Abstract Glioblastoma (GBM) is the most aggressive primary tumor of the central nervous system, with a median survival of approximately 14 months despite standard-of-care treatment consisting of maximal surgical resection followed by radiotherapy and temozolomide (TMZ) chemotherapy. Although TMZ remains the most commonly used chemotherapeutic agent for GBM, patient responses vary widely. In clinical practice, its benefit is often more limited in older patients (≥65 years) and in those with poorer performance status, who also tend to experience greater treatment-related toxicity. These observations suggest that age-related differences in tumor biology and cellular stress responses may influence therapeutic outcomes and highlight the need for molecular markers that better predict TMZ sensitivity. To explore age-associated transcriptional differences following TMZ treatment, the public bulk RNA-sequencing dataset GSE263890 was reanalyzed, a transcriptomic dataset of GBM tumors from younger and senior patients after TMZ. Raw gene expression data were processed, normalized, and log-transformed, with low-expression and unannotated transcripts removal to improve data quality. Differentially expressed genes (DEGs) were identified using thresholds of |log2 fold change| 0. 2 and FDR 0. 05. Heatmaps and volcano plots were used to visualize expression patterns, and Gene Ontology (GO) enrichment analysis was performed to identify biological pathways. DEGs analysis between younger and older patients revealed 402 up-regulated genes and 522 down-regulated genes in tumors from senior patients. Prominent up-regulated genes included ZYG11A, HMX1, AP1M2, KERA, GARIL6, USP6, SFTPA1, PAX9, TSPAN19, and TPH2, whereas down-regulated genes included MEST, FLNC, H3C12, NDUFB2, CAV1, GAS2L1, ID4, ATP6V1F, POLR2J, DENND2A, EDNRB, TREM2, RARRES2, and CDC42EP1. Gene Ontology enrichment analysis showed that up-regulated genes were significantly associated with pathways related to cilium organization, microtubule bundle formation, axoneme assembly, ciliary movement, and calcium ion transport, pointing to changes in cytoskeletal structure and intracellular signaling in older patients following TMZ exposure. In contrast, down-regulated genes were enriched in pathways involved in cytoplasmic ribosome biogenesis, peptide chain elongation, eukaryotic translation initiation and termination, nonsense-mediated mRNA decay, and EIF2AK4 (GCN2) -mediated amino acid stress responses, suggesting an overall reduction in protein synthesis and translational activity. In conclusion, these results reveal age-associated transcriptional differences in GBM tumors following TMZ treatment. The observed alteration markers in cellular structure, signaling pathways, and translational regulation may help explain differences in therapeutic response and tolerance between younger and older patients. This study provides molecular insight into age-related variability in TMZ efficacy and supports the development of age-informed biomarkers to improve outcomes for patients with GBM. Citation Format: Catherine Chen, Wlliam Xu, Qian Wang. Age-Associated Transcriptomic Alterations in Glioblastoma Following Temozolomide Treatment abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (6Suppl): Abstract nr A049.
Chen et al. (Mon,) studied this question.