Citations 1
Chromosome-arm-specific telomere length governs dual modes of structural genome evolution in IDH-mutant astrocytoma
Jehangir, Maryam , Drucker, Kristen , Keskus, Ayse G. , Ranallo-Benavidez, T R, Benamozig, Orléna , Kollmeyer, Thomas , Giannini, Caterina , Kipp, Benjamin R. , Murphy, Stephen James, Bridgeman, Amber R. , Walsh, Jesse R. , Majumdar, Ramanath, Lachance, Daniel H , Eckel‐Passow, Jeanette E. , Jenkins, RB , Kollmeyer, Thomas M. , Ranallo-Benavidez, T. Rhyker , Drucker, Kristen L , Keskus, Ayse , Ranallo-Benavidez, T Rhyker , Giannini, Caterina , Kipp, Benjamin , Bridgeman, Amber R , Walsh, Jesse R , Lachance, Daniel , Eckel-Passow, Jeanette E , Shoshani, Ofer , Kolmogorov, Mikhail , Barthel, Floris P , Jehangir, Maryam , Burns, Terry C. , Jenkins, Robert B.
No container title available | April 23, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
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.