Hakobyan Meline, Binder Hans, Arakelyan Arsen
Bioinformatics Group, Institute of Molecular Biology National Academy of Sciences of the Republic of Armenia (NAS RA), Yerevan 0014, Armenia.
Interdisciplinary Centre for Bioinformatics, University of Leipzig, 04103 Leipzig, Germany.
Int J Mol Sci. 2025 Apr 28;26(9):4175. doi: 10.3390/ijms26094175.
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.
端粒维持机制（TMMs）在癌症生物学中起着关键作用，尤其是在低级别胶质瘤（LGGs）中，而在低级别胶质瘤中端粒动态变化和通路活性仍知之甚少。在本研究中，我们分析了TCGA-LGG和CGGA数据集，重点关注不同异柠檬酸脱氢酶（IDH）亚型的端粒长度变化、通路活性和生存数据。使用GEO慢性阻塞性肺疾病（COPD）和胶质母细胞瘤（GBM）数据集进行了额外验证，确保了数据处理的一致性和批次效应校正。我们的分析揭示了短端粒长度（Short-TL）组和长端粒长度（Long-TL）组之间端粒酶逆转录酶（TERT）通路激活存在显著差异，强调了TERT在端粒维持中的核心作用。相比之下，端粒延长替代机制（ALT）通路激活呈现出亚型特异性模式，异柠檬酸脱氢酶野生型（IDH-wt）肿瘤的ALT活性最高，主要由RAD51分支驱动。使用CGGA数据进行的验证证实了这些发现，表明各数据集之间TERT和ALT通路行为一致。此外，基因亚型分析揭示了与ATRX和IDH突变状态相关的显著端粒长度变异性。值得注意的是，IDH野生型-ATRX野生型（IDHwt-ATRX WT）肿瘤的端粒长度最短，ALT通路活性最高。这些发现突出了低级别胶质瘤不同基因亚型之间独特的端粒调控动态，并为靶向端粒维持通路的潜在治疗策略提供了新见解。
