Chromosome-arm-specific telomere length governs dual modes of structural genome evolution in IDH-mutant astrocytoma
Jehangir, M.; Drucker, K. L.; Keskus, A.; Ranallo-Benavidez, T. R.; Benamozig, O.; Kollmeyer, T.; Burns, T. C.; Giannini, C.; Kipp, B. R.; Murphy, S. J.; Bridgeman, A. R.; Walsh, J. R.; Majumdar, R.; Lachance, D.; Eckel-Passow, J.; Shoshani, O.; Kolmogorov, M.; Jenkins, R. B.; Barthel, F.
Show abstract
IDH-mutant astrocytomas maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, producing extreme inter-arm telomere length heterogeneity, yet how this heterogeneity shapes structural genome evolution remains unknown. Using Oxford Nanopore long-read sequencing of 20 IDH-mutant astrocytomas, we profiled structural variants (SVs), copy number variants, extrachromosomal DNA (ecDNA) and measured allele-specific telomere lengths from individual long reads. We identified pervasive complex rearrangements, including chromothripsis and foldback events consistent with breakage-fusion-bridge cycles, and widespread ecDNAs. SV breakpoints were enriched at telomeric and centromeric regions regardless of local telomere length, revealing constitutive structural fragility. Arm-level telomere length analysis uncovered a dual-mode model: arms with short telomeres preferentially harbored breakage-associated events, while arms with long ALT-maintained telomeres were enriched for ecDNA and amplification-associated events. These findings identify chromosome-arm-specific telomere length as a determinant of structural genome evolution in ALT-driven tumors.
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