Telomere Maintenance Pathways in Lower-Grade Gliomas: Insights from Genetic Subtypes and Telomere Length Dynamics
written by Meline Hakobyan, Hans Binder and Arsen Arakelyan
ABSTRACT
Telomere maintenance mechanisms (TMMs) play a critical role in cancer biology, particularly in lower-grade gliomas (LGGs), where telomere dynamics and pathway activity remain poorly understood. In this study, we analyzed TCGA-LGG and CGGA datasets, focusing on telomere length variations, pathway activity, and survival data across IDH subtypes. Additional validation was performed using the GEO COPD and GBM datasets, ensuring consistency in data processing and batch effect correction. Our analysis revealed significant differences in TEL pathway activation between Short- and Long-TL groups, emphasizing the central role of TERT in telomere maintenance. In contrast, ALT pathway activation displayed subtype-specific patterns, with IDH-wt tumors exhibiting the highest ALT activity, primarily driven by the RAD51 branch. Validation using CGGA data confirmed these findings, demonstrating consistent TEL and ALT pathway behaviors across datasets. Additionally, genetic subtype analysis revealed substantial telomere length variability associated with ATRX and IDH mutation status. Notably, IDHwt-ATRX WT tumors exhibited the shortest telomere length and the highest ALT pathway activity. These findings highlight distinct telomere regulatory dynamics across genetic subtypes of LGG and provide new insights into potential therapeutic strategies targeting telomere maintenance pathways.
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CONCLUSIONS
Our study provides comprehensive insights into telomere length dynamics and TMM in LGG, highlighting their association with IDH mutation status and survival outcomes. We observed that a shorter telomere length is associated with increased activation of the TEL pathway, particularly through TERT, while the ALT pathway exhibited significant variation in specific nodes but remained stable overall across telomere length categories. Notably, IDH-wt tumors displayed the highest ALT pathway activation, primarily driven by RAD51. Telomere length variability was significantly influenced by ATRX and IDH status, with the IDHwt-ATRX WT and IDHwt-ATRX Mutant groups exhibiting the lowest TL ratios and the highest ALT activities. Survival analysis revealed that LGG patients with high ALT and high TEL pathway activities had the worst prognosis, while those with moderate TMM activity exhibited the most favorable outcomes.
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