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Secondary glioblastoma (sGBM), which arises through malignant progression from lower-grade diffuse glioma, represents a clinically and biologically distinct subset of GBM. In this disease context, the protein tyrosine phosphatase receptor type Z1\u2013mesenchymal-epithelial transition factor (PTPRZ1-MET; ZM) fusion has emerged as a recurrent oncogenic driver associated with adverse clinical outcomes. In this study, we analyzed 159 patients with sGBM, including 15 ZM-positive and 144 ZM-negative cases, and confirmed that ZM-positive tumors were associated with significantly shorter overall and progression-free survival. Transcriptomic profiling identified 359 genes upregulated in ZM-positive tumors, with enrichment in cell-cycle regulation and mitotic spindle-related pathways. To explore surrogate biomarkers associated with ZM fusion status, we benchmarked eight machine-learning classifiers and retained XGBoost as the primary feature-prioritization model. MET, PCDHGA3, and FAM3C emerged as the most informative biomarkers, and the fixed three-gene panel showed stable discriminative performance across cross-validation, nested evaluation, feature-pool sensitivity analyses, repeated random seeds, and class-weighted modeling. Protein-level validation in an independent formalin-fixed, paraffin-embedded (FFPE) cohort using multiplex and conventional chromogenic immunohistochemistry supported the pathology-compatible detection of elevated MET, PCDHGA3, and FAM3C expression in ZM-positive tumors. Collectively, these findings support a robust three-gene molecular signature that may facilitate the identification and stratification of ZM fusion-positive sGBM and provide biological insights with potential translational relevance for precision glioma diagnosis.<\/jats:p>","DOI":"10.1186\/s43556-026-00529-x","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T23:01:15Z","timestamp":1785798075000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Artificial intelligence-based diagnostic model for identifying PTPRZ1-MET fusion in a clinically defined secondary glioblastoma cohort"],"prefix":"10.1186","volume":"7","author":[{"given":"Jin-Hao","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han-Xiao","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Lu","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8945-9632","authenticated-orcid":false,"given":"Zheng","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"issue":"7","key":"529_CR1","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1001\/jama.2023.0023","volume":"329","author":"LR Schaff","year":"2023","unstructured":"Schaff LR, Mellinghoff IK. 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Approval was granted by the Institutional Review Board of Beijing Tiantan Hospital (KYSQ 2025\u2013625-01). Informed consent was obtained from all individual participants included in the study.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no competing financial interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"124"}}