Mutational signature stratification of recurrent gliomas reveals distinct patterns of genomic traits
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ID: 321733
2026
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Abstract
Abstract Background Although temozolomide (TMZ) is widely used for glioma treatment, its therapeutic benefit is limited by acquired resistance and recurrence, facilitated by intratumor heterogeneity. Mutational signatures (MSs) inform tumor evolution and reveal alterations associated with treatment response. Methods We performed molecular analyses of 96 glioma recurrences with sufficient private single-nucleotide variants relative to their matched primary tumors, stratified by their dominant MS. Results Four groups were identified: MS11/TMZ-related (n = 38), MS1/5/aging-related (n = 32), MS6/15/21/26/microsatellite instability (MSI)-related (n = 13), and other MS-related recurrences (n = 13). MS11/TMZ-related recurrences showed higher acquired mutational counts than the other groups (1338 vs 59 (MS1/5/aging) vs 57 (MS6/15/21/26/MSI) vs 57 (other MSs); p < 0.01). Mutations in SYNE2, SZT2, and FBN3 were restricted to recurrences with dominant or second-dominant MS11/TMZ-related signature (n = 41), and 85% (35/41) harbored mutations in these genes. In MS11/TMZ-related recurrences with RNA sequencing data (n = 17), mRNA co-expression analyses identified SYNE2–ATAD5 and SZT2–MAPKBP1 associations. Among MS11/TMZ-related recurrences, MS23 was frequent (44%, 18/41) and associated with higher acquired mutational counts (2089 vs 1188; p = 0.018) and more IDH-wildtype tumors (67% vs 30%; p = 0.037). MAPKBP1 mutations were enriched in MS23-positive recurrences (56% (10/18) vs 0% (0/23); p < 0.001). MS1/5/aging-related recurrences showed more frequent acquired chromosome 16q losses (22% vs 8% (TMZ) vs 0% (MSI) vs 0% (other); p < 0.05), which were associated with increased fraction of genome altered relative to 16q-diploid cases (15% vs 7%; p = 0.01). Conclusions These findings show that MS-based stratification of recurrences refines molecular characterization after therapy and nominates candidate biomarkers and pathways for functional studies of treatment-associated glioma evolution.
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| Authors | Joana Peixoto, Prof. Dr. Miguel Castanho, Bárbara Soares-Ferreira, Bruno Esteves, Patrícia Ferreira-Torre, Nuno Higino, G B Silva, Lorenzo Ferrando, Yingjie Zhu, Luı́s Cardoso, Bruno Carvalho, Paula Soares, Arnaud Da Cruz Paula, J A de Lima |
| Journal | Neuro-Oncology Advances |
| Year | 2026 |
| DOI |
10.1093/noajnl/vdag188
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| URL | |
| Keywords | Keywords not found |
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