetlana Gorokhova, Shahram Attarian, Guilhem Solé, Florence Esselin, Marie-Laure Martin-Négrier, Corinne Métay, Christian Jorgensen, Anne Bergougnoux, Michel Koenig, Mireille Cossée","doi":"10.1186/s40478-026-02363-2","DOIUrl":"10.1186/s40478-026-02363-2","url":null,"abstract":"<p><p>Titinopathies are complex neuromuscular disorders with multiple phenotypes. The gene's size, comprising 364 exons, as well as the protein's size of 3.8 MDa and its extensive network of protein interactors, are key factors underlying this complexity. Various phenotypes characterize titinopathies, and this study focuses on two of them: arthrogryposis and myofibrillar myopathies. The protein deregulations associated with these two phenotypes remain unknown or have been minimally explored; however, understanding these consequences is essential for better characterizing the pathophysiological aspects of these titinopathies.The objective was to analyze protein deregulations in two cohorts of French patients with titinopathies exhibiting the arthrogryposis and myofibrillar myopathy phenotypes, and to compare them with control individuals. Protein extracts were obtained from muscle biopsies of patients, and changes in protein levels within these two groups were analyzed by mass spectrometry. The results indicate specific deregulations in each group. The networks analyzed revealed deregulation of proteins involved in fibrosis mechanisms or in the actomyosin complex for the arthrogryposis phenotype. Regulation of the muscle contraction system through deregulation of proteins involved in the cytoskeleton is impacted in patients with myofibrillar myopathy. The proteins that are quantitatively abnormal in these two groups also provide insights into the major signaling networks disrupted in titinopathies. These findings will contribute to a more precise characterization of titinopathies, enabling the identification of phenotype-specific biomarkers and potentially guiding the search for targeted therapies for these neuromuscular disorders.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374149","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":"MET-associated immune prognostic signature predicts survival and guides personalized therapy in glioma.","authors":"Ying Zhang, Chengjun Zheng, Qiaodong Chen, Wenlu Tan, Fei Liu, Zheng Fang, Hanxiao Zhou, Changyuan Ren, Jinhao Zhang, Changlin Yang, Menghui Xu, Lingxiang Wu, Ji Shi, Zheng Zhao, Zhaoshi Bao","doi":"10.1186/s40478-026-02360-5","DOIUrl":"10.1186/s40478-026-02360-5","url":null,"abstract":"<p><p>Glioma is an aggressive malignancy characterized by an immunosuppressive tumor microenvironment (TME) that drives therapeutic resistance. MET alterations promote tumor progression and immune evasion, yet their clinical implications in glioma immunotherapy remain unclear. Here, we integrated multi-omics data from four independent cohorts to establish a MET-associated immune prognostic signature (MIPS) comprising 18 immune-related genes. MIPS effectively stratified glioma patients into low- and high-MIPS subgroups. High-MIPS patients exhibited significantly poorer overall survival than low-MIPS patients across all cohorts and was an independent prognostic factor independent of clinicopathological and molecular features. High-MIPS scores correlated with increased M2 macrophage infiltration, elevated B7-H3 expression, and higher TIDE scores, indicating immunotherapy resistance. Bioinformatic prediction and patient-derived organoid assays verified that low-MIPS tumors were sensitive to multiple targeted drugs (e.g., Axitinib, AZD-8055, Gefitinib, and Lenalidomide), while high-MIPS tumors were relatively resistant. MIPS derived from MET alteration serves as a robust biomarker for prognosis and predictive tool for immunotherapy and chemotherapy, facilitating patient stratification and precision therapy.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13591705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366468","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":"Nanopore-based DNA methylation profiling for rapid molecular classification of NOS/NEC CNS tumors: multi-institutional evaluation using FFPE archives and frozen tissues.","authors":"Wanming Hu, Jin Zhu, Hang Li, Qiubo Yu, Song Chen, Qinglan Ren, Jingxian Wu, Youde Cao, Yanghao Hou","doi":"10.1186/s40478-026-02359-y","DOIUrl":"https://doi.org/10.1186/s40478-026-02359-y","url":null,"abstract":"<p><strong>Background: </strong>DNA methylation profiling has become crucial for accurate classification of CNS tumors, yet Illumina EPIC arrays are restricted by long turnaround times, batching requirements, and limited accessibility in non-specialized centers. Rapid, affordable alternatives are urgently needed, particularly in resource-constrained settings. We aimed to evaluate nanopore sequencing as a real-world diagnostic tool for resolving diagnostically challenging CNS tumors.</p><p><strong>Methods: </strong>We applied the ROBIN pipeline to 34 consecutive CNS tumors that remained NOS/NEC after routine histopathological and molecular workup. Samples comprised 16 routine FFPE blocks and 18 frozen tissues (9 fresh-frozen, 9 pre-extracted DNA) from three pathology centers. Nanopore sequencing was performed on PromethION R10.4.1 flow cells, targeting definitive methylation-based classification report within 24 h.</p><p><strong>Results: </strong>A confident methylation class was assigned in 28/34 cases (82.4%), including 14/16 (87.5%) methylation calls of FFPE samples with median target coverage of 0.03×. Integration of simultaneously generated CNV profiles rescued an integrated glioblastoma diagnosis in two methylation-unclassifiable cases via 7+/10- signatures. The nanopore-based classifications also achieved 84.6% (11/13) concordance with paired result from Illumina Methylation EPIC arrays. In high-coverage samples, diagnostic-relevant SNVs (BRAF V600E, PTEN, NF1/TP53) were recovered from the same run. SNV detection was strongly coverage-dependent, however: it was not achievable in the low-coverage FFPE and fresh-frozen specimens.</p><p><strong>Conclusions: </strong>Nanopore sequencing enables rapid, accurate, multidimensional molecular classification of diagnostically intractable CNS tumors using routine FFPE and frozen tissue, achieving high diagnostic resolution in comparison with reference methods while drastically reducing turnaround time and cost, making precision neuropathology feasible beyond quaternary centers.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Induction of CNS α-synuclein pathology by fibrillar and non-amyloidogenic recombinant α-synuclein.","authors":"Amanda N Sacino, Mieu Brooks, Nicholas H McGarvey, Alex B McKinney, Michael A Thomas, Yona Levites, Yong Ran, Todd E Golde, Benoit I Giasson","doi":"10.1186/s40478-026-02325-8","DOIUrl":"10.1186/s40478-026-02325-8","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13312694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350287","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":"Dynamic integration of skeletal muscle signals via extracellular vesicles in motor neuron diseases.","authors":"Flaminia Riggio, Gianmarco Fenili, Daniela Caporossi, Maria Paola Paronetto","doi":"10.1186/s40478-026-02356-1","DOIUrl":"10.1186/s40478-026-02356-1","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are heterogenous lipid bilayer-enclosed particles secreted by virtually all cell types. They encapsulate a diverse array of bioactive molecules, including proteins, lipids, nucleic acids, and metabolites, which can be transferred to recipient cells, thereby modulating their function and phenotype. In recent years, skeletal muscle-derived EVs (SkM-EVs) have emerged as key players in the bidirectional communication between skeletal muscle and motor neurons, contributing to the establishment and maintenance of neuromuscular homeostasis. Disruptions in this intercellular signalling have been implicated in the pathophysiology of motor neuron diseases (MNDs) such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). In these contexts, SkM-EVs may contribute to disease progression by delivering pathogenic cargo, including misfolded proteins and aberrant RNAs, to motor neurons. A comprehensive understanding of SkM-EV biology, particularly their roles in neuromuscular communication, could offer critical insights into disease mechanisms and identify novel opportunities for biomarker discovery and therapeutic intervention. This review synthesizes current knowledge on the functional roles of SkM-EVs in motor neuron health and disease and evaluates their potential as diagnostic tools and therapeutic vectors in the context of MNDs.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148325310","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":"VGLL-fused intraparenchymal schwannoma with EWSR1::VGLL1 fusion: integrated clinicopathological and molecular characterization.","authors":"Ryosuke Ikemachi, Yohei Inoue, Yoshihiro Otani, Kyohei Kin, Ryo Mizuta, Yasuhiko Hattori, Kohei Izumihara, Shuichiro Hirano, Joji Ishida, Fumiyo Higaki, Kyosuke Horikawa, Kotaro Yoshio, Takahiro Tsuchiya, Satoru Miyawaki, Koichi Ichimura, Sumihito Nobusawa, Shota Tanaka","doi":"10.1186/s40478-026-02355-2","DOIUrl":"10.1186/s40478-026-02355-2","url":null,"abstract":"<p><p>Intraparenchymal schwannomas are rare intracranial tumors confined to the brain parenchyma without connection to peripheral nerves. While conventional schwannomas are often associated with NF2 inactivation, the pathogenesis of intraparenchymal schwannomas remains poorly understood. Recent molecular studies have identified a distinct subgroup characterized by VGLL family fusions, suggesting a unique pathogenetic mechanism. Here, we report a 24-year-old woman presenting with dizziness and facial palsy who underwent resection of a brainstem tumor that showed histopathological features consistent with schwannoma. DNA methylation profiling classified the tumor as a VGLL-fused schwannoma, and RNA sequencing identified an EWSR1::VGLL1 fusion with markedly higher VGLL1 mRNA expression compared to a reference cohort of 17 vestibular schwannomas. Copy number analysis revealed loss of chromosome 19 without loss of chromosome 22q. These findings support a potential role for VGLL1 fusion in the pathogenesis of this rare tumor subtype. Importantly, this case further substantiates the emerging molecular subset of VGLL-fused intraparenchymal schwannomas and underscores the value of integrated molecular and histopathological analyses in the classification of central nervous system tumors.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13647600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148325274","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":"A rare missense variant impacting NEK1 kinase function is associated with ALS.","authors":"David Brenner, Anna Ponomarenko, Iris Petrut, Sofia Beyrle, Matilde Contardo, Isabel Loss, Constantin Radke, Jonas Frank, Eleni Zimmer, Matthias Schlesner, Pascal Achenbach, Wendy Scheveneels, Amr Aly, Hülya Nazlican, Jasper Hesebeck-Brinkmann, Patrick Oeckl, Kathrin Müller, Reiner Siebert, Tobias Böckers, Kristel van Eijk, Jan Veldink, Alexander Kleger, Medhanie Mulaw, Peter M Andersen, Karin Forsberg, Jochen H Weishaupt, Seyed Babak Loghmani, Thorsten Grehl, Philip van Damme, Joachim Weis, Alberto Catanese","doi":"10.1186/s40478-026-02351-6","DOIUrl":"10.1186/s40478-026-02351-6","url":null,"abstract":"<p><p>Heterozygous truncating loss-of-function (LoF) variants in NEK1 are a known cause of amyotrophic lateral sclerosis (ALS). NEK1 encodes the pleiotropic serine/threonine kinase NIMA-related kinase 1, and prior in vitro studies have implicated kinase dysfunction as the principal pathogenic mechanism underlying NEK1-associated ALS. However, bona fide pathogenic missense variants causally linked to ALS have not previously been reported, leaving this hypothesis unconfirmed. Here, we identify a rare NEK1 missense variant, p.N598S, that co-segregates with disease in a familial ALS pedigree and is enriched in European ALS cohorts. This variant exhibits normal protein expression levels, indicating a functional rather than quantitative defect. Using isogenic human motor neurons, we directly compared the effects of p.N598S with those of the ALS-associated truncating variant p.R812* to delineate disease mechanisms. The p.N598S variant induced pathological phenotypes consistent with NEK1 haploinsufficiency, including increased susceptibility to DNA damage, increased apoptosis, ciliary dysmorphia, and nucleocytoplasmic translocation of TDP-43. Importantly, p.N598S impaired NEK1 kinase activity, and pharmacological inhibition of NEK1 recapitulated the cellular phenotypes observed in both p.N598S- and p.R812*-mutant motor neurons. Collectively, these findings provide strong genetic and functional evidence for a disease-causing role of NEK1 kinase disruption in NEK1-ALS. Our findings provide immediate diagnostic and therapeutic implications, particularly for the functional interpretation of missense variants of uncertain significance and the development of targeted treatment strategies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13307424/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148325337","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":"Ceramide-rich extracellular vesicles as pathogenic biomarkers in traumatic brain injury.","authors":"Zainuddin Quadri, Zhihui Zhu, Xiaojia Ren, Simone Crivelli, Liping Zhang, P D Kunjadia, Patrick G Sullivan, Bibi B Broome, Tritia R Yamasaki, Erhard Bieberich","doi":"10.1186/s40478-026-02357-0","DOIUrl":"10.1186/s40478-026-02357-0","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) contribute to the damage caused by traumatic brain injury (TBI) and can cross the blood-brain barrier (BBB). We analyzed plasma-derived EVs from human TBI patients to identify factors potentially contributing to TBI pathology. EVs were isolated using membrane affinity (ExoEasy) and size exclusion chromatography, both yielding CD9(+) and CD63(+) EVs with minimal contamination by serum albumin and apolipoprotein. Immunoblotting detected GFAP in TBI but not control EVs, indicating astrocyte-derived EVs crossing the BBB. Proteomic analysis and immunoblotting of EVs from TBI samples identified C-reactive protein and 14-3-3 proteins, which were not detected in control EVs, indicating inflammation associated with TBI. Lipidomic analysis showed ceramide enrichment in TBI EVs, validated by anti-ceramide immunoprecipitation. In a mouse closed head-controlled cortical impact model, brain EVs similarly showed elevated ceramide, confirming ceramide-rich EV release after TBI. Immunocytochemistry localized acid sphingomyelinase (ASM), a ceramide-generating enzyme, to ependymal cilia, suggesting these sites as a potential source of EVs. This was further supported by the detection of ASM in both brain- and plasma-derived EVs, along with the ciliary marker Arl13b in the brain. To assess function, we treated murine neuronal (N2a) cells with TBI EVs. Transcriptomics and STRING analyses revealed enrichment of mitochondrial-associated transcripts. Immunoblotting showed increased p53 and voltage-dependent anion channel 1 (VDAC1), both of which have been implicated in ceramide-induced apoptosis. Seahorse assays showed that TBI EVs suppressed glycolysis, as indicated by reduced ECAR, while mitochondrial respiration (OCR) remained unchanged. LDH assays further indicated that TBI EVs were more neurotoxic than control EVs. Together, these findings identify ceramide-rich EVs as plasma biomarkers of TBI-induced inflammation, potential mediators of neuronal mitochondrial dysfunction, and pharmacological targets to prevent TBI-induced damage.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148325304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-input CSF cfDNA shallow whole-genome sequencing for CNV-based diagnosis and monitoring of leptomeningeal metastasis in lung cancer.","authors":"Xiudong Guan, Yubing Li, Zongkun Shi, Juan An, Yichun Hua, Xiaosheng Ding, Xixi Zheng, Weiran Xu, Dainan Zhang, Zhan Xue, Peng Kang, Dandan Cao, Xiaoyan Li, Wang Jia","doi":"10.1186/s40478-026-02350-7","DOIUrl":"10.1186/s40478-026-02350-7","url":null,"abstract":"<p><p>Leptomeningeal metastasis (LM) is a life-threatening complication of lung cancer for which magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) cytology may miss disease and provide limited molecular guidance. Because the low cfDNA input typical of CSF constrains deep sequencing and mutation-focused approaches may underrepresent the copy-number-rich genomic architecture of CNS metastases, we developed a low-input shallow whole-genome sequencing approach to quantify genome-wide copy-number changes from trace CSF cfDNA. In 57 patients with lung cancer and CNS metastases (28 with LM and 29 with brain metastasis only), CSF showed stronger tumor-DNA signals and a higher burden of genome amplification than matched plasma (54 pairs), despite lower cfDNA concentrations. Among samples with detectable tumor DNA, genome amplification proportion (GAP), defined as the fraction of the genome showing amplification, identified LM with 86% sensitivity and no false positives observed in this cohort, and showed performance comparable to cytology as a complementary quantitative readout. Copy-number profiling further highlighted chromosomal regions and focal gene amplifications enriched within LM, supporting a CNV-enriched molecular state in the CSF compartment. Serial CSF sampling also captured treatment-associated molecular shifts, including progressive TYMS amplification during intrathecal pemetrexed in an exploratory case. Together, these findings support low-input CSF sequencing as a practical molecular approach to complement LM diagnosis and longitudinal monitoring in lung cancer and provide a rationale for prospective validation in independent multi-center cohorts.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13411578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315348","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}