Abstract PR009: Telomere length heterogeneity shapes structural and amplification landscapes in IDH-mutant astrocytoma

Abstract Background: Alternative lengthening of telomeres (ALT) is common in isocitrate dehydrogenase (IDH) mutant astrocytomas, but how telomere length variability contributes to genome instability remains unclear. We hypothesized that chromosome arm–specific telomere heterogeneity underlies distinct patterns of somatic structural variation (SV), copy-number alteration (CNA), and extrachromosomal DNA (ecDNA) formation. Methods: Oxford Nanopore long-read whole-genome sequencing (∼20–40x coverage) was performed in a clinical cohort of n = 20 IDH-mutant astrocytomas. Somatic SVs were called with Severus and filtered to a high-confidence tumor-specific set. CNAs were inferred by read-depth segmentation (DNAcopy) and further refined using a long-read CNA framework (Wakhan). Chromosome arm–specific telomere length was estimated with Telogator, and SV breakpoints were annotated for enrichment near subtelomeric and pericentromeric regions. Associations between arm-level telomere length and SV/CNA features (rate and proportion) were tested using linear mixed-effects models with patient as a random effect. High-level amplification regions were defined directly from CNA segments with high copy number, and ecDNA-like circular amplicons were subsequently reconstructed from amplified intervals using Decoil. Results: IDH-mutant astrocytomas displayed pronounced SV heterogeneity, with complex breakends (BNDs) dominating the somatic SV landscape. SVs were spatially patterned, as deletions and insertions preferentially accumulated near subtelomeric and pericentromeric domains, implicating chromosome ends and repeat-rich regions as recurrent substrates for rearrangement. At the tumor level, markedly shortened telomeres were associated with increased SV burden and CNA burden, consistent with telomere attrition as a correlate of genome-wide structural instability in highly rearranged genomes. At higher resolution, telomere length varied substantially across chromosome arms and classified distinct structural outcomes: arms with shorter telomeres were enriched for complex insertional SVs, whereas arms with relatively elongated telomeres more frequently carried focal high-level amplifications and ecDNA-like circular amplicons. Conclusions: These findings reveal a link between arm-specific telomere heterogeneity and the emergence of structural and amplification architectures in IDH-mutant astrocytomas. Telomere remodeling may influence where rearrangements and ecDNA structures arise, offering potential biomarkers of genome instability and tumor evolution. Generative AI was used to improve language clarity; all content was verified by the authors. Citation Format: Maryam Jehangir, Kristen Drucker, T. Rhyker Ranallo-Benavidez, Thomas M. Kollmeyer, Ayse Keskus, Daniel Lachance, Jeanette E. Eckel-Passow, Ofer Shoshani, Mikhail Kolmogorov, Robert B. Jenkins, Floris P. Barthel. Telomere length heterogeneity shapes structural and amplification landscapes in IDH-mutant astrocytoma [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(6_Suppl):Abstract nr PR009.