MET fusions and splicing variants in glioma: a landscape integrating clinical, pathological, and survival features

MET alterations, including MET fusions and splicing variants (F/SVs), are linked to glioma progression, but the clinical features remain underexplored since the 2021 WHO classification of tumors of the CNS. We aimed to systematically depict the MET F/SVs and patient characteristics in a multicenter cohort focusing on clinical, pathological, and survival features. We studied data from 1,041 patients with MET F/SVs data from the public Chinese Glioma Genome Atlas database and the TruSight Tumor 170 study. Clinical outcomes were evaluated based on the RANO criteria. We used chi-square and Fisher's exact tests for variable analysis. Kaplan-Meier analysis was used to assess survival trends, while univariate and multivariate analyses revealed the prognostic value of MET F/SVs. Immunohistochemical staining was performed to demonstrate the MET expression level. Among the 1,041 patients, 49 patients had F/SVs (4.70%), and 23 had ZM fusion (PTPRZ1-MET fusion gene; 2.21%). Among the 67 recurrent grade 4 astrocytomas, the proportions of F/SVs (11.94%, n = 8) and ZMs (5.97%, n = 4) were the highest. MET F/SVs were significantly associated with malignant clinical outcomes in the IDH-mutant astrocytoma cohort, with a frequency of 5.04% (18/357) across all WHO grades. Multivariate analysis revealed that the MET F/SVs were independently associated with worse survival in astrocytoma patients [overall survival (OS): p = 0.0011; progression-free survival (PFS): p = 0.004]. ZM fusion was associated with a worse prognosis in both astrocytoma (OS p < 0.001, PFS p < 0.001) and glioblastoma (OS, p = 0.252; PFS, p = 0.010) patients. We highlight the utmost relevance of ZM fusion as an adverse prognostic factor in astrocytoma (11/382, 2.88%) and glioblastoma grade 4 (11/401, 2.74%) patients and suggest that the grading of these tumors should be refined.